AU2018227575A1

AU2018227575A1 - Processes for the preparation of fungicidal compounds

Info

Publication number: AU2018227575A1
Application number: AU2018227575A
Authority: AU
Inventors: Shomir Ghosh; Geraldine C. Harriman; Jon P. Lawson; Matthew W. LEIGHTY; Silvana Marcel LEIT DE MORADEI; William H. Miller; Toni-Jo Poel; Heinrich J. Schostarez; Lloyd J. Simons; Urszula J. Slomczynska; Daniel P. Walker
Original assignee: Monsanto Technology LLC; Gilead Apollo LLC
Current assignee: Monsanto Technology LLC; Gilead Apollo LLC
Priority date: 2017-03-03
Filing date: 2018-03-02
Publication date: 2019-09-19
Also published as: EA201991880A1; AR111224A1; JP2020509038A; BR112019017915A2; CN110382504A; EP3589635A1; CA3054810A1; CO2019009579A2; WO2018161008A1; KR20190125359A

Abstract

Provided herein are processes for the preparation of stereomerically enriched compounds of Formulas I-014, I-020, I-064, I-074, I-082, I-089, I-090, I-095, I-171, I-181, I-184, I-186, I-189, I-191, I-192, I-193, I-205, I-206, I-208, I-211, I-212, I-213, I-220, I-229, I-231, I-233, I-234, I-246, I-251, I-258, I-259, I-262, I-263, I-285, I-323 and I-400. The compounds described herein exhibit activity as pesticides and are useful, for example, in methods for the control of fungal pathogens and diseases caused by fungal pathogens in plants. A preferred process is directed to preparing a stereomerically enriched compound of Formula V-1 or V-2-F by assymetrical reduction in the presence of a chiral organometallic catalyst.

Description

PROCESSES FOR THE PREPARATION OF FUNGICIDAL COMPOUNDS

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application Number 62/466,944, filed on March 3, 2017, the entirety of which is incorporated herein by reference.

FIELD [0002] Provided herein are processes for the preparation of stereomerically enriched compounds that are useful as fungicides.

BACKGROUND [0003] Acetyl-CoA carboxylase (“ACCase”) is an essential catalyst for the rate-limiting step of fatty acid biosynthesis in both eukaryotes and prokaryotes. Phytopathogenic fungi can infect crop plants either in the field or after harvesting, resulting in considerable economic losses to farmers and producers worldwide. In addition to the agricultural impact, when food and feed contaminated with fungi or the toxins they produce are ingested by humans or livestock, a number of debilitating diseases or death can occur. Approximately 10,000 species of fungi are known to damage crops and affect quality and yield. Crop rotation, breeding of resistant cultivars, the application of agrochemicals and combinations of these strategies is commonly employed to stem the spread of fungal pathogens and the diseases they cause.

[0004] Compounds that exhibit fungicidal activity, and which are useful in the preparation of compositions and in accordance with methods for control of fungal pathogens, are described in U.S. Patent Publication Nos. 2017/0166584, 2017/0166582, 2017/0166583, and 2017/0166585, each filed on November 22, 2016, the entirety of which are incorporated herein by reference.

[0005] There is a need in the art to provide processes and methods for the synthesis of these and other compounds exhibiting fungicidal activity.

SUMMARY [0006] Provided herein are processes that are useful for preparing stereomerically enriched compounds of Formulas 1-014,1-020,1-064,1-074,1-082,1-089,1-090,1-095,1-171, 1-181,1-184,1-186,1-189,1-191,1-192,1-193,1-205,1-206,1-208,1-211,1-212,1-213,1-220, 1-229,1-231,1-233,1-234,1-246,1-251,1-258,1-259,1-262,1-263,1-285,1-323, and 1-400 salts thereof, and intermediates and precursors thereof.

WO 2018/161008

PCT/US2018/020728 [0007] For example, provided herein is a process for preparing a stereomerically

Formula V-2-F

or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-l or V-2-F, respectively; wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH3; and R² is hydrogen or F.

[0008] Also provided herein is a process for preparing a stereomerically enriched compound of Formula V-3, V-4-F or V-4-F-la:

Formula V-3

Formula V-4-F

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Formula V-4-F-la or a salt thereof, the process comprising contacting a compound of Formula IV-3,IV-4-F or IV4-F-la:

IV-4-F-la or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium to provide the stereomerically enriched compound or salt of Formula V-3 or V-4-F, respectively; wherein R¹ is 2H-1,2,3triazol-2-yl or -C(O)OCH2CH3; and R² is hydrogen or F.

[0009] Also provided herein is a process for preparing a stereomerically enriched compound of Formula V-5,V-6-F or V-6-F-la:

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PCT/US2018/020728

Formula V-6-F-la or a salt thereof, the process comprising contacting a compound of Formula IV-5,IV-6-F or IV6-F-la:

IV-6-F-la

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PCT/US2018/020728 or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium to provide the stereomerically enriched compound or salt of Formula V-5, V-6-F, or V-6-F-la, respectively; wherein R¹ is 2H-

1,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH₃; and R² is hydrogen or F.

[0010] Also provided herein is a process for preparing a stereomerically enriched compound of Formula V-7-F or V-7-F-la:

Formula V-7-F

Formula V-7-F-la or a salt thereof, the process comprising contacting a compound of Formula IV-7-F or IV-7-Fla:

Formula IV-7-F

Formula IV-l-F-la or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium to provide the stereomerically enriched compound or salt of Formula V-7-F or V-7-F-la; wherein R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH₂CH₃.

[0011] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-020,1-074,1-064,1-014,1-184,1-211,1-212, or 1-213:

PCT/US2018/020728

WO 2018/161008

1-020 1-074

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PCT/US2018/020728

1-212 1-213 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-5-F:

Formula V-5-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-5-F:

Formula VI-5-F or a salt thereof; and reacting the compound or salt of Formula VI-5-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, ethylene glycol, (R)-3-hydroxy-2methylpropanenitrile, (S)-3-hydroxy-2-methylpropanenitrile, and 3-hydroxy-2,2dimethylpropanenitrile, thereby providing the stereomerically enriched compound or salt of

WO 2018/161008

PCT/US2018/020728

Formula 1-020,1-074,1-064,1-014,1-184,1-211,1-212, or 1-213 wherein R¹ is 2H-1,2,3triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3.

[0012] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-082 or 1-171:

1-082 1-171 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-6-T-F:

Formula V-6-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-6-T-F:

Formula VI-6-T-F

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PCT/US2018/020728 or a salt thereof; reacting the compound or salt of Formula VI-6-T-F with methoxy ethanol, thereby providing the stereomerically enriched compound or salt of Formula 1-082; and separating the compound or salt of Formula 1-082, thereby providing the stereomerically enriched compound or salt of Formula 1-171.

[0013] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-020,1-074,1-014,1-211,1-212, or 1-213:

1-020 1-074

1-014

1-211 1-212

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1-213 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-l-F:

Formula V-l-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-l-F:

Formula VI-l-F or a salt thereof; reacting the compound or salt of Formula VI-l-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, (S)-3-hydroxy-2-methylpropanenitrile, (R)-3-hydroxy-2-methylpropanenitrile, and 3-hydroxy-2,2-dimethylpropanenitrile, thereby providing a stereomerically enriched compound of Formula VII-l-T-F-1, VII-l-T-F-2, VII-1P-F-l, VII-l-T-F-3, VII-l-T-F-4, or VII-l-T-F-5:

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PCT/US2018/020728 // W

VII-l-T-F-3 VII-l-T-F-4

VII-l-T-F-5 or a salt thereof; treating the compound or salt of Formula VII-l-T-F-1, VII-l-T-F-2, VII-l-PF-l, VII-l-T-F-3, VII-l-T-F-4, or VII-l-T-F-5 with an acid in a deprotection zone, thereby

WO 2018/161008

PCT/US2018/020728 providing a corresponding carboxylic acid compound of Formula ΥΠΙ-1-T-F-l, VIII-l-T-F-2,

VIII-l-P-F-1, VIII-l-T-F-3, VIII-l-T-F-4, or VIII-l-T-F-5:

VIII-l-T-F-1

VIII-l-P-F-1

VIII-l-T-F-3

VIII-l-T-F-4

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PCT/US2018/020728 or a salt thereof; and forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-020,1-074,1-014, 1-211,1-212, or 1-213; wherein R¹ is 2H-l,2,3-triazol-2-yl or 1-pyrazolyl.

[0014] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-082 or 1-171:

1-082 1-171 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-2-T-F:

Formula V-2-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-2-T-F:

Formula VI-2-T-F

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PCT/US2018/020728 or a salt thereof; reacting the compound or salt of Formula VI-2-T-F with methoxy ethanol, thereby providing a stereomerically enriched compound of Formula VII-2-T-F-2:

VII-2-T-F-2 or a salt thereof; treating the compound or salt of Formula VII-2-T-F-2 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-2-T-F-2:

VIII-2-T-F-2 or a salt thereof; forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-082; and separating the compound or salt of Formula 1-082, thereby providing the stereomerically enriched compound or salt of Formula 1-171.

[0015] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-208,1-206,1-193,1-095,1-192,1-191,1-234,1-231,1-233, or 1-181:

WO 2018/161008

PCT/US2018/020728 /ΓΛ ΓΛ

1-206

1-234

1-231

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PCT/US2018/020728

or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-l:

Formula V-l or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-4:

Formula VII-1-4 or a salt thereof; treating the compound or salt of Formula VII-1-4 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-1-4:

WO 2018/161008

PCT/US2018/020728

Formula VIII-1-4 or a salt thereof; and forming an amide with an amine selected from the group consisting of ethylamine and isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-208,1-206,1-193,1-095,1-192,1-191, 1-234,1-231,1-233, or 1-181; wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or C(O)OCH2CH3; and R² is hydrogen or F.

[0016] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-211,1-212,1-262,1-263,1-258,1-259, or 1-213:

1-211 1-212

1-262

1-263

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PCT/US2018/020728

Formula V-l-F or a salt thereof, with an alkenyl compound of CH2=C(CH3)CN in the presence of a base in a

Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-l-F-5:

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PCT/US2018/020728

Formula VII-l-F-5 or a salt thereof; treating the compound or salt of Formula VII-l-F-5 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-l-F-5:

Formula VIII-l-F-5 or a salt thereof;

forming an amide with isopropylamine in an amide formation zone, thereby providing a compound of Formula 1-211/212,1-262/263, or 1-258/259:

Formula 1-211/212 Formula 1-262/263

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1-258/259 or a salt thereof; and separating the compound or salt of Formula 1-211/212,1-262/263, or I258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211,1212,1-262,1-263,1-258, or 1-259; or reacting the compound or salt of Formula 1-211/212 with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-213; wherein R¹ is 2H-1,2,3-triazol-2yl, 1-pyrazolyl, or-C(O)OCH2CH3.

[0017] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-205,1-220 or 1-229:

1-205

1-220 1-229 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-2-F:

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PCT/US2018/020728

Formula V-2-F or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-2-F-4:

or a salt thereof; treating the compound or salt of Formula VII-2-F-4 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-2-F-4:

or a salt thereof; forming an amide with an amine selected from the group consisting of isopropylamine and 7V-methylisopropylamine in an amide formation zone, thereby providing a compound of Formula I-205-RR/RS, I-220-RR/RS, or I-229-RR/RS:

WO 2018/161008

PCT/US2018/020728

or a salt thereof; and separating the compound or salt of Formula I-205-RR/RS, I-220-RR/RS, or I-229-RR/RS, thereby providing the stereomerically enriched compound or salt of Formula I-

205,1-220, or 1-229; wherein R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH₂CH₃.

[0018] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-285:

1-285 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-l-E-F:

WO 2018/161008

PCT/US2018/020728

Formula V-l-E-F or a salt thereof, with an alkenyl compound of CH2=CHSO2CH3 in the presence of a base in a

Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-l-E-F-6:

Formula VII-l-E-F-6 or a salt thereof; treating the compound or salt of Formula VII-l-E-F-6 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-l-E-F6:

Formula VIII-l-E-F-6 or a salt thereof; and forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-285.

[0019] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-208,1-206,1-234, or 1-231:

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PCT/US2018/020728

1-206

1-234

1-231 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-3:

Formula V-3 or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-208,1-206,1-234, or 1-231; wherein R¹ is 2H-1,2,3triazol-2-yl or -C(O)OCH2CH3; and R² is hydrogen or F.

[0020] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-193,1-095,1-192,1-191,1-233, or 1-181:

WO 2018/161008

PCT/US2018/020728

1-233 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-5:

Formula V-5

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PCT/US2018/020728 or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-193,1-095,1-192,1-191,1-233, or 1-181; wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH3; and R² is hydrogen or F.

[0021] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-211,1-212,1-262,1-263,1-258,1-259, or 1-213:

1-211 1-212

1-262 1-263

1-258 1-259

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1-213 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-5-F:

Formula V-5-F or a salt thereof, with an alkenyl compound of CH2=C(CH3)CN in the presence of a base in a

Michael-addition zone comprising a reaction medium, thereby providing a compound of

Formula 1-211/212,1-262/263, or 1-258/259:

Formula 1-211/212

Formula 1-262/263

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[0022] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-220:

1-220 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-6-E-F:

Formula V-6-E-F

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PCT/US2018/020728 or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a compound of Formula I-220-RR/RS:

I-220-RR/RS or a salt thereof; and separating the compound or salt of Formula I-220-RR/RS, thereby providing the stereomerically enriched compound or salt of Formula 1-220.

[0023] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-205 or 1-229:

1-229 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-7-F:

Formula V-7-F

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PCT/US2018/020728 or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a

Formula I-205-RR/RS or I-229-RR/RS:

I-205-RR/RS

I-229-RR/RS or a salt thereof; and separating the compound or salt of Formula I-205-RR/RS or 1-229RR/RS, thereby providing the stereomerically enriched compound or salt of Formula 1-205 or I229; wherein R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH₂CH₃.

[0024] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-285:

1-285 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-5-E-F:

Formula V-5-E-F

WO 2018/161008

PCT/US2018/020728 or a salt thereof, with an alkenyl compound of CH2=CHSO2CH3 in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-285.

[0025] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-064:

or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-l-T-F:

Formula V-l-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium; reacting the product with a compound of XCH2C(O)OR3 in the oc-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-l-T-F-7:

Formula VII-l-T-F-7

WO 2018/161008

PCT/US2018/020728 or a salt thereof; treating the compound or salt of Formula VII-l-T-F-7 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-l-T-F-7:

OH

Formula VIII-l-T-F-7 or a salt thereof; forming an amide with isopropylamine in an amide formation zone, thereby providing a stereomerically enriched compound of Formula IX-l-T-F-7:

Formula IX-l-T-F-7 or a salt thereof; and contacting the compound or salt of Formula IX-l-T-F-7 with a reducing agent in a reduction zone, thereby providing the stereomerically enriched compound or salt of Formula 1-064; wherein X is Cl or Br, and R³ is selected from the group consisting of methyl and ethyl.

[0026] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-089 or 1-090:

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PCT/US2018/020728

1-090 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-2-T-F:

Formula V-2-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium; reacting with a compound of XCH2C(O)OR³ in the α-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-2-T-F-7:

Formula VII-2-T-F-7 or a salt thereof; treating the compound or salt of Formula VII-2-T-F-7 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-2-T-F-7:

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PCT/US2018/020728

Formula VIII-2-T-F-7 or a salt thereof; forming an amide with A'-methylisopropylamine in an amide formation zone, thereby providing a stereomerically enriched compound of Formula IX-2-T-F-7:

Formula IX-2-T-F-7 or a salt thereof; contacting the compound or salt of Formula IX-2-T-F-7 with a reducing agent in a reduction zone, thereby providing a compound of Formula I- 1-089/090:

1-089/090 or a salt thereof; and separating the compound or salt of Formula 1-089/090, thereby providing the stereomerically enriched compound or salt of Formula 1-089 or 1-090; wherein X is Cl or Br, and R³ is selected from the group consisting of methyl and ethyl.

[0027] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-251:

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PCT/US2018/020728

1-251 or a salt thereof, the process comprising contacting a stereomerically enriched compound of Formula V-l-E-F:

Formula V-l-E-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium; reacting the product with a compound of XCH2CN in the α-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-l-E-F-8:

Formula VII-l-E-F-8 or a salt thereof; treating the compound or salt of Formula VII-l-E-F-8 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-l-E-F-8:

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PCT/US2018/020728

Formula VIII-l-E-F-8 or a salt thereof; and forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-251; wherein X is Cl or Br.

[0028] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-246:

Formula V-8-T-F:

or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium; reacting the product with a compound of XCH2C(O)OR3 in the oc-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-8-T-F-7:

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Formula VII-8-T-F-7 or a salt thereof; treating the compound or salt of Formula VII-8-T-F-7 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-8-T-F-7:

Formula VIII-8-T-F-7 or a salt thereof; forming an amide with isopropylamine in an amide formation zone, thereby providing a stereomerically enriched compound of Formula IX-8-T-F-7:

Il

Formula IX-8-T-F-7 or a salt thereof; and contacting the compound or salt of Formula IX-8-T-F-7 with a reducing agent in a reduction zone, thereby providing the stereomerically enriched compound or salt of Formula 1-246; wherein X is Cl or Br, and R³ is selected from the group consisting of methyl and ethyl.

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PCT/US2018/020728 [0029] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-323:

1-323 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-3-T-F:

Formula V-3-T-F or a salt thereof, with acetic anhydride or acetyl chloride in the presence of a base in an acetylation zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-323.

[0030] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-189:

1-189 or a salt thereof, the process comprising separating a compound of Formula V-7-T-F:

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Formula V-7-T-F or a salt thereof, thereby providing the stereomerically enriched compound or salt of Formula I189 [0031] Also provide herein is a process for preparing a stereomerically enriched compound of Formula 1-400

Formula 1-400 or a salt thereof, the process comprising contacting a compound of Formula IV-6-T-F-la:

Formula IV-6-T-F-1 a or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-400.

[0032] Other objects and features will be in part apparent and in part pointed out hereinafter.

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DETAILED DESCRIPTION [0033] Provided herein are processes that are useful for preparing stereomerically enriched compounds of Formulas 1-014,1-020,1-064,1-074,1-082,1-089,1-090,1-095,1-171, 1-181,1-184,1-186,1-189,1-191,1-192,1-193,1-205,1-206,1-208,1-211,1-212,1-213,1-220, 1-229,1-231,1-233,1-234,1-246,1-251,1-258,1-259,1-262,1-263,1-285,1-323, and 1-400 and salts thereof.

Formula 1-014

Formula 1-020

Formula 1-064

Formula 1-074

Formula 1-082

Formula 1-089

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Formula 1-090

Formula 1-095

Formula 1-171 Formula 1-181

Formula 1-184

Formula 1-186

Formula 1-189

Formula 1-191

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Formula 1-193

Formula 1-205

Formula 1-206

Formula 1-211

Formula 1-212

Formula 1-213

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Formula 1-220

Formula 1-229

Formula 1-246

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Formula 1-259

Formula 1-263

Formula 1-323

Formula 1-400 [0034] As described in U.S. Patent Publication Nos. 2017/0166584, 2017/0166582, 2017/0166583, and 2017/0166585, each filed on November 22, 2016, the entirety of which are incorporated herein by reference, these compounds exhibit pesticidal activity, and in particular exhibit fungicidal activity. The compounds may be used, for example, in the preparation of compositions and in accordance with methods for control of fungal pathogens.

[0035] Also described herein are process for preparing various intermediates and precursors of the compounds described above.

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A. Asymmetric Reduction of a Ketone Compound of Formula IV [0036] Provided herein are processes that are useful for preparing stereomerically enriched compounds of Formulas V-l, V-2-F, V-3, V-4-F, V-5, V-6-F, and V-7-F as described herein.

[0037] For example, provided herein is a process for preparing stereomerically enriched compounds of Formula V-l or V-2-F, or salts thereof:

Formula V-l

Formula V-2-F wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH3; and R² is hydrogen or F.

Generally, the process comprises contacting a compound of Formula IV-1 or IV[0038]

2-F:

Formula IV-1

Formula IV-2-F or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-l or V-2-F, respectively.

[0039] In the compounds of Formulas V-l, V-2-F, IV-1, and IV-2-F, R¹ can be 2H- l,2,3-triazol-2-yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be C(O)OCH₂CH3.

[0040] In the compounds of Formulas V-l and IV-1, R² can be hydrogen. Alternatively, R² can be F.

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PCT/US2018/020728 [0041] For example, in some embodiments, the stereomerically enriched compound of

Formula V-l is a compound of Formula V-l-T-H, V-l-T-F, V-l-P-H, V-l-P-F, V-l-E-H, or V1-E-F:

and the corresponding compound of Formula IV-1 is a compound of Formula IV-l-T-H, IV-1T-F, IV-l-P-H, IV-l-P-F, IV-l-E-H, or IV-l-E-F:

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Formula IV-l-T-H

Formula IV-l-T-F

Formula IV-l-P-H

Formula IV-l-P-F

Formula IV-l-E-H

Formula IV-l-E-F respectively.

[0042] In other embodiments, the stereomerically enriched compound of Formula V-2-F is a compound of Formula V-2-T-F or V-2-E-F:

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Formula V-2-E-F

Formula V-2-T-F and the corresponding compound of Formula IV-2-F is a compound of Formula IV-2-T-F or

IV-2-E-F:

Formula IV-2-T-F

Formula IV-2-E-F respectively.

[0043] Also provided herein is a process for preparing a stereomerically enriched compound of Formula V-3, V-4-F or V-4-F-la:

Formula V-4-F

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Formula V-4-F-la or a salt thereof, the process comprising contacting a compound of Formula IV-3, IV-4-F or IV4-F-la:

Formula IV-4-F-1 a or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-3, V-4-F, V-4-F-la respectively, wherein R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH2CH3; and R² is hydrogen or F.

[0044] In the compounds of Formulas V-3, V-4-F, V-4-F-la, IV-3, IV-4-F, and IV-4-Fla R¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be -C(O)OCH2CH3.

[0045] In the compounds of Formulas V-3 and IV-3, R² can be hydrogen. Alternatively, R² can be F.

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PCT/US2018/020728 [0046] For example, in some embodiments, the stereomerically enriched compound of

Formula V-3 or V-4-F is a compound of Formula V-3-T-H, V-3-T-F, V-3-E-H, V-3-E-F, V-4T-F, V-4-T-F-la or V-4-E-F:

Formula V-3-T-F

Formula V-4-T-F

Formula V-4-T-F-la

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Formula V-4-E-F and the corresponding compound of Formula IV-3 or IV-4-F is a compound of Formula IV-3T-H, IV-3-T-F, IV-3-E-H, IV-3-E-F, IV-4-T-F, IV-4-T-F-la or IV-4-E-F:

Formula IV-3-E-H

Formula IV-3-E-F

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Formula IV-4-E-F respectively.

[0047] Also provided herein is a process for preparing a stereomerically enriched compound of Formula V-5, V-6-F or V-6-F-la:

Formula V-5

Formula V-6-F

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Formula V-6-F-la or a salt thereof, the process comprising contacting a compound of Formula IV-5, IV-6-F or IV6-F-la:

Formula IV-6-F-1 a or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-5, V-6-F, or V-6-F-la respectively, wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH3; and R² is hydrogen or F.

[0048] In the compounds of Formulas V-5, V-6-F, V-6-F-la, IV-5, IV-6-F, and IV-6-FlaR¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be -C(O)OCH₂CH3.

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PCT/US2018/020728 [0049] In the compounds of Formulas V-5 and IV-5, R² can be hydrogen. Alternatively, R² can be F.

[0050] For example, in some embodiments, the stereomerically enriched compound of Formula V-5 or V-6-F is a compound of Formula V-5-T-H, V-5-T-F, V-5-P-H, V-5-P-F, V-5E-H, V-5-E-F, V-6-T-F, V-6-T-F-la or V-6-E-F:

Formula V-5-T-H

Formula V-5-P-H

Formula V-5-E-F (1-186)

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Formula V-6-E-F and the corresponding compound of Formula IV-5 or IV-6-F is a compound of Formula IV-5T-H, IV-5-T-F, IV-5-P-H, IV-5-P-F, IV-5-E-H, IV-5-E-F, IV-6-T-F, IV-6-T-F-la or IV-6-EF:

Formula IV-5-T-H

Formula IV-5-T-F

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Formula IV-5-E-H

Formula IV-5-E-F

Formula IV-6-E-F respectively.

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PCT/US2018/020728 [0051] Also provided herein is a process for preparing a stereomerically enriched compound of Formula V-7-F:

Formula V-7-F or a salt thereof, the process comprising contacting a compound of Formula IV-7-F:

Formula IV-7-F or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-7-F, wherein R¹ is 2H-l,2,3-triazol-2yl or -C(O)OCH₂CH₃.

[0052] In the compounds of Formulas V-7-F and IV-7-F, R¹ can be 2H-1,2,3-triazol-2yl. Alternatively, R¹ can be -C(O)OCH2CH3.

[0053] For example, in some embodiments, the stereomerically enriched compound of Formula V-7-F is a compound of Formula V-7-T-F, V-7-T-F-la or V-7-E-F:

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Formula V-7-T-F

Formula V-7-T-F-la

and the corresponding compound of Formula IV-7-F is a compound of Formula IV-7-T-F, IV7-T-F-la or IV-7-E-F:

Formula IV-7-T-F

Formula IV-7-T-F-la

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Formula IV-7-E-F respectively.

[0054] In the processes described above, a chiral organometallic catalyst is used to facilitate the preparation of the stereomerically enriched compounds of Formulas V-l, V-2-F, V3, V-4-F, V-5, V-6-F, and V-7-F. The chiral organometallic catalyst can be a chiral ruthenium catalyst. In some embodiments, the chiral ruthenium catalyst comprises a compound of a chiral (5,5)-ruthenium-diamine complex. By way of non-limiting example, the chiral (5,5)-ruthenium diamine complex can be selected from the group consisting of Formulas X-l (S,S), X-2 (S,S),

X-3 (.SYS’), and X-4 (SYS)

Formula X-2 (S,S)

Formula X-l (S,S)

Formula X-3 (S,S)

Formula X-4 (S,S) [0055] In other embodiments, the chiral ruthenium catalyst can be selected from, but not limited to, Ru(OTf)[(R,R)-BnSO2-dpen](p-cymene), RuCl[(R,R)-Ts-dpen](p-cymene), RuCl[(R,R)-Ts-dpen](p-cymene), (S)-RUCY™-XylBINAP], RuC12[(R)-xylylPhanephos][lS,2S-DPEN], RuCl₂[(S)-xylbinap][(S,S)-dpen], RuC12[(S)-dm-segphos][(S,S)dpen], RuCh[(R)-xylbinap][(R)-daipen], RuC12[(S)-xylbinap][(S)-daipen], RuCh[(S)binap][(S)-daipen], RuC12[(S)-xyl-PPhos][(S)-daipen], [NMe2H2][{RuCl(S-TunePhos)}2^

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Cl)₃], [NMe₂H2][{RuCl(MeO-BIPHEP)}2(p-Cl)₃], [NMe2H₂][{RuCl((S)-binap)}2(p-Cl)₃], [NMe₂H₂][{RuCl((S)-xylbinap)}₂(p-Cl)₃], and [NMe₂H₂][{RuCl((S)-dm-segphos®)}2(μ-Ο)₃].

[0056] When the chiral organometallic catalyst is a chiral ruthenium catalyst, the chiral ruthenium catalyst can be present in the reaction medium of the asymmetrical reduction zone in an amount of from 0.1 mol% to 10 mol%, based on the compound of Formula IV-1, IV-2-F, IV3, IV-4-F, IV-5, IV-6-F, or IV-7-F [0057] In other embodiments, the chiral organometallic catalyst can be a non-Ruthenium containing catalyst. In some embodiments, the chiral organometallic catalyst can be selected from, but not limited to, (S)-2-methyl-CBS-oxazaborolidine, (S,S)-Me-DuPhos; Pd2(CF₃CO₂)2, [Rh(NBD)(TangPhos)] SbFe.

[0058] In the processes described above, the hydrogen source in the asymmetrical reduction zone can be substantially hydrogen gas. Alternatively, the hydrogen source in the symmetrical reduction zone can be a hydrogen transfer agent. Non-limiting examples of hydrogen transfer agents include formic acid, formates, and mixtures thereof. Non-limiting examples of suitable formates include alkali metal formates, ammonium formate, and trialkylammonium formates. For example, the hydrogen source in the symmetrical reduction zone can comprise sodium formate.

[0059] In some embodiments, the hydrogen source in the symmetrical reduction zone comprises trialkylammonium formate that is formed in situ by mixing formic acid and trialkylamine in the reaction medium of the asymmetrical reduction zone. For example, the trialkylammonium formate can be triethylammonium formate.

[0060] In the processes described above, the enantiomeric excess of the stereomerically enriched compound of Formula V-l, V-2-F, V-3, V-4-F, V-5, V-6-F, or V-7-F can be at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. For example, the enantiomeric excess of the stereomerically enriched compound of Formula V-l, V-2-F, V-3, V-4-F, V-5, V-6F, or V-7-F can range from 60% to 70%, from 70% to 80%, from 80% to 90%, or from 90% to 99%.

B. Alkylation of a Substituted Aryl α-haloketone to a Compound of Formula IV [0061] Also provided herein are processes that are useful for preparing compounds of Formulas IV-1,, IV-3, IV-5, and stereomerically enriched compounds of Formulas IV-2-F, IV4-F, IV-6-F, and IV -7-F as described herein.

[0062] For example, provided herein is a process for preparing a compound of Formula

IV-1 or IV-2-F:

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Formula IV-1

Formula IV-2-F or a salt thereof, the process comprising contacting a compound of Formula II-l or II-2:

or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-1 or IV-2-F, wherein R¹ is 2H-1,2,3triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH₃; R² is hydrogen or F; and X is Cl, Br, or I.

[0063] In the compounds of Formulas IV-1, IV-2-F, II-l, and II-2, R¹ can be 2H-1,2,3triazol-2-yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be C(O)OCH₂CH₃.

[0064] In the compounds of Formulas IV-1 and III, R² can be hydrogen. Alternatively, R² can be F.

[0065] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As a further alternative, X can be I.

[0066] Also provided herein is a process for preparing a compound of Formula IV-3,

IV-4-F or IV-4-F-la:

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Formula IV-3

Formula IV-4-F

Formula IV-4-F-1 a or a salt thereof, the step comprising contacting a compound of Formula II-3, II-4 or II-4-la:

H

Formula II-3

H

Formula II-4

H

Formula II-4-la or a salt thereof, with a compound of Formula III:

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Formula III

or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-3, IV-4-F, IV-4-F-la wherein R¹ is 2H- l,2,3-triazol-2-yl or -C(O)OCH2CH3; R² is hydrogen or F; and X is Cl, Br, or I.

[0067] In the compounds of Formulas IV-3, IV-4-F, IV-4-F-la, II-3, II-4, and II-4-la R¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be -C(O)OCH2CH3.

[0068] In the compounds of Formulas IV-3 and III, R² can be hydrogen. Alternatively, R² can be F.

[0069] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As a further alternative, X can be I.

[0070] Also provided herein is a process for preparing a compound of Formula IV-5,IV6-F or IV-6-F-la:

Formula IV-5

Formula IV-6-F

Formula IV-6-F-1 a or a salt thereof, the step comprising contacting a compound of Formula II-5, II-6 or II-6-la:

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Η

Formula II-5

Η

Formula ΙΙ-6

Η

Formula II-6-la

Formula III or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-5, IV-6-F or IV-6-F-la, wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH3; R² is hydrogen or F; and X is Cl, Br, or

I.

[0071] In the compounds of Formulas IV-5, IV-6-F, IV-6-F-la, II-5, II-6, and II-6-la

R¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹can be -C(O)OCH₂CH3.

[0072] In the compounds of Formulas IV-5 and III, R² can be hydrogen. Alternatively, R² can be F.

[0073] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As a further alternative, X can be I.

[0074] Also provided herein is a process for preparing a compound of Formula IV-7-F or IV-7-F-la:

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Formula IV-7-F

Formula IV-7-F-la or a salt thereof, the step comprising contacting a compound of Formula II-7 or II-7-la:

Formula II-7

H

Formula II-7-la or a salt thereof, with a compound of Formula III-F:

Formula III-F or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-7-F or IV-7-F-la, wherein R¹ is 2H- l,2,3-triazol-2-yl or -C(O)OCH2CH3; and X is Cl, Br, or I.

[0075] In the compounds of Formulas IV-7-F, IV-7-F-la, II-7 and II-7-la, R¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be -C(O)OCH2CH3.

[0076] In the compounds of Formula III, X can be Cl. Alternatively, X can be Br. As a further alternative, X can be I.

[0077] In some embodiments of the processes for preparation of the compounds of Formulas IV-1, IV-2-F, IV-3, IV-4-F, IV-4-F-la, IV-5, IV-6-F, IV-6-F-la, IV-7-F, and IV-7F-la as described above, X is Cl and the reaction medium in the alkylation zone comprises an alkali metal bromide or an alkali metal iodide. For example, the alkali metal bromide can be sodium bromide or potassium bromide.

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PCT/US2018/020728 [0078] The alkali metal bromide can be present in the reaction medium in an amount of from about 1 mol% to about 20 mol%, based on the compound of Formula II-l, II-2, II-3, II-4, II-4-la, II-5, II-6, II-6-la, II-7, or II-7-la [0079] In some embodiments of the processes for preparation of the compounds of Formulas IV-1, IV-2-F, IV-3, IV-4-F, IV-4-F-la, IV-5, IV-6-F, IV-6-F-la, IV-7-F, and IV-7F-la as described above, the base in the alkylation zone comprises an alkali metal carbonate. For example, the alkali metal carbonate can be potassium carbonate.

[0080] The alkali metal carbonate can be present in the reaction medium in an amount of from about 1 equivalent to about 10 equivalents, based on the compound of Formula II-l, II-2, II-3, II-4, II-4-la, II-5, II-6, II-6-la, II-7, or II-7-la

C. Mesylation and Ether Formation [0081] Also provided herein are processes that are useful for preparing stereomerically enriched compounds of Formulas 1-014,1-020,1-064,1-074,1-082,1-171, and 1-184 as described herein.

[0082] For example, provided herein is a process for preparing a stereomerically enriched compound of Formula 1-020,1-074,1-064,1-014,1-184,1-211,1-212, or 1-213:

1-064

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1-014 1-184

1-211

Formula V-5-F:

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or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-5-F:

Formula VI-5-F or a salt thereof; and reacting the compound or salt of Formula VI-5-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, ethylene glycol, (S)-3-hydroxy-2methylpropanenitrile, (R)-3-hydroxy-2-methylpropanenitrile, and 3-hydroxy-2,2dimethylpropanenitrile, thereby providing the stereomerically enriched compound or salt of Formula 1-020,1-074,1-064,1-014,1-184,1-211,1-212, or 1-213, wherein R¹ is 2H-1,2,3triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3.

[0083] In the compounds of Formulas V-5-F, and VI-5-F, R¹ can be 2H-l,2,3-triazol-2yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be -C(O)OCH2CH3.

[0084] The compound or salt of Formula VI-5-F can be reacted with isopropanol. Alternatively, the compound or salt of Formula VI-5-F can be reacted with methoxy ethanol. As a further alternative, the compound or salt of Formula VI-5-F can be reacted with ethylene glycol. As a further alternative, the compound or salt of VI-5-F can be reacted with (S)-3hydroxy-2-methylpropanenitrile. Alternatively, the compound or salt of VI-5-F can be reacted with (R)-3-hydroxy-2-methylpropanenitrile. In yet another alternative, the compound or salt of VI-5-F can be reacted with 3-hydroxy-2,2-dimethylpropanenitrile.

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PCT/US2018/020728 [0085] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-082 or 1-171:

1-082 1-171 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-6-T-F:

Formula VI-6-T-F or a salt thereof; reacting the compound or salt of Formula VI-6-T-F with methoxy ethanol, thereby providing the stereomerically enriched compound or salt of Formula 1-082; and

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PCT/US2018/020728 separating the compound or salt of Formula 1-082, thereby providing the stereomerically enriched compound or salt of Formula 1-171.

[0086] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-020,1-074,1-014,1-211,1-212, or 1-213:

1-020 1-074

1-014

1-211 1-212

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VII-l-T-F-1

VII-l-T-F-2 ch₃

VII-l-P-F-1

VII-l-T-F-3

VII-l-T-F-4

VII-l-T-F-5

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PCT/US2018/020728 or a salt thereof; treating the compound or salt of Formula VII-l-T-F-1, VII-l-T-F-2, VII-l-PF-l, VII-l-T-F-3, VII-l-T-F-4, or VII-l-T-F-5 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-l-T-F-1, VIII-l-T-F-2,

VIII-l-P-F-1, VIII-l-T-F-3, VIII-l-T-F-4, or VIII-l-T-F-5:

VIII-l-T-F-1

VIII-l-T-F-2

VIII-l-P-F-1

VIII-l-T-F-3

VIII-l-T-F-4

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VIII-l-T-F-5 or a salt thereof; and forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-020,1-074,1-014, 1-211,1-212,1-213; wherein R¹ is 2H-l,2,3-triazol-2-yl or 1-pyrazolyl.

[0087] In the compounds of Formulas V-l-F and VI-l-F, R¹ can be 2H-1,2,3-triazol-2yl. Alternatively, R¹ can be 1-pyrazolyl.

[0088] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-082 or 1-171:

Formula V-2-T-F:

Formula V-2-T-F

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PCT/US2018/020728 or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-2-T-F:

or a salt thereof; reacting the compound or salt of Formula VI-2-T-F with methoxy ethanol, thereby providing a stereomerically enriched compound of Formula VII-2-T-F-2:

VIII-2-T-F-2

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PCT/US2018/020728 or a salt thereof; forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-082; and separating the compound or salt of Formula 1-082, thereby providing the stereomerically enriched compound or salt of Formula 1-171.

[0089] In some embodiments of the processes for preparation of the compounds of

Formulas 1-014,1-020,1-064,1-074,1-082,1-171,1-184,1-211,1-212, and 1-213 as described above, the base in the mesylation zone is a pyridine-based base. The pyridine-based base can be a substituted pyridine. For example, the substituted pyridine can be 2,6-lutidine. Alternatively, the substituted pyridine can be 2,4,6-collidine.

[0090] In some embodiments of the processes for preparation of the compounds of Formulas 1-014,1-020,1-064,1-074,1-082,1-171,1-184,1-211,1-212, and 1-213 as described above, the stereochemistry of the fragment

N

in the stereomerically enriched compound of Formula V-l-F, V-2-T-F, V-2-T-F-la, V-5-F, V6-T-F, V-6-T-F-la remains substantially the same in the stereomerically enriched compound of Formula 1-020,1-074,1-014,1-184,1-082,1-171,1-211,1-212, or 1-213 [0091] In some embodiments of the processes for preparation of the compounds of Formulas 1-014,1-020,1-064,1-074,1-082,1-171,1-184,1-211,1-212, and 1-213, as described above, the acid in the deprotection zone is selected from the group consisting of hydrochloride, formic acid, trifluoracetic acid, and sulfuric acid. For example, the acid in the deprotection zone can comprise formic acid or sulfuric acid.

[0092] In some embodiments of the processes for preparation of the compounds of Formulas 1-014,1-020,1-064,1-074,1-082,1-171,1-184,1-211,1-212, and 1-213 as described above, the amide is formed in the presence of an amide coupling reagent in a reaction medium. As a non-limiting example, the amide coupling reagent can be selected from the group consisting of (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 3-(Diethoxyphosphoryloxy)-1,2,3- benzotriazin-4(3H)-one (DEPBT), N,N'~ dicyclohexylcarbodiimide (DCC), A; A^f'-Diisopropylcarbodiimide (DIC), 1[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-[Bis(dimethylamino)methyliumyl]-3//-benzotriazol-l-oxide

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PCT/US2018/020728 hexafluorophosphate (HBTU), 3-Hydroxytriazolo[4,5-Z>]pyridine (HOAt), (7-Azabenzotriazol-lyloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (Benzotriazol-1yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and propylphosphonic anhydride (T3P). For example, the amide coupling reagent can be HATU or T3P.

[0093] Alternatively, the amide can be formed by converting the stereomerically enriched compound of Formula VIII-l-T-F-1, VIII-l-T-F-2, VIII-l-P-F-1, or VIII-2-T-F-2 to a corresponding acid chloride and reacting the acid chloride compound with isopropylamine. Conversion of acid halides to amides are well known in the art (see R. C. Larock Comprehensive Organic Tranfor mations: A Guide to Functional Group Preparations, VCH, New York, 1989, p 979).

D. Michael Addition and Ether Formation [0094] Also provided herein are processes that are useful for preparing stereomerically enriched compounds of Formulas 1-095,1-181,1-191,1-192,1-193,1-205,1-206,1-208,1-211, 1-212,1-213,1-220,1-229,1-231,1-233,1-234,1-258,1-259,1-262,1-263, and 1-285 as described herein.

[0095] For example, provided herein is a process for preparing a stereomerically enriched compound of Formula 1-208,1-206,1-193,1-095,1-192,1-191,1-234,1-231,1-233, or 1-181:

1-208

1-206

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PCT/US2018/020728 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-l:

Formula VIII-1-4 or a salt thereof; and forming an amide with an amine selected from the group consisting of ethylamine and isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-208,1-206,1-193,1-095,1-192,1-191,

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1-234,1-231,1-233, or 1-181; wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or C(O)OCH2CH3; and R² is hydrogen or F.

[0096] In the compounds of Formulas V-l, VII-1-4, and VII-1-4, R¹ can be 2H-1,2,3triazol-2-yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be C(O)OCH₂CH3.

[0097] In the compounds of Formulas V-l, VII-1-4, and VII-1-4, R² can be hydrogen. Alternatively, R² can be F.

[0098] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-211,1-212,1-262,1-263,1-258,1-259, or 1-213:

1-211 1-212

1-262

1-263

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Formula VIII-l-F-5 or a salt thereof;

Formula 1-211/212 Formula 1-262/263

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1-258/259 or a salt thereof; and separating the compound or salt of Formula 1-211/212,1-262/263, or I258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211,1212,1-262,1-263,1-258, or 1-259; or reacting the compound or salt of Formula 1-211/212 with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-213; wherein R¹ is 2H-1,2,3-triazol-2yl, 1-pyrazolyl, or-C(O)OCH2CH₃.

[0099] In the compounds of Formulas V-l-F, VII-l-F-5, and VIII-l-F-5, R¹ can be 2H- l,2,3-triazol-2-yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be C(O)OCH₂CH₃.

[00100] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-205,1-220 or 1-229:

1-205

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Formula V-2-F:

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Formula VIII-2-F-4 or a salt thereof; forming an amide with an amine selected from the group consisting of isopropylamine and 7V-methylisopropylamine in an amide formation zone, thereby providing a compound of Formula I-205-RR/RS, I-220-RR/RS, or I-229-RR/RS:

205,1-220, or 1-229; wherein R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH₂CH₃.

[00101] In the compounds of Formulas V-2-F, VII-2-F-4, and VIII-2-F-4, R¹ can be 2H- l,2,3-triazol-2-yl. Alternatively, R¹ can be -C(O)OCH2CH3.

[00102] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-285:

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[00103] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-208,1-206,1-234, or 1-231:

1-208

1-206

1-234

Formula V-3:

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Formula V-3

or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-208,1-206,1-234, or 1-231; wherein R¹ is 2H-1,2,3triazol-2-yl or -C(O)OCH2CH₃; and R² is hydrogen or F.

[00104] In the compounds of Formula V-3, R¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be -C(O)OCH2CH₃.

[00105] In the compounds of Formula V-3, R² can be hydrogen. Alternatively, R²can be F.

[00106] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-193,1-095,1-192,1-191,1-233, or 1-181:

1-193 1-095

1-192 1-191

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1-233 1-181 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-5:

Formula V-5 or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-193,1-095,1-192,1-191,1-233, or 1-181; wherein R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or -C(O)OCH2CH₃; and R² is hydrogen or F.

[00107] In the compounds of Formula V-5, R¹ can be 2H-l,2,3-triazol-2-yl.

Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be -C(O)OCH2CH₃.

[00108] In the compounds of Formula V-5, R² can be hydrogen. Alternatively, R²can be F.

[00109] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-211,1-212,1-262,1-263,1-258,1-259, or 1-213:

PCT/US2018/020728

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1-258

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Formula V-5-F:

1-258/259 or a salt thereof; and separating the compound or salt of Formula 1-211/212,1-262/263, or I258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211,1212,1-262,1-263,1-258, or 1-259; or reacting the compound or salt of Formula 1-211/212 with methyl halide in the presence of base in a methylation zone, thereby providing the

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PCT/US2018/020728 stereomerically enriched compound or salt of Formula 1-213; wherein R¹ is 2H-1,2,3-triazol-2yl, 1-pyrazolyl, or-C(O)OCH2CH3.

[00110] In the compounds of Formula V-5-F, R¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be 1-pyrazolyl. As a further alternative, R¹ can be -C(O)OCH2CH3.

[00111] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-220:

Formula V-6-E-F:

Formula V-6-E-F or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a compound of Formula I-220-RR/RS:

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[00112] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-205 or 1-229:

Formula V-7-F:

Formula V-7-F or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a compound of Formula I-205-RR/RS or I-229-RR/RS:

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I-205-RR/RS

[00113] In the compounds of Formula V-7-F, R¹ can be 2H-l,2,3-triazol-2-yl. Alternatively, R¹ can be -C(O)OCH2CH3.

[00114] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-285:

Formula V-5-E-F:

Formula V-5-E-F

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[00115]

In some embodiments of the processes for preparation of the compounds of Formulas 1-095,1-181,1-191,1-192,1-193,1-205,1-206,1-208,1-211,1-212,1-213,1-220,1229,1-231,1-233,1-234,1-258,1-259,1-262,1-263, and 1-285 as described above, the base in the Michael-addition zone is an alkali metal hydroxide or a quaternary ammonium hydroxide. In some embodiments, the alkali metal hydroxide is selected from the group consisting of potassium hydroxide, sodium hydroxide, and lithium hydroxide. For example, the alkali metal hydroxide can be potassium hydroxide.

[00116] In some embodiments of the processes for preparation of the compounds of Formulas 1-095,1-181,1-191,1-192,1-193,1-205,1-206,1-208,1-211,1-212,1-213,1-220,1229,1-231,1-233,1-234,1-258,1-259,1-262,1-263, and 1-285 as described above, the base is present in the reaction medium in an amount of no more than 1.0 molar equivalents, based on the compound of Formula V-l, V-l-F, V-2-F, V-l-E-F, V-3, V-5, V-5-F, V-6-E-F, V-7-F, or V-5-E-F. For example, the base can be present in the reaction medium in an amount of from about 0.05 molar equivalents to about 0.9 molar equivalents, from about 0.1 molar equivalents to about 0.5 molar equivalents, or from about 0.1 molar equivalents to 0.3 molar equivalents, based on the compound of Formula V-l, V-l-F, V-2-F, V-l-E-F, V-3, V-5, V-5-F, V-6-E-F, V7-F, or V-5-E-F.

[00117] In some embodiments of the processes for preparation of the compounds of Formulas 1-095,1-181,1-191,1-192,1-193,1-205,1-206,1-208,1-211,1-212,1-213,1-220,1-

229,1-231,1-233,1-234,1-258,1-259,1-262,1-263, and 1-285 as described above, the stereochemistry of the fragment

N

in the stereomerically enriched compound of Formula V-l, V-l-F, V-2-F, V-l-E-F, V-3, V-5, V-5-F, V-6-E-F, V-7-F, or V-5-E-F remains substantially the same in the stereomerically enriched compound of Formula 1-208,1-206,1-193,1-095,1-192,1-191,1-234,1-231,1-233,1-

181,1-211,1-212,1-213,1-262,1-263,1-258,1-259,1-205,1-220,1-229, or 1-285 R² can hydrogen or F as described above.

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PCT/US2018/020728 [00118] In some embodiments of the processes for preparation of the compounds of Formulas 1-095,1-181,1-191,1-192,1-193,1-205,1-206,1-208,1-211,1-212,1-213,1-220,1229,1-231,1-233,1-234,1-258,1-259,1-262,1-263, and 1-285 as described above, the acid in the deprotection zone is selected from the group consisting of hydrochloride, formic acid, trifluoracetic acid, and sulfuric acid. For example, in some embodiments, the acid in the deprotection zone comprises formic acid or sulfuric acid.

[00119] In some embodiments of the processes for preparation of the compounds of Formulas 1-095,1-181,1-191,1-192,1-193,1-205,1-206,1-208,1-211,1-212,1-213,1-220,1229,1-231,1-233,1-234,1-258,1-259,1-262,1-263, and 1-285 as described above, the amide is formed in the presence of an amide coupling reagent in a reaction medium. As a non-limiting example, the amide coupling reagent can be selected from the group consisting of (Benzotri azol l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 3(Diethoxyphosphoryloxy)-1,2,3- benzotriazin-4(3H)-one (DEPBT), N,N'dicyclohexylcarbodiimide (DCC), A; A^f'-Diisopropylcarbodiimide (DIC), 1[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-[Bis(dimethylamino)methyliumyl]-37/-benzotriazol- l-oxide hexafluorophosphate (HBTU), 3-Hydroxytriazolo[4,5-Z>]pyridine (HOAt), (7-Azabenzotriazol-lyloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (Benzotriazol-1yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and propylphosphonic anhydride (T3P). For example, the amide coupling reagent can be HATU or T3P.

[00120] Alternatively, the amide can be formed by converting the stereomerically enriched compound of Formula VIII-1-4, VIII-l-F-5, VIII-2-F-4, or VIII-l-E-F-6 to a corresponding acid chloride and reacting the acid chloride compound with isopropylamine.

E. α-Bromoester Akylation and Ether Formation [00121] Also provided herein are processes that are useful for preparing stereomerically enriched compounds of Formulas 1-064,1-089,1-090,1-246, and 1-251 as described herein.

[00122] For example, provided herein is a process for preparing a stereomerically enriched compound of Formula 1-064:

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Formula V-l-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium; reacting with a compound of XCH2C(O)OR3 in the α-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-l-T-F-7:

Formula VII-l-T-F-7 or a salt thereof; treating the compound or salt of Formula VII-l-T-F-7 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-l-T-F-7:

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[00123] In the compound of Formula XCH2C(O)OR³, X can be Cl. Alternatively, X can be Br.

[00124] In the compounds of Formulas XCH₂C(O)OR³, VII-l-T-F-7, VIII-l-TF-7, and IX-l-T-F-7, R³ can be methyl. Alternatively, R³ can be ethyl.

[00125] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-089 or 1-090:

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Formula V-2-T-F:

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[00126] In the compound of Formula XCH2C(O)OR³, X can be Cl. Alternatively, X can be Br.

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WO 2018/161008 PCT/US2018/020728 [00127] In the compounds of Formulas XCH₂C(O)OR³, VII-2-T-F-7, VIII-2-TF-7, and IX-2-T-F-7, R³ can be methyl. Alternatively, R³ can be ethyl.

[00128] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-251:

Formula VII-l-E-F-8

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[00129] In the compound of Formula XCH2CN, X can be Cl. Alternatively, X can be Br.

[00130] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-246:

Formula V-8-T-F:

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or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium; reacting the product with a compound of XCH2C(O)OR₃ in the oc-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-8-T-F-7:

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[00131] In the compound of Formula XCH2C(O)OR³, X can be Cl. Alternatively, X can be Br.

[00132] In the compounds of Formulas XCH₂C(O)OR³, VII-8-T-F-7, VIII-8-TF-7, and IX-8-T-F-7, R³ can be methyl. Alternatively, R³ can be ethyl.

[00133] In some embodiments of the processes for preparation of the compounds of Formulas 1-064,1-089,1-090, and 1-251 as described above, the strong deprotonating agent comprises an alkali metal hydride or an alkaline earth metal hydride. In some embodiments, the alkali metal hydride is sodium hydride or potassium hydride. For example, the alkali metal hydride can be sodium hydride.

[00134] Alternatively, the strong deprotonating agent can comprise sodium tbutoxide or potassium Lbutoxide. For example, the strong deprotonating agent can comprise potassium Lbutoxide.

[00135] In some embodiments of the processes for preparation of the compounds of Formulas 1-064,1-089,1-090, and 1-251 as described above, wherein X in the compound of Formula XCH2CN is Cl, the reaction medium in the α-alkylation zone further comprises an alkali metal bromide or an alkali metal iodide. In some embodiments, the alkali metal bromide comprises sodium bromide or potassium bromide.

[00136] In some embodiments of the processes for preparation of the compounds of Formulas 1-064,1-089,1-090, and 1-251 as described above, the stereochemistry of the fragment

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in the stereomerically enriched compound of Formula V-l-T-F, V-2-T-F, or V-l-E-F remains substantially the same in the stereomerically enriched compound of Formula 1-064,1-089,1-090, or 1-251.

[00137] In some embodiments of the processes for preparation of the compounds of Formulas 1-064,1-089,1-090, and 1-251 as described above, the acid in the deprotection zone is selected from the group consisting of hydrochloride, formic acid, trifluoracetic acid, and sulfuric acid. For example, wherein the acid in the deprotection zone can comprise formic acid or sulfuric acid.

[00138] In some embodiments of the processes for preparation of the compounds of Formulas 1-064,1-089,1-090, and 1-251 as described above, the amide is formed in the presence of an amide coupling reagent in a reaction medium. As a non-limiting example, the amide coupling reagent can be selected from the group consisting of (Benzotriazol-1yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 3(Diethoxyphosphoryloxy)-1,2,3- benzotriazin-4(3H)-one (DEPBT), N,N'dicyclohexylcarbodiimide (DCC), TV./V'-Diisopropylcarbodiimide (DIC), 1[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-[Bis(dimethylamino)methyliumyl]-3/7-benzotriazol-l-oxide hexafluorophosphate (HBTU), 3-Hydroxytriazolo[4,5-Z>]pyridine (HOAt), (7-Azabenzotriazol-lyloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), (Benzotriazol-1yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and propylphosphonic anhydride (T3P). For example, the amide coupling reagent can be HATU or T3P.

[00139] Alternatively, the amide can be formed by converting the stereomerically enriched compound of Formula VIII-l-T-F-7, VIII-2-T-F-7, or VIII-l-E-F-8 to a corresponding acid chloride and reacting the acid chloride compound with isopropylamine.

[00140] In some embodiments of the processes for preparation of the compounds of Formulas 1-064,1-089,1-090, and 1-251 as described above, the reducing agent in the reduction zone comprises a hydride reducing agent. In some embodiments, the hydride reducing agent is selected from the group consisting of lithium borohydride (LiBHi), lithium triethylborohydride (LiBH(C2Hs)₃), potassium borohydride (KBHi), sodium borohydride (NaBH4), sodium

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PCT/US2018/020728 cyanoborohydride (NaBH₃CN), and calcium borohydride (Ca(BH4)2). For example, the hydride reducing agent can comprise lithium borohydride (LiBEh).

F. Acetylation to Prepare the Compound of Formula 1-323 [00141] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-323:

Formula V-3-T-F:

[00142] In some embodiments, the acetylation reaction is carried with acetic anhydride.

[00143] In some embodiments, the base in the acetylation zone is a substituted tertiary amine. For example, the substituted tertiary amine can comprise diisopropylethylamine. Alternatively, the base in the acetylation zone can be a pyridine-based base. For example, in some embodiments, the pyridine-based base is selected from the group consisting of pyridine,

2,6-lutidine, and 2,4,6-collidine.

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G. Separation to Prepare the Compound of Formula 1-189 [00144] Also provided herein is a process for preparing a stereomerically enriched compound of Formula 1-189:

Formula V-7-T-F or a salt thereof, thereby providing the stereomerically enriched compound or salt of Formula I189 [00145] Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.

EXAMPLES [00146] The following non-limiting examples are provided to further illustrate the present invention.

[00147] Example 1: Description of synthesis of compound 1-074

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PCT/US2018/020728 [00148] 2-Methoxyethyl 2-{l-[(27?)-2-(5-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-

5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-2methylpropanoate (Compound 1-074) was generally synthesized according to Scheme 1 below. Reactions were monitored by analytical HPLC or 400 MHz ¹H NMR in CDCh.

Scheme 1: Synthetic scheme for the preparation of compound 1-074

K₂CO₃cat. NaBr

H isopropylamine

2.1

HATU, DIEA 2MeTHF, rt

H

2.2

MeCN

Me Ts I N > r<_c ,.,.

N„ ^UH ^H catalyst: RuCI[(S,S)-Tsdpen] (mesitylene)

[00149] HPLC was conducted on an AGILENT 1100 HPLC, AGILENT XDB-C18 50 x 4.6 mm/1.8 micron column; 1.5 mL/min; solvent A: water (0.1% TFA), solvent B: acetonitrile (0.07% TFA); gradient: 6 min, 95% A to 90% B, then 1 minute hold, detection at 210 and 254 nm.

[00150] Chiral HPLC conditions: 7?,7?-Whelk-01, 5-75% ethanol in hexanes, 30 min, 1.0 mL/min, 30 °C column heater, 5 pL injection, detection at 220 nm.

[00151] Reactions were monitored via mass spectroscopy under the following conditions. LCMS: ESI +/- Polarity, 120-750amu; AGILENT XDB-C18 50 x 4.6 mm/1.8 micron column; 1.5 mL/min; solvent A: water (0.1% formic acid), solvent B: acetonitrile (0.07% formic acid); gradient: 5 min, 5-95% B then 30 sec hold, 60 °C column heater. Loop injection: FIA +/- Polarity, 120-750amu, MeOH/water (1:1), 0.3mL/min, 1.5 min run.

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PCT/US2018/020728 [00152] Example 1.2: Preparation of 2-chloro-l-(5-fluoro-2methoxyphenyl)ethanone (compound 1.2) [00153] Compound 1.2 was prepared according to the following scheme.

Scheme 1A2: Synthetic scheme for the preparation of compound 1.2

[00154] 1 -Fluoro-4-methoxybenzene (compound 1.1, 38 mL, 330 mmol, 1.2 eq.) (HPLC retention time=3.535) was added to a 500-mL 4-necked flask containing a mixture of methanesulfonic anhydride (48.6 g, 279 mmol, 1 eq.) and chloroacetic acid (32.0 g, 339 mmol,

1.2 eq.). The mixture was placed in an oil bath under nitrogen and heated to 80 °C (bath temperature) with mechanical stirring and internal temperature monitoring. The maximum internal temperature was 75 °C. HPLC analysis after 1.5 hours showed little conversion to ketone compound 1.2. HPLC after an additional hour showed 36% conversion to the desired product (retention time=3.650 min) when adjusted for differences in extinction coefficients between starting material and product. Water (49 mL) was added to the mixture dropwise via addition funnel (drop the oil bath, keeping internal temp below 95 °C). The mixture was allowed to stir for 15 minutes during which time the internal temperature had dropped to 73 °C. nPropanol (100 mL) was added to the mixture and the temperature was increased to 80 °C. As the reaction was allowed to cool, additional π-propanol was added to maintain a homogeneous solution (20 mL). The reaction was seeded at 50 °C and allowed to further cool to room temperature overnight with continued slow stirring. Crystallization began at ~40 °C. The reaction was cooled to 0 °C with an ice bath and allowed to stir an additional 1 hour then the solid was isolated by suction filtration. The solid was washed with cold 30% water in n-propanol (3 x 50 mL, fully deliquored) and water (3 x 50 mL). The solid (~26 g wet) was placed on the nitrogen press (15 scfh) to dry. After 3 hours, the solid was weighed (22.2 g) and returned to the press for 2 hours. No change in mass was observed. Compound 1.2 (22.2 g; 39%) was isolated as a white crystalline solid. 33% yield based on anisole. 'H NMR (300 MHz, CDCh) δ ppm 7.59 (dd, J= 8.8, 3.3 Hz, 1H), 7.23 (m, 1H), 6.96 (dd, J= 9.1, 4.0 Hz, 1H), 4.78 (s, 2H), 3.95 (s, 3H).

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PCT/US2018/020728 [00155] Example 1.3: Preparation of /V-Isopropyl-2-methyl-2-[5-methyl-2,4dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]propanamide (compound 2.2) [00156] A 250-mL round bottomed flask was charged with acid 2.1 (15.4 g, 45.9 mmol, 1 eq.), HATU (19.2 g, 50.5 mmol, 1.1 eq.), and 2-MeTHF (50 mL, 500 mmol), in sequence, at room temperature. DIEA (20.0 mL, 115 mmol, 2.5 eq.) and isopropylamine (9.80 mL, 115 mmol, 2.5 eq.) were added sequentially in a dropwise manner and the resulting mixture was stirred under ambient conditions. When complete consumption of acid 2.1 was observed by HPLC, the reaction was quenched with IM aqueous HC1 and transferred to a separatory funnel containing 1 M aqueous HC1 and ethyl acetate. The layers were separated and the aqueous phase was extracted with ethyl acetate (2x). The combined organic phases were washed with saturated aqueous sodium bicarbonate, brine, dried with magnesium sulfate, filtered, and concentrated. The crude material was recrystallized from hot acetone to yield amide 2.2 as brown solid (2 crops, 13.7 g, 79%). Ή NMR (400 MHz, DMSO-Je) δ ppm 11.96 (s, 1 H), 8.14 (s, 2 H), 7.33 (d, J= 8.1 Hz, 1 H), 3.75-3.90 (m, 1 H), 2.47 (s, 3 H), 1.61 (s, 6 H), 0.99 (s, 3 H), 0.97 (s, 3 H).

[00157] Example 1.4: Preparation of V-lsopropyl-2-methyl-2-|5-methyl-2.4dioxo-6-(2H-l,2,3-ti'iazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]propanamide (compound 3.1) [00158] A 250-mL round bottomed flask was charged with amide 2.2 (2.76 g, 7.33 mmol, 1.0 eq.), ketone 1.2 (1.78 g, 8.80 mmol, 1.2 eq.), potassium carbonate (2.53 g, 18.3 mmol, 2.5 eq.), sodium bromide (37.7 mg, 0.366 mmol, 5 mol%), and acetonitrile (24.0 mL, 8.7 vol), in sequence, at room temperature. The reaction mixture was heated to 50 °C and the resulting solution was allowed to stir overnight under an ambient atmosphere. After stirring overnight, the reaction did not reach full conversion as determined by HPLC analysis. Additional potassium carbonate (1.01 g, 7.33 mmol) was added and the reaction was continued. Once the reaction mixture contained less than 5% amide 2.2 as judged by HPLC, the reaction was quenched by adding water and the product precipitated from the stirring solution. The heterogeneous solution was vigorously stirred for 1 hour and the precipitate was filtered, washed with water, and dried to give the crude product as a brown solid. The crude material was dissolved in THF (3 mL) and activated carbon (~25 mg) was added. The resulting mixture was stirred overnight under ambient conditions. The mixture was filtered over MAGNESOL, eluting with ethyl acetate. The filtrate was concentrated and the crude material was crystallized from hot hexanes/ethyl acetate to afford ketone 3.1 as a light brown solid (two crops, 2.6 g, 66%). 'H NMR (400 MHz, DMSO-Je) δ ppm 8.13-8.17 (m, 2 H), 7.57 (ddd, J = 92, 7.6, 3.4 Hz, 1 H),

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7.50 (dd, J = 9.1, 3.3 Hz, 1 H), 7.31-7.37 (m, 2 H), 5.33 (s, 2 H), 3.99 (s, 3 H), 3.76-3.87 (m, 1 H), 2.54 (s, 3 H), 1.62 (s, 6 H), 1.00 (s, 3 H), 0.98 (s, 3 H) [00159] Example 1.5: Preparation of 2-{l-[(21?)-2-(5-Fluoro-2-methoxyphenyl)-2hydroxy ethyl] -5-methyl-2,4-dioxo-6-(2H-1,2,3-triazol-2-yl)-1,4-dihydrothieno [2,3d]pyrimidin-3(2H)-yl}-N-sopropyl-2-methylpropanamide (compound 4.1) [00160] A 500-mL round bottom flask was charged with ketone 3.1 (17.1 g, 31.5 mmol, 1 eq.), RuCl[(5,5)-Tsdpen](mesitylene) (196 mg, 0.32 mmol, 1 mol%), sodium formate (10.7 g, 158 mmol, 5.0 eq.), water (15 mL, 0.9 vol), and isopropanol (15 mL, 0.9 vol), in sequence, under ambient conditions. The reaction mixture was heated to 75 °C and reaction progress was monitored by HPLC. After stirring ~3 hours, HPLC analysis indicated complete consumption of ketone 3.1. The flask was cooled to room temperature, transferred to a 2-L round bottom flask, diluted with water (~90 vol), and stirred overnight. The precipitated solid was filtered, washed with water, dried, and collected to afford the crude product. The resulting precipitate was purified by MPLC (Silica Gold (Isco, 120 g HP Silica), 5-40% ethyl acetate in di chloromethane, 85 ml/min, 12.5 column vol.) to give alcohol 4.1 as a white foam (13.5 g, 76%, 92% ee). Further purification can done by crystallizing the material from hot Ze/7-butyl methyl ether and hexanes. 'H NMR (400 MHz, DMSO-όΑ) δ ppm 8.16 (s, 2 H), 7.20-7.31 (m, 2 H), 7.05 (td, J = 8.5, 3.2 Hz, 1 H), 6.93 (dd, J = 9.1, 4.3 Hz, 1 H), 5.82 (d, J = 4.3 Hz, 1 H), 5.29-5.36 (m, 1 H), 3.94-4.06 (m, 1 H), 3.79-3.92 (m, 2 H), 3.71 (s, 3 H), 2.51 (s, 3 H), 1.63 (s, 3 H), 1.63 (s, 3 H), 1.01 (s, 3 H), 0.99 (s, 3 H).

[00161] Example 1.6: Preparation of 2-Methoxyethyl 2-{l-[(21?)-2-(5-fluoro-2methoxyphenyl)-2-hydroxyethyl]-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-2-methylpropanoate (compound 1-074) [00162] Alcohol 4.1 was placed in an amber bottle and dried overnight in a vacuum oven set to 60 °C. The vessel was removed from the vacuum oven, cooled to room temperature, and subsequently used in the following reaction. Later experiments identified that rigorous drying is not essential for reaction success. Lots used within these examples typically contained 0.5% water or less as determined by KF analysis.

[00163] A 20-mL scintillation vial was charged with alcohol 4.1 (218 mg, 0.400 mmol, 1 eq.) and 1,2-dimethoxyethane (650 pL, 3.0 vol) under ambient conditions. It should be noted that increasing the reaction temperature at any point during the course of the reaction leads to greater loss of stereochemical integrity. Whereas decreasing the reaction temperature to 5 °C

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PCT/US2018/020728 led to a marginal improvement in the stereochemical erosion (loss of chiral integrity to -10% ee) and decreasing the reaction temperature to -40 °C led to no observable reaction.

[00164] 2,6 -Lutidine (139 pL, 1.20 mmol, 3.0 eq.) and methanesulfonic anhydride (115 mg, 660 pmol, 1.65 eq.) were added sequentially, each as single charges, under ambient conditions and the reaction was sealed with a screw-top cap that was fitted with a Teflon-lined septum. The resulting reaction mixture was aged 2 hours (at least one hour for this activation period is required for full conversion) at which time 2-methoxyethanol (950 pL, 12.0 mmol, 30 eq.) was added in one portion and the resulting solution was stirred under ambient conditions. After 24 hours, the reaction reached complete starting material consumption as determined by HPLC and MS. The resulting reaction mixture was quenched with IM aqueous HC1 (3 mL, 14 vol) and further diluted with water (-10 mL, 60 vol) which caused the product to precipitate from the solution. The solid was filtered, washed with water, and dried to afford compound I074 as a white solid (223 mg, 91%, 79% ee). Additional purification can be performed by RPMPLC; C18_aq Gold (Isco, 50g HP C18), 50-100% MeCN in water containing 0.1% TFA, 40 ml/min, 12.5 column vol. Ή NMR (400 MHz, DMSO-Je) δ ppm 8.16 (s, 2 H), 7.28 (d, J = 8.1 Hz, 1H), 7.19 (dd, J = 9.2, 3.2 Hz, 1 H), 7.06-7.14(m, 1 H), 6.96 (dd, J = 9.1, 4.3 Hz, 1 H), 5.09 (t, J = 6.4 Hz, 1 H), 4.01 (d, J= 6.1 Hz, 2 H), 3.79-3.90 (m, 1 H), 3.70 (s, 3 H), 3.44-3.53 (m, 1 H), 3.34-3.44 (m, 2 H), 3.26-3.32 (m, 1 H), 3.11 (s, 3 H), 2.50 (s, 3 H), 1.64 (s, 3 H), 1.61 (s, 3 H), 1.02 (d, J = 5.8 Hz, 3 H), 0.99 (d, J = 5.8 Hz, 3 H).

[00165] Example IB: Preparation of Compound V-6-T-F-la (1-400) [00166] R)-2-(l-((R)-2-(5-fluoro-2-methoxyphenyl)-2-hydroxyethyl)-5-methyl-2,4dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-Nisopropylpropanamide (Compound V-6-T-F-la) was generally synthesized according to Scheme 1A.

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Scheme IB: Preparation of Compound V-6-T-F-la (1-400)

IV-6-T-F-1a

[00167] Example 1B.1: Preparation of IV-6-T-F-la [00168] Acetonitrile (230 mL, 4400 mmol) was added to a 2-dram vial containing (2R)-N-isopropyl-2-[5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3d]pyrimidin-3(2H)- yl]propanamide (23.0 g, 63.5 mmol), 2-bromo-l-(5-fluoro-2 methoxyphenyl)ethanone (19 g, 76 mmol), and potassium carbonate (26 g, 190 mmol). The mixture was allowed to stir with a magnetic bar at 50°C overnight. After 12 hours HPLC indicated 100% conversion to the desired product [Formula IV-6-T-F-la at R=4.067). The mixture was diluted with water (-600 mL). The mixture was stirred for 30 min and solid that formed was isolated by filtration. The solid was dried via suction and high vac providing (2R)-2 {l-[2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl]-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)- l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-N-isopropylpropanamide (28.7 g; Yield = 85.6%; The product was isolated as an off-white solid. The NMR spectra was consistent with the desired structure.

[00169] Example 1B.2: Preparation of V-6-T-F-la (1-400) [00170] To a stirring solution of (2R)-2-[l-[2-(5-fluoro-2-methoxyphenyl)-2oxoethyl]-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin3(2H)-yl}-N-isopropylpropanamide (0.20 g, 0.38 mmol) in THF (0.76 ml) at ambient temperature was added triethylamine (1.05 mL, 7.57 mmol). The catalyst RuCl[(S,S)Tsdpen](mesitylene) (2.35 mg, 0.00378 mmol) was added to the stirring solution, followed by

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PCT/US2018/020728 the dropwise addition of formic acid (0.285 mL, 7.57 mmol). The reaction was stirred at ambient temperature and reaction progress was monitored by HPLC. After 12 h complete starting material consumption was observed. Water was added to cause to product to precipitate from the solution. The solid was filtered, washed with water, dried, and collected to afford the crude product. The resulting precipitate was dissolved in ethyl acetate, treated with sodium sulfate and DARCO and filtered through magnesol, eluting with ethyl acetate and followed with washing with DCM. After solvents evaporation the desired product, (2R)-2-{l-[(2R)-2-(5-fluoro-2methoxyphenyl)-2-hydroxyethyl]-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4dihydrothienof 2,3-d]pyrimidin-3(2H)-yl}-N-isopropylpropanamide, 1-400, was obtained as a white solid (0.10 g; Yield = 51%) . The chiral purity as determined by chiral HPLC was 98.3 to 99.3%ee. The NMR spectra was consistent with the desired structure.

[00171] Example 2: Description of the synthesis of compound 1-095 [00172] 2-{l-[(27?)-2-(2-Cyanoethoxy)-2-(5-fluoro-2-methoxyphenyl)ethyl]-5methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-Nisopropyl-2-methylpropanamide (compound 1-095) was generally synthesized according to Scheme 3 below. Reactions were monitored by analytical HPLC or 400 MHz ¹H NMR in CDCI3.

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Scheme 3: Synthetic scheme for the preparation of compound 1-095 ci

1-095

catalyst:

RuCI[(S,S)-Tsdpen] (mesitylene) [00173] Example 2.2: Preparation of te/7-Butyl 2-{l-[(21?)-2-(2-cyanoethoxy)-2-(5fluor o-2-methoxyphenyl)ethyl] -5-methyl-2,4-dioxo-6-(2H-1,2,3-tr iazol-2-yl)-1,4dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-2-methylpropanoate (compound 24) [00174] 43% Aqueous potassium hydroxide (21 pL, 23 μιηοΐ, 26 mol%) was added to a stirring 0 °C solution of tert-butyl 2-{l-[(27?)-2-(5-fluoro-2-methoxyphenyl)-2-hydroxyethyl]5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-2methylpropanoate (compound 23, 50 mg, 89 μιηοΐ) (HPLC retention time = 4.870 min) and 2propenenitrile (600 μΙ., 9.13 mmol, 5 eq.) in acetonitrile (5 mL). The mixture was allowed to stir for 1.5 hours. HPLC indicated 97% conversion to the ether 24 (retention time = 4.978 min) with a small amount starting alcohol 23 remaining (3%). The mixture was allowed to stir an additional hour at 0 °C. HPLC indicated similar conversion so the reaction was quenched with water (10 mL) at 0 °C. The mixture was allowed to stir 30 min. The solid that formed was isolated by filtration and dried at under ambient conditions overnight to give compound 24 (50 mg; 91%) as a tan solid. HPLC indicated 95% purity. 'H NMR (300 MHz, DMSO-όΑ) δ ppm

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8.16 (s, 2H), 7.16 (m, 2H), 7.00 (m, 1H), 5.16 (t, J= 6.1 Hz, 1H), 4.08 (m, 2H), 3.72 (s, 3H), 3.51 (m, 2H), 2.69 (t, J = 5.7 Hz, 2H), 2.53 (s, 3H), 1.59 (s, 3H), 1.63 (s, 3H), 1.38 (s, 9 H).

[00175] Example 2.3: Preparation of 2-{l-[(21?)-2-(2-Cyanoethoxy)-2-(5-fluoro-2methoxyphenyl)ethyl]-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3d]pyrimidin-3(2H)-yl}-2-methylpropanoic acid (compound 25) [00176] Formic acid (3.0 mL, 80 mmol, 5 vol) was added to a 2 dram vial containing a mixture of compound 24 (0.580 g, 0.947 mmol) and ethanol (3.0 mL, 51 mmol, 5 vol) . The mixture was allowed to stir in an 80 °C heating block overnight. HPLC after 18 hours indicated 96% conversion. After an additional 6 hours, conversion reached 99%. The mixture was concentrated to half the original volume, diluted with water (5 mL), and allowed to stir overnight. The light tan solid that formed was isolated by filtration and washed with water to give compound 25 (465 mg; 88%) as a tan solid. 'H NMR (300 MHz, DMSO-όΑ) δ ppm 12.38 (br. s., 1H), 8.17 (m, 2H), 7.16 (m, 2H), 6.99 (m, 1H), 5.15 (t, J= 6.2 Hz, 1H), 4.08 (m, 2H),

3.72 (s, 3H), 3.52 (m, 2H), 2.69 (t, J= 5.9 Hz, 2H), 2.52 (br. s., 3H), 1.64 (d, J= 3.8 Hz, 6 H).

[00177] Example 2.4: Preparation of 2-{l-[(21?)-2-(2-Cyanoethoxy)-2-(5-fluoro-2methoxyphenyl)ethyl]-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3d]pyrimidin-3(2H)-yl}-N-isopropyl-2-methylpropanamide (compound 1-095) [00178] Compound 24 (252 mg, 0.45 mmol) (HPLC retention time = 3.913 min) and HATU (207 mg, 0.54 mmol, 1.2 eq.) were added to a 1 dram vial, followed by methylene chloride (0.76 mL) and 2-propanamine (116 μΕ, 1.35 mmol, 3 eq.). The mixture was allowed to stir at room temperature overnight. The reaction turned very dark upon addition of the amine. HPLC after 18 hours indicated -95% conversion. The mixture was allowed to stir for 4 hours. HPLC indicated complete conversion. The mixture was diluted with ethyl acetate (30 mL) and washed with water, IN aqueous HC1, water, saturated sodium bicarbonate, and brine (10 mL each). The organic layer was then dried with sodium sulfate, filtered and concentrated in vacuo. The mixture was loaded onto diatomaceous earth with di chloromethane and dried via suction. The material was purified by reverse phase MPLC (C18_aq Gold (Isco, 50g HP Cl8), 35-100% MeCN in water containing 0.1% TFA, 40 ml/min, 13 column vol.). The purest fractions containing the product were combined and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with saturated sodium bicarbonate and brine (20 mL each). The organic layer was then dried with sodium sulfate, filtered, and concentrated in vacuo. The pure product was dissolved in a small amount of methanol and concentrated to remove residual solvent. The material was placed under high vacuum overnight. Compound 1-095 (160

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PCT/US2018/020728 mg, 59%) was isolated as a white amorphous solid. HPLC gave very high purity and chiral HPLC showed 98.6% ee for the R enantiomer. 'H NMR (300 MHz, DMSO-όΑ) δ ppm 8.15 (s, 2H), 7.24 (dd, J= 9.2, 3.1 Hz, 1H), 7.13 (m, 2H), 6.99 (m, 1H), 5.15 (t, J= 6.4 Hz, 1H), 4.04 (d, J= 6.3 Hz, 2H), 3.85 (m, 1H), 3.72 (s, 3H), 3.52 (m, 2H), 2.69 (t, J= 5.8 Hz, 2H), 2.51 (s, 3H), 1.63 (d, J= 8.9 Hz, 6 H), 1.00 (d, J =4.8 Hz, 3H), 1.02 (d, J =4.8 Hz, 3H).

[00179] Example 3: Description of Synthesis of Compound 1-181 [00180] Ethyl l-[(2R)-2-(2-cyanoethoxy)-2-(5-fluoro-2-methoxyphenyl)ethyl]-3-[2(isopropylamino)-l,l-dimethyl-2-oxoethyl]-5-methyl-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3d]pyrimidine-6-carboxylate (compound 1-181) was generally synthesized according to Scheme 4 below. Reactions were monitored by analytical HPLC or 400 MHz 'H NMR in CDCh.

[00181] Analytical HPLC conditions used an AGILENT 1100 HPLC, AGILENT ZORBAX XDB C18 50 x 4.6 mm, 1.8 micron column. Solvent A: water (0.1% TFA); Solvent B: acetonitrile (0.07% TFA); Gradient: 5 min., 95% A to 90% B, 1 min. hold, then recycle to 95% A; UV detection at 214 and 254 nm. The reported percent area was determined at 214 nm.

[00182] Chiral determination was performed on intermediates on a CHIRALCEL IA3 column, with conditions at 2-12% IPA/hexanes, 30 min., 1.0 mL/min, 30 °C column temperature, detection at 220 nm.

[00183] Chiral determination was performed on the final product 1-181 on a (R,R)Whelk-01 column with conditions at 5-75% EtOH/hexanes, 30 min., 1.0 mL/min, 30° C column temperature, detection at 220 nm.

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Scheme 4: Synthetic scheme for the preparation of compound 1-181

[00184] Example 3.2: Preparation of Diethyl 5-{[(2-tert-butoxy-l,l-dimethyl-2oxoethyl)carbamoyl]amino}-3-methylthiophene-2,4-dicarboxylate (compound 3) [00185] A stirred heterogeneous mixture of diethyl 5-amino-3-methylthiophene-2,4dicarboxylate (compound 2, 9.00 g, 35.0 mmol) in dry acetonitrile (45 mL) under nitrogen was treated with CDI (7.09 g, 43.7 mmol) followed by triethylamine (24.4 mL, 175 mmol). The mixture was heated to 50 °C. The resulting homogenous mixture was stirred at 50 °C for 4 hours, at which point HPLC indicated complete conversion to the acyl imidazole intermediate. HPLC was performed on aliquots of the mixture quenched with morpholine. ieri-Butyl 2methylalaninate hydrochloride (8.56 g, 43.7 mmol) was added to form a slightly heterogeneous mixture. The mixture was stirred at 50 °C for 1.5 hours. Stirring was continued overnight at room temperature. The mixture was diluted with water (100 mL), and the resulting solids were filtered, washed with water (6x30 mL), and dried in a vacuum oven at 40 °C over the weekend to give compound 3 (15.55 g, 100%) as a white solid. HPLC indicated a purity of greater than 99% (5.44 min retention time). Ή NMR (300 MHz, DMSO-lA) δ ppm 10.60 (s, 1H), 8.41 (s, 1H), 4.33 (q, J = 6.9 Hz, 2H), 4.22 (q, J = 6.9 Hz, 2H), 2.66 (s, 3H), 1.37 (s, 9H), 1.38-1.24 (m, 12H).

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PCT/US2018/020728 [00186] Example 3.3: Preparation of Ethyl 3-(2-ZerZ-butoxy-l,l-dimethyl-2oxoethyl)-5-methyl-2,4-dioxo-l,2,3,4-tetrahydrothieno[2,3-d]-pyrimidine-6-carboxylate (compound 4) [00187] A stirred heterogeneous mixture of compound 3 (12.00 g, 27.12 mmol) in dry acetonitrile (120 mL) under nitrogen was treated with potassium ZerZ-butoxide (6.08 g, 54.2 mmol). The tan, nearly homogeneous mixture was stirred at room temperature. Within minutes, the mixture became cloudy. HPLC after a reaction time of 12 minutes showed -2% of compound 3 remaining, with 80% of compound 4 and -8% acid by-product resulting from ethyl ester hydrolysis of compound 4. After 20 minutes of reacting, the reaction was quenched quickly with 0.05 M aqueous citric acid (-550 mL, -27 mmol). The mixture cleared during this addition, and the product precipitated out to give a thick slurry. The mixture was stirred for 8-10 minutes, and the solids were filtered, washed with water (5 x 120 mL) and dried in a vacuum oven at 45 °C over the weekend to give compound 4 (8.75 g, 77%) as a white solid. HPLC indicated a purity of 94.1% (4.75 min retention time). ¹H NMR (300 MHz, DMSO-ά) δ ppm 12.38 (s, 1H), 4.26 (q, J =6.9 Hz, 2H), 2.70 (s, 3H), 1.63 (s, 6H), 1.36 (s, 9H), 1.28 (t, J =6.9 Hz, 3H).

[00188] Example 3.4: Preparation of Ethyl 3-(2-ZerZ-butoxy-l,l-dimethyl-2oxoethyl)-l-[2-(5-fluoro-2-methoxyphenyl)-2-oxoethyl]-5-methyl-2,4-dioxo-l,2,3,4tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (compound 5) [00189] A thick, stirring slurry of compound 4 (2.00 g, 5.04 mmol) in dry acetonitrile (36 mL) under nitrogen was treated sequentially with 2-chloro-l-(5-fluoro-2methoxyphenyl)ethanone (compound 1, 1.23 g, 6.05 mmol), NaBr (52 mg, 0.50 mmol) and K2CO3 (1.74 g, 12.6 mmol) while being warmed to 60 °C. During heating, it was necessary to keep the reaction stirred. The resulting pale yellow, heterogeneous mixture was stirred at 60 °C overnight and monitored by HPLC for consumption of compound 4. At 24 hours, the mixture was cooled to room temperature, diluted with water (40 mL) and extracted with EtOAc (50 mL + 25 mL). The combined organic phase was washed with water (25 mL) and brine (15 mL), dried over MgSCU, and concentrated and dried under vacuum to give the crude product. The crude product was then triturated with EtOH (12 mL) with sonication and filtered. The solids were washed with EtOH (4x3 mL) and dried in a vacuum oven at 40 °C over the weekend to give compound 5 (2.51 g, 88%) as a faint yellow solid. HPLC indicated a purity of 98.5% (5.87 min r.t.). Ή NMR (300 MHz, DMSO-<A) δ ppm 7.58 (m, 1H), 7.50 (dd, J = 9.0, 3.3 Hz, 1H), 7.35 (dd, J= 9,0, 3.9 Hz, 1H), 5.35 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.99 (s, 3H), 2.75 (s, 3H),

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1.63 (s, 6H), 1.35 (s, 9H), 1.26 (t, J = 7.2 Hz, 3H).

[00190] Example 3.5: Preparation of Ethyl 3-(2-tert-butoxy-l,l-dimethyl-2oxoethyl)-l-[(2R)-2-(5-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-5-methyl-2,4-dioxo1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate (compound 6) [00191] A thick, stirred slurry of compound 5 (5.40 g, 9.60 mmol) in isopropyl alcohol/water (1:1, 22 mL) under nitrogen was warmed to 50 °C and treated with sodium formate (3.26 g, 48.0 mmol) and RuCl[(S,S)-Tsdpen](mesitylene) (60.0 mg, 0.0964 mmol). The resulting mixture was heated to 75 °C, at which point most solids had dissolved. The mixture was stirred vigorously for 2 hours, at which point HPLC indicated complete reaction. The mixture was cooled to room temperature, added portion-wise to water (-150 mL), and stirred for 15 minutes. The resulting solids (some tacky material also formed) were isolated by filtration, rinsing in and washing with -5% acetonitrile/water (2 x 50 mL). The filtration became sluggish, and a significant amount of tacky residue settled out. Because of the tacky residue, it may be necessary to do an aqueous workup and then flush through a pad of MAGNESOL. The solids were dried in the vacuum oven at 40 °C overnight to give compound 6 (5.24 g, 97%) as a light brown foam. A portion of this solid (2.41 g) was taken up in a minimum of di chloromethane and flushed through a pad of MAGNESOL (7.5 g) using di chloromethane (-75 mL) as eluent. The filtrate was concentrated and dried under high vacuum to give a quantitative recovery of the product as a beige foam (dark impurities removed). HPLC indicated a purity of 98.9% (5.59 min retention time). Chiral HPLC, 96.3% ee. 'H NMR (300 MHz, DMS0-<7) δ ppm 7.24 (dd, 7=9.3, 3.0 Hz, 1H), 7.07 (m, 1H), 6.92 (dd, J = 9.3, 4.5 Hz, 1H), 5.84 (d, J =4.5 Hz, 1H), 5.30 (m, 1H), 4.28 (m, 2H), 3.98 (m, 2H), 3.69 (s, 3H), 2.72 (s, 3H), 1.60 (s, 3H), 1.58 (s, 3H), 1.37 (s, 9H), 1.30 (t, 7= 7 Hz, 3H).

[00192] Example 3.6: Preparation of Ethyl 3-(2-tert-butoxy-l,l-dimethyl-2oxoethyl)-l-[(2R)-2-(2-cyanoethoxy)-2-(5-fluoro-2-methoxy-phenyl)ethyl]-5-methyl-2,4dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (compound 7) [00193] A stirred mixture of compound 6 (2.77 g, 4.90 mmol) in acetonitrile (28 mL) under nitrogen was cooled to 0-5 °C and treated with acrylonitrile (1.61 mL, 24.5 mmol) followed by 40% aqueous KOH (150 pL, 1.5 mmol). The resulting mixture was stirred at 0-5 °C and monitored by HPLC for consumption of compound 6. At 3 hours, the mixture was diluted dropwise with water (80 mL) and extracted with EtOAc (80 mL). The organic phase was washed with water (50 mL) and brine (25 mL), dried over MgSO4, and concentrated and dried

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PCT/US2018/020728 under vacuum. The crude product [3.01 g light brown foam at 93.8% HPLC purity, 93% yield] was combined with a similar batch of product and purified by silica gel chromatography (40 g cartridge, 10-30% EtOAc/hexanes eluent) to give 86% (avg. combined yield) of compound 7 as a white foam. Silica gel chromatography was used to afford an upgrade in purity at this step since initial attempts to triturate or crystallize had failed in the chiral series. HPLC indicated a purity of 96.4% (5.67 min retention time). Chiral HPLC, 96.8% ee. 'H NMR (300 MHz, DMSO-Je) δ ppm 7.20 (dd, J = 9.3, 3.0 Hz, 1H), 7.14 (m, 1H), 7.00 (dd, J = 9.0, 4.2 Hz, 1H), 5.15 (m, 1H), 4.28 (m, 2H), 4.23 (m, 1H), 4.00 (m, 1H), 3.71 (s, 3H), 3.50 (m, 2H), 2.71 (s, 3H), 2.68 (m, 2H), 1.60 (s, 3H), 1.57 (s, 3H), 1.37 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H).

[00194] Example 3.7: Preparation of 2-{l-[(2R)-2-(2-Cyanoethoxy)-2-(5-fluoro-2methoxyphenyl)ethyl]-6-(ethoxycarbonyl)-5-methyl-2,4-dioxo-2,4-dihydrothieno[2,3d]pyrimidin-3(2H)-yl}-2-methylpropanoic acid (compound 8) [00195] Compound 8 was prepared as described below, through methods using either formic acid (Example 3.7a) or sulfuric acid (Example 3.7b).

[00196] Example 3.7a: Preparation of compound 8 using formic acid [00197] A stirred mixture of compound 7 (4.87 g, 7.88 mmol) in EtOH (24 mL) under nitrogen was treated with formic acid (24 mL), and the mixture was heated to gentle reflux (78-80 °C) and monitored by HPLC for consumption of compound 7. At 48 hours, the mixture was cooled to room temperature and stirred overnight to allow the product to precipitate out. The resulting solids were isolated by filtration, rinsing in with water (3x15 mL) and washing with water (4 x 20 mL), and dried in the vacuum oven at 45 °C overnight to give compound 8 (3.33 g, 75%) as a white solid. HPLC indicated a purity of 98.1% (4.49 min retention time). The filtrate was extracted with EtOAc (50 mL), and the organic phase was washed with water (25 mL) and brine (20 mL), dried over MgSCU and concentrated and dried under vacuum to give additional crude product (77% HPLC purity). These solids were slurried in isopropyl alcohol (9.5 mL, 10 V) for 1 hour, filtered, washed with isopropyl alcohol (4x1 mL), and dried in a vacuum oven at 45 °C overnight to give additional compound 8 (655 mg, 14%) as a white solid. HPLC, 93.2% purity (4.48 min retention time).

[00198] Example 3.7b: Preparation of compound 8 using sulfuric acid [00199] A stirred mixture of compound 7 (199 mg, 0.322 mmol) in isopropyl alcohol (1 mL) in a small vial was treated with 9 M sulfuric acid (1 mL) dropwise. The resulting thick,

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PCT/US2018/020728 white slurry was stirred at room temperature and monitored for consumption of compound 7. Additional isopropyl alcohol (0.5 mL) and concentrated H2SO4 (2-3 drops) were added to thin out the slurry and push the reaction to completion. At 44 hours, the reaction mixture was added dropwise to water (8 mL), rinsing in with additional water (4 mL), and the slurry was stirred for several minutes. The solids were isolated by filtration, washed with water (4x3 mL) and dried in a vacuum oven at 45 °C overnight to give compound 8 (165 mg, 91%) as a white solid. HPLC indicated a purity of 97.3% (4.47 min retention time). 'H NMR (300 MHz, DMSO-A) δ ppm 12.39 (s, 1H), 7.20 (dd, J = 9.3, 3.0 Hz, 1H), 7.14 (td, J = 8.4, 3.0 Hz, 1H), 6.99 (dd, J = 9.0, 4.2 Hz, 1H), 5.14 (m, 1H), 4.28 (m, 2H), 4.18 (m, 1H), 3.97 (m, 1H), 3.72 (s, 3H), 3.50 (m, 2H), 2.70 (s, 3H), 2.68 (m, 2H), 1.63 (s, 3H), 1.62 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[00200] Example 3.8: Preparation of Ethyl l-[(2R)-2-(2-cyanoethoxy)-2-(5-fluoro2-methoxyphenyl)ethyl]-3-[2-(isopropylamino)-l,l-dimethyl-2-oxoethyl]-5-methyl-2,4dioxo-l,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-6-carboxylate (1-181) [00201] Compound 1-181 was prepared with methods using acid chloride (Example 3.8a) and propylphosphonic anhydride (Example 3.8b).

[00202] Example 3.8a: Preparation of Compound 1-181 using acid chloride [00203] A flame-dried flask was charged compound 8 (225 mg, 0.401 mmol) and dry dichloromethane (2.2 mL) under nitrogen, and the stirred white slurry was treated with oxalyl chloride (35.6 pL, 0.421 mmol) dropwise followed by catalytic DMF (6.2 pL, 0.080 mmol). Gas evolution occurred, the mixture thinned initially, and then a white precipitate began forming. The resulting slurry was stirred vigorously at room temperature for 2 hours, at which point HPLC (aliquot quenched into MeOH to form the methyl ester) indicated <5% compound 8 remaining. The mixture was treated with isopropylamine (171 pL, 2.00 mmol) quickly via syringe below the solvent line to give a homogeneous mixture. The flask was sealed, and the mixture was allowed to stir at room temperature overnight, although HPLC indicated nearly complete reaction at 15 minutes. The reaction was diluted with di chloromethane (20 mL), washed with water (2x15 mL) and brine (10 mL), dried over Na2SC>4, and concentrated and dried under vacuum. The crude product was purified by silica gel chromatography (40 g cartridge, 35-55% EtOAc/hexanes eluent) and the product fractions were pooled, concentrated and stripped down from MeOH several times to give compound 1-181 (226 mg, 94%) as a white solid. HPLC indicated a purity of 99.7% (4.76 min retention time). Chiral HPLC, >99% ee.

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PCT/US2018/020728 [00204] Example 3.8b: Preparation of Compound 1-181 using propylphosphonic anhydride [00205] A stirred slurry of compound 8 (100 mg, 0.178 mmol) in dry dichloromethane (1.0 mL) under nitrogen was treated with triethylamine (74.4 pL, 0.534 mmol) dropwise. Once the mixture had cleared, isopropylamine (75.8 pL, 0.890 mmol) and propylphosphonic anhydride (50% in EtOAc, 159 pL, 0.267 mmol) were added dropwise (created a slight exotherm), and the resulting mixture was stirred at room temperature. HPLC indicated -88% conversion at 15 minutes, but little change overnight. At 18 hours, additional isopropylamine (15 pL, 1 eq.) and propylphosphonic anhydride (53 pL, 0.5 eq.) were added, and the mixture was stirred for 1.5 hours, diluted with di chloromethane (15 mL), washed with water (2x10 mL) and brine (5 mL), dried over Na2SO4, and concentrated and dried under vacuum. Purification by radial chromatography (2000 micron silica gel rotor, 60% EtOAc/hexanes eluent) gave compound 1-181 (108 mg, 100%) as a white film. HPLC indicated a purity of 99.7% (4.75 min retention time). Chiral HPLC, >99% ee. Ή NMR (400 MHz, DMSO-tL) δ ppm 7.20 (dd, J = 9.2, 3.2 Hz, 1H), 7.15 (m, 2H), 6.99 (dd, J = 9.2, 4.4 Hz, 1H), 5.13 (m, 1H), 4.28 (m, 2H), 4.10 (m, 1H), 4.00 (m, 1H), 3.83 (m, 1H), 3.71 (s, 3H), 3.53 (m, 1H), 3.46 (m, 1H), 2.70 (s, 3H), 2.68 (m, 2H), 1.62 (s, 3H), 1.60 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 6.2 Hz, 6H).

[00206] Example 3.9: Two-Step Preparation of 2-chloro-l-(5-fluoro-2methoxyphenyl)ethanone (compound 1) [00207] Compound 1 in Scheme 4 was generally prepared in a two-step procedure according to Scheme 5 below.

Scheme 5: Synthetic scheme for the preparation of Compound 1 of Scheme 4

OMe

F

1.2 eq AICI₃

1.4 eq AcCI

DCM, 0-5 °C (89%)

OMe O

F

OH O

F

SO2CI2

DCM (80%)

OMe O

F [00208] Step 1. A 125-mL three-necked jacketed reaction flask fitted with a temperature probe and nitrogen balloon was charged with aluminum chloride (12.7 g, 95.1 mmol) and di chloromethane (50 mL). This mixture was cooled to 1-2 °C and 4-fluoroanisole (compound 9, 8.98 mL, 79.3 mmol) was added slowly over a period of 30 minutes to maintain the temperature below 5 °C. After the mixture had re-cooled to 1-2 °C, neat acetyl chloride (7.89 mL, 111 mmol) was added dropwise over a period of 30 minutes, maintaining the temperature below 5 °C. The reaction was then allowed to stir at 1-2 °C for 18 hours.

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PCT/US2018/020728 [00209] A 1-L three-necked round bottom flask fitted with a temperature probe and mechanical stirrer was charged with sodium hydroxide (20.2 g, 504 mmol) and water (200 mL) followed by the slow addition of acetic acid (28.7 mL, 504 mmol) while cooling in an ice bath. The homogeneous Friedel-Crafts mixture was diluted with di chloromethane (25 mL) and slowly added dropwise via cannula to this cold (0-5 °C) solution of sodium acetate at a rate that maintained the temperature below 8 °C. Di chloromethane (100 mL) was added after the addition was complete and the mixture allowed to warm to room temperature and stirred for 60 minutes. This solution was transferred to an addition funnel, the layers were separated and the aqueous layer was extracted with di chloromethane (2 x 100 mL). The organics were combined, washed with INNaOH (3 x 75 mL), dried with anhydrous sodium sulfate and concentrated. This provided 11,9g (89% yield, 96 area%) of compound 10 as an oil. Ή NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 3.92 (s, 3 H) 6.94 (dd, 7=9.09, 4.04 Hz, 1 H) 7.18 (ddd, 7=9.09, 7.33, 3.28 Hz, 1 H) 7.48 (dd, 7=8.97, 3.16 Hz, 1 H); HPLC Retention Time: 3.39 min; MS (ESI+) for C9H9FO2 m/z 169.1 (M+H)⁺.

[00210] Step 2. A 100-mL three-necked round bottom flask fitted with a pressure equalized addition funnel, temperature probe and a nitrogen balloon was charged with compound lOScheme 5 (11.9 g, 70.8 mmol), methanol (11 mL), and di chloromethane (36 mL). This solution was cooled in an ice bath to ~5 °C and a solution of sulfuryl chloride (8.0 mL, 99 mmol) in dichloromethane (14 mL) was added dropwise at a rate to keep the reaction temperature below 15 °C. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature over 1 hour. This mixture was cooled at 0-5 °C and a solution of water (12 mL) and ethanol (47.6 mL) was added dropwise over a period of 20 minutes. This material was transferred to a 500-mL flask and concentrated in vacuo until the di chloromethane was removed resulting in a slurry containing a white precipitate. This solid was collected and washed with 75% ethanol/ water (2 x 20 mL) and water (2 x 20 mL). The material was dried on a nitrogen press to provide 11.6g (80% yield, 98 area%) of compound 1 as a white solid. Ή NMR (400 MHz, CDCh) δ ppm 3.96 (s, 3 H) 4.80 (s, 2 H) 6.98 (dd, 7=9.09, 4.04 Hz, 1 H) 7.17 - 7.32 (m, 1 H) 7.62 (dd, 7=8.84, 3.28 Hz, 1 H); HPLC Retention Time: 3.73 min. MS (ESI+) for CgHsClFCh m/z 203.0 (M+H)⁺.

[00211] Example 3.10: Three-Step Preparation of 2-chloro-l-(5-fluoro-2methoxyphenyl)ethanone (compound 1) [00212] Compound 1 in Scheme 4 was generally prepared in a three-step procedure according to Scheme 6 below.

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Scheme 6: Synthetic scheme for the preparation of Compound 1 of Scheme 4

DMS, K₂CO₃

OMe

F

1.2 eq AICI₃

1.4 eq AcCI

DCM, 0-5 °C acetone, Δ (98%)

OMe O OH O

F F

SO2CI2

DCM (89%)

OMe O

F (97%) [00213] Step 1. A 125-mL three-necked jacketed reaction flask fitted with a temperature probe and nitrogen balloon was charged with aluminum chloride (12.7 g, 95.1 mmol) and di chloromethane (50 mL). This mixture was cooled to 1-2 °C and 4-fluoroanisole (compound 9, 8.98 mL, 79.3 mmol) was added slowly over a period of 30 minutes to maintain the temperature below 5 °C. After the mixture had re-cooled to 1-2 °C, neat acetyl chloride (7.89 mL, 111 mmol) was added dropwise over a period of 30 minutes, maintaining the temperature below 5 °C. The reaction was then allowed to stir at 1-2 °C for 18 hours.

[00214] A 1-L three-necked round bottom flask fitted with a temperature probe and mechanical stirrer was charged with sodium hydroxide (20.2 g, 504 mmol) and water (200 mL) followed by the slow addition of acetic acid (28.7 mL, 504 mmol) while cooling in an ice bath. The homogeneous Friedel-Crafts mixture was diluted with di chloromethane (25 mL) and slowly added dropwise via cannula to this cold (0-5 °C) solution of sodium acetate at a rate that maintained the temperature below 8 °C. Di chloromethane (lOOmL) was added after the addition was complete and the mixture allowed to warm to room temperature and stirred for 60 minutes. This solution was transferred to an addition funnel, the layers were separated, and the aqueous layer was extracted with di chloromethane (2 x 100 mL). The organics were combined, dried with anhydrous sodium sulfate, and concentrated. This provided 13.0 g (97% yield, 98 area%) of a 4.1:1 mixture of 1-(5-fluoro-2-methoxyphenyl)ethanone (compound 10) and l-(5-fluoro-2hydroxyphenyl)ethanone (compound 11) as an oil.

[00215] Compound 10: Ή NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 3.92 (s, 3 H) 6.94 (dd, 7=9.09, 4.04 Hz, 1 H) 7.18 (ddd, 7=9.09, 7.33, 3.28 Hz, 1 H) 7.48 (dd, 7=8.97, 3.16 Hz, 1 H); HPLC Retention Time: 3.39 min; MS (ESI+) for CgHgFChm/z 169.1 (M+H)⁺.

[00216] Compound 11: Ή NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 6.98 (dd, 7=9.09, 4.55 Hz, 1 H) 7.17 - 7.30 (m, 1 H) 7.42 (dd, 7=8.84, 3.03 Hz, 1 H) 12.00 (s, 1 H); HPLC Retention Time: 3.37 min; MS (ESI+) for CsHvFChm/z 153.0 (M+H)⁺.

[00217] Step 2. The 4.1:1 mixture of compound 10(10.4 g, 61.8 mmol) and compound 11 (2.54 g, 16.5 mmol ) was dissolved in acetone (50 mL) and potassium carbonate (2.50 g, 18.1 mmol) and dimethyl sulfate (0.25 mL, 2.6 mmol) were added. The reaction was refluxed for 18 hours, cooled to room temperature, and water (20 mL) added. This mixture was 125

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PCT/US2018/020728 stirred at room temperature for 3 hours and partitioned between di chloromethane and brine (50 mL each). The layers were separated and the aqueous layer was extracted with dichloromethane (3 x 50 mL). The organics were combined, dried with anhydrous sodium sulfate, and concentrated. This provided 13.0 g (98% yield, 97 area%) of compound 10 as a yellow oil. Ή NMR (400 MHz, CDCh) δ ppm 2.64 (s, 3 H) 3.92 (s, 3 H) 6.94 (dd, 7=9.09, 4.04 Hz, 1 H) 7.18 (ddd, 7=9.09, 7.33, 3.28 Hz, 1 H) 7.48 (dd, 7=8.97, 3.16 Hz, 1 H); HPLC Retention Time: 3.39 min; MS (ESI+) for C9H9FO2 m/z 169.1 (M+H)⁺.

[00218] Step 3. A 100-mL three-necked round bottom flask fitted with a pressure equalized addition funnel, temperature probe and a nitrogen balloon was charged with compound 10 (13.0 g, 77.3 mmol) , methanol (12 mL), and di chloromethane (40 mL). This solution was cooled in an ice bath to 5 °C and a solution of sulfuryl chloride (8.8 mL, 110 mmol) in di chloromethane (16 mL) was added dropwise at a rate to keep the reaction temperature below 10 °C. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was cooled at 0-5 °C and a mixture of water (13 mL) and ethanol (52.0 mL) was added dropwise over a period of 20 minutes. This material was transferred to a 500-mL flask and concentrated in vacuo until the dichloromethane was removed resulting in a slurry containing a white precipitate. This solid was collected, washed with 75% ethanol/water (2 x 20 mL) and water (2 x 20 mL). The material was dried on a nitrogen press to provide 14.0 g (89% yield, 99 area%) of compound 1 as a white solid. 'H NMR (400 MHz, CDCh) δ ppm 3.96 (s, 3 H) 4.80 (s, 2 H) 6.98 (dd, 7=9.09, 4.04 Hz, 1 H) 7.17 - 7.32 (m, 1 H) 7.62 (dd, 7=8.84, 3.28 Hz, 1 H); HPLC Retention Time: 3.73 min. MS (ESI+) for CgHsClFCh m/z 203.0 (M+H)⁺.

[00219] Example 4: Description of Synthesis of Compound 1-191 [00220] 2-{l-[(2R)-2-(2-Cyanoethoxy)-2-(5-fluoro-2-methoxyphenyl)ethyl]-5methyl-2,4-dioxo-6-(lH-pyrazol-l-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-Nisopropyl-2-methylpropanamide (compound 1-191) was generally synthesized according to Scheme 7 below. Reactions were monitored by analytical HPLC or 400 MHz ¹H NMR in CDCh.

[00221] Analytical HPLC conditions used an AGILENT 1100 HPLC, AGILENT ZORBAX XDB C18 50 x 4.6 mm, 1.8 micron column. Solvent A: water (0.1% TFA); Solvent B: acetonitrile (0.07% TFA); gradient: 5 min., 100% A to 100% B, 1 min. hold, then recycle; UV detection at 210 and 254 nm. The reported percent area was determined at 210 nm.

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PCT/US2018/020728 [00222] Chiral determination was performed for intermediates on a CHIRALCEL IA3 column, with conditions at 5-75% IPA/hexanes, 30 min., 1.0 mL/min, 30 °C column temperature, detection at 220 nm. The R/S ratio was 97:3 [00223] Chiral determination was performed for the final product 1-191 on a (R,R)Whelk-01 column with conditions at 5-75% EtOH/hexanes, 30 min., 1.0 mL/min, 30° C column temperature, detection at 220 nm. The R/S ratio was 97.5:2.5.

Scheme 7: Synthetic scheme for the preparation of compound 1-191

o

MeQ^ 1 _r

K₂CO₃, cat. NaBr

MeCN (92%)

40% KOH/H₂O

MeCN, 0°C (96%)

KXN Sample NC1233, 95%ee

Reference NC1233, 97%ee [00224] Example 4.2: Preparation of 2-{[(2-tert-Butoxy-l,l-dimethyl-2oxoethyl)carbamoyl]amino}-4-methyl-5-(lH-pyrazol-l-yl)thiophene-3-carboxylate (compound 13) [00225] To a well-stirred slurry of ethyl 2-amino-4-methyl-5-(lH-pyrazol-lyl)thiophene-3-carboxylate (compound 12, 1.0 g, 4.0 mmol) and CDI (0.806 g, 4.97 mmol) in dry acetonitrile (5.0 mL) under nitrogen was added triethylamine (2.77 mL, 19.9 mmol) via

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PCT/US2018/020728 syringe. The reaction was then heated at 50 °C for 3 hours. Solid tert-butyl 2-methylalaninate hydrochloride (0.973 g, 4.97 mmol) was then added and stirring at 50 °C continued for 1 hour, followed by cooling to room temperature and stirring for 72 hours. The reaction was diluted with water (5 mL), stirred for 2 hours, and a precipitate formed. The solids were collected by filtration, washed with water (3x5 mL), and dried under vacuum. This provided 1.59 g (92% yield, 96 area%) of compound 13 as an off-white solid. 'H NMR (400 MHz, CDCI3) δ ppm 1.41 (t, 7=7.07 Hz, 3 H) 1.49 (s, 9 H) 1.59 (s, 3 H) 1.61 (s, 3 H) 2.22 (s, 3 H) 4.37 (q, 7=7.07 Hz, 2 H)

5.70 (s, 1 H) 6.42 (t, 7=2.15 Hz, 1 H) 7.56 (dd, 7=2.27, 0.51 Hz, 1 H) 7.71 (dd, 7=2.02, 0.51 Hz, 1 H) 10.76 (s, 1 H); HPLC Retention Time: 4.68 min; MS (ESI⁺) for C20H28N4O5S m/z 437.1 (M+H) ⁺.

[00226] Example 4.3: Preparation of te/7-Butyl 2-Methyl-2-[5-methyl-2,4-dioxo-6(lH-pyrazol-l-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]propanoate (compound 14) [00227] To a well-stirred slurry of compound 13 (2.00 g, 4.58 mmol) in dry 1,4dioxane (60.0 mL) at room temperature under nitrogen was added solid potassium te/7-butoxide (2.57 g, 22.9 mmol). This mixture was briefly sonicated to give a thick slurry and heated at 80 °C for 30 minutes. Complete conversion was observed. The reaction was cooled to room temperature and diluted with acetic acid (1.43 mL, 25.2 mmol) in water (60 mL). This mixture was stirred at room temperature for 1 hour and a precipitate formed over time. The mixture was then concentrated under vacuum to approximately half the volume and the precipitate was collected, washed with water (3x10 mL) and air dried overnight to give 1.17 g (65% yield, 99 area%) of compound 14 as a tan solid. 'H NMR (400 MHz, CDCI3) δ ppm 1.48 (s, 9 H) 1.81 (s, 6 H) 2.41 (s, 3 H) 6.48 (dd, 7=2.40, 1.89 Hz, 1 H) 7.68 (dd, 7=2.53, 0.51 Hz, 1 H) 7.75 (dd, 7=2.02, 0.51 Hz, 1 H) 9.77 (brs, 1 H); HPLC Retention Time: 3.98 min. MS (ESI⁺) for C18H22N4O4S m/z 391.2 (M+H)⁺.

[00228] Example 4.4: Preparation of te/7-Butyl 2-{l-[2-(5-Fluoro-2methoxyphenyl)-2-oxoethyl]-5-methyl-2,4-dioxo-6-(lH-pyrazol-l-yl)-l,4dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-2-methylpropanoate (compound 15) [00229] A slurry of 2-chloro-1 -(5-fluoro-2-methoxyphenyl)ethanone (compound 1) (3.61 g, 17.8 mmol), compound 14 (5.81 g, 14.9 mmol), K2CO3(5.13 g, 37.1 mmol) andNaBr (306 mg, 2.97 mmol) in dry acetonitrile (60 mL) was stirred at 50 °C under nitrogen. After 18 hours, the mixture was allowed to cool to room temperature, diluted with water (60 mL) and stirred at room temperature for 2 hours. The precipitated product was isolated by filtration, washed with water (3 x 30 mL), and dried under vacuum. This provided 7.63 g (92% yield, 99

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PCT/US2018/020728 area%) compound 15 as a white solid. Ή NMR (400 MHz, CDCh) δ ppm 1.47 (s, 9 H) 1.81 (s, 6 H) 2.46 (s, 3 H) 4.01 (s, 3H) 5.25 (s, 2 H) 6.46 (dd, 7=2.53, 2.02 Hz, 1 H) 7.02 (dd, 7=9.22,

3.92 Hz, 1 H) 7.25 - 7.34 (m, 1 H) 7.64 (dd, 7=8.84, 3.28 Hz, 1 H) 7.67 (dd, 7=2.53, 0.51 Hz, 1 H) 7.68 - 7.71 (m, 1 H); HPLC Retention Time: 5.12 min. MS (ESI⁺) for C27H29FN4O6S m/z

557.1 (M+H)⁺.

[00230] Example 4.5: Preparation of tert-Butyl 2-{l-[(2R)-2-(5-Fluoro-2methoxyphenyl)-2-hydroxyethyl]-5-methyl-2,4-dioxo-6-(lH-pyrazol-l-yl)-l,4dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-2-methylpropanoate (compound 16) [00231] To a well-stirred mixture of compound 15 (7.00 g, 12.6 mmol), RuCl[(S,S)Tsdpen](mesitylene) (79 mg, 0.13 mmol) , sodium formate (4.29 g, 63.1 mmol) and water (28 mL) under nitrogen was added isopropyl alcohol (28 mL, 360 mmol). The reaction was then heated at 75 °C for 60 minutes. The reduction was complete and the mixture was added to a flask containing water (200 mL) and allowed to stir at room temperature overnight. The precipitate that had formed was filtered, washed with water (3x30 mL), and air dried to give 7.01 g (99% yield, 99 area%) of compound 16 as an off-white solid. 'H NMR (400 MHz, CDCh) δ 1.49 (s, 9 H) 1.81 (s, 6 H) 2.43 (s, 3 H) 3.74 (d, 7=6.32 Hz, 1 H) 3.90 (s, 3 H) 4.01 4.17 (m, 1 H) 4.19-4.31 (m, 1 H) 5.2 - 5.4 (m.,1 H) 6.50 (dd, 7=2.40, 1.89 Hz, 1 H) 6.83 (dd, 7=8.97, 4.17 Hz, 1 H) 6.92 - 7.04 (m, 1H) 7.22 - 7.32 (m, 1H) 7.64 - 7.72 (m, 1 H) 7.72 - 7.79 (m, 1 H); HPLC Retention Time:4.84 min. Chiral HPLC: 94% ee; MS (ESI⁺) for C27H31FN4O6S m/z 559.2 (M+H)⁺.

[00232] Example 4.6: Preparation of tert-Butyl 2-{l-[(2R)-2-(2-Cyanoethoxy)-2(5-fluoro-2-methoxyphenyl)ethyl]-5-methyl-2,4-dioxo-6-(lH-pyrazol-l-yl)-l,4dihydrothieno[2,3-d]pyrimidin-3(2H)-yl}-2-methylpropanoate (compound 17) [00233] To a well-stirred mixture of compound 16 (1.0 g, 1.8 mmol) and acrylonitrile (2.50 mL, 38.0 mmol) in dry acetonitrile (10.0 mL) at 0 °C was added 40% aqueous KOH (1.20 mL, 12.0 mmol). This mixture was allowed to stir at 0-5 °C for 18 hours. The mixture was allowed to warm to room temperature and water (10 mL) was added. The mixture was partitioned between di chloromethane (50 mL) and brine (20 mL), the layers were separated, and the aqueous layer was extracted with di chloromethane (3 x 20 mL). The organics were combined, dried with anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel chromatography (Silicycle, 230-400 mesh, 100 g, elution with 20-50% ethyl acetate/hexane) to give 1.04 g (96% yield, 99 area%) of compound 17 as a white foam. 'H NMR (400 MHz, CDCh) δ ppm 1.49 (s, 9 H) 1.77 (s, 3 H) 1.80 (s, 3 H) 2.41 (s, 3 H) 2.58 (t, 7=6.69

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Hz, 2 H) 3.55 (dt, 7=9.47, 6.38 Hz, 1 H) 3.68 (dt, 7=9.47, 6.51 Hz, 1 H) 3.80 (s, 3 H) 4.01 - 4.13 (m, 2H) 5.26 (m, 1 H) 6.49 (dd, 7=2.40, 1.89 Hz, 1 H) 6.81 (dd, 7=8.97, 4.17 Hz, 1 H) 7.01 (ddd, 7=8.91, 7.89, 3.16 Hz, 1 H) 7.19 (dd, 7=8.72, 3.16 Hz, 1 H) 7.68 (dd, 7=2.53, 0.51 Hz, 1 H) 7.75 (dd, 7=2.02, 0.51 Hz, 1 H); HPLC Retention Time: 5.00 min. MS (ESI⁺) for C30H34FN4O6S m/z

612.3 (M+H)⁺.

[00234] Example 4.7: Preparation of 2-{l-[(2R)-2-(2-Cyanoethoxy)-2-(5-fluoro-2methoxyphenyl)ethyl]-5-methyl-2,4-dioxo-6-(lH-pyrazol-l-yl)-l,4-dihydrothieno[2,3d]pyrimidin-3(2H)-yl}-2-methylpropanoic acid (compound 18) [00235] To a well-stirred solution of compound 17 (275.0 mg, 0.45 mmol) in isopropyl alcohol (1.4 mL) at room temperature was added 9.0M sulfuric acid (1.4 mL). The reaction was allowed to stir at room temperature for 2 hours and water (2.8 mL) was added. The mixture was partitioned between brine and dichloromethane (20 mL each), the layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 20 mL). The organics were combined, dried with anhydrous sodium sulfate, and concentrated. The solid obtained was slurried with heptane and concentrated in vacuo to remove residual solvent and give 245 mg (98% yield, 94 area%) of compound 18 as a white solid. 'H NMR (400 MHz, CDCI3) δ ppm 1.87 (s, 3 H) 1.88 (s, 3 H) 2.42 (s, 3 H) 2.59 (t, 7=6.32 Hz, 2 H) 3.53 (dt, 7=9.60, 6.44 Hz, 1 H)

3.70 (dt, 7=9.66, 6.28 Hz, 1H) 3.82 (s, 3 H) 4.01 - 4.09 (m, 1 H) 4.15 - 4.24 (m, 1 H) 5.28 (dd, 7=8.21, 4.67 Hz, 1 H) 6.46 - 6.51 (m, 1 H) 6.82 (dd, 7=9.09, 4.04 Hz, 1 H) 7.01 (ddd, 7=8.97, 7.83, 3.16 Hz, 1 H) 7.20 (dd, 7=8.72, 3.16 Hz, 1 H) 7.68 (d, 7=2.27 Hz, 1H) 7.73 - 7.78 (m, 1 H) (the carboxylate proton was not observed in ^XHNMR); HPLC Retention Time: 3.91 min. MS (ESI⁺) for C26H26FN4O6S m/z 556.3 (M+H)⁺.

[00236] Example 4.8: Preparation of 2-{l-[(2R)-2-(2-Cyanoethoxy)-2-(5-fluoro-2methoxyphenyl)ethyl]-5-methyl-2,4-dioxo-6-(lH-pyrazol-l-yl)-l,4-dihydrothieno[2,3d]pyrimidin-3(2H)-yl}-N-isopropyl-2-methylpropanamide (compound 1-191) [00237] To a well-stirred solution of compound 18 (240 mg, 0.43 mmol), TEA (180.6 uL, 1.29 mmol), and isopropyl amine (110.4 uL, 1.29 mmol) in di chloromethane (5.0 mL) at room temperature under nitrogen was added 1.57 M propylphosphonic anhydride in ethyl acetate (0.55 mL, 0.86 mmol) dropwise over several minutes. The reaction was then stirred at room temperature overnight. The reaction mixture was quenched by the addition of 10% citric acid (5.0 mL) and stirring continued for 30 minutes. The mixture was partitioned between di chloromethane and brine (30 mL each). The layers were separated and the aqueous layer was extracted with di chloromethane (3x10 mL). The organics were combined, dried with

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[00238] Example 5: Description of Synthesis of Compound 1-193 [00239] Starting with l-(2-methoxyphenyl)ethan-l-one and tert-butyl 2-methyl-2-(5methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)yljpropanoate, the synthesis of (R)-2-(l-(2-(2-cyanoethoxy)-2-(2-methoxyphenyl)ethyl)-5methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-Nisopropyl-2-methylpropanamide (compound 1-193) was carried out as diagramed below:

Scheme 8: Synthetic scheme for the preparation of compound 1-193

1.1

1.2

2.2

3.1

2.1

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PCT/US2018/020728 [00240] The synthesis was completed twice to yield a total of 203 g of product Formula 1-193. Each step in the synthetic scheme is described in further detail in the following Examples 5.1 to 5.6.

[00241] Example 5.1: Preparation of 2-bromo-l-(2-methoxyphenyl)ethan-l-one (compound 1.2)

Br

-(2-methoxyphenyl)ethan-1 -one 2-bromo-1 MW: 150.17 (2-methoxyphenyl)ethan-1-one

MW: 229.07 [00242] l-(2-methoxyphenyl)ethanone, 1.1, (300 g, 1.0 eq) was added to a reactor containing acetonitrile (1.2 L, 4.0 V). Bn (319.62 g, 1.0 eq) was added by cooling the reaction to below 25°C. The reaction mixture was stirred for 4 h at 20-25 °C and sampled for IPC until the content of l-(2-methoxyphenyl)ethanone was 6.5%. NaHSCh (600 ml, 2V) was added to quench the reaction and then stirred for an additional 0.5h at 20-25°C. Product was extracted with methyl tert-butyl ether (600 ml, 2V), three times, to yield a black oil (418 g, crude), which was purified using a column to yield 330 g of 2-bromo-l-(2-methoxyphenyl)ethan-l-one, 1.2, as an off-white solid (98% purity).

[00243] Example 5.2: Preparation of 2-methyl-2-(5-methyl-2,4-dioxo-6-(2H-l,2,3triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)propanoic acid (compound 2.2).

tert-butyl 2-methyl-2-(5-methyl-2,4-dioxo-6(2/-/-1,2,3-triazol-2-yl)1,4-dihydrothieno[2,3-c/]pyrimidin3(2/7)-yl)propanoate

MW: 391.44

2-methyl-2-(5-methyl-2,4dioxo-6-(2/7-1,2,3-triazol-2 yl)-1,4-dihydrothieno[2,3cf]pyrimidin-3(2/7)yl)propanoic acid

MW: 335.34 [00244] Compound 2.1 (580.Og, 1.0 eq) was added to a reactor containing di chloromethane (5.8L, 10V). Trifluoroacetic acid (1.2L, 2 V) was added dropwise and the

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PCT/US2018/020728 reaction was stirred for 18 h at 20±5 °C. Samples were taken for HPLC until the content of Compound 2.1 < 1.0%. Reaction was cooled to <10°C and H2O (23.2 L, 40V) was added dropwise. Reaction was stirred for 2 h at 5-10 °C and then filtered. The resulting solid was washed with water (580ml, 1 V) before drying under vacuum at 35±5°C to obtain 448 g of Compound 2.2 (purity 98%) as an off-white solid.

[00245] Example 5.3: Preparation of N-isopropyl-2-methyl-2-(5-methyl-2,4dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)propanamide (compound 3.1)

CDI,ACN

Step 3

3.1

H

A/-isopropyl-2-methyl-2-(5methyl-2,4-dioxo-6-(2H-1,2,3triazol-2-yl)-1,4dihydrothieno[2,3-c/]pyrimidin3(2/7)-yl)propanamide

MW: 376.43 [00246] A reactor was charged with acetonitrile (4.5L, 10V) under an atmosphere of nitrogen before the addition of Compound 2.2 (15.Og, l.Oeq). Reaction mixture was cooled to 010°C and Ι,Γ-Carbonyldiimidazole (433.3 g, 2.0 eq) was added between 5-10°C. Reaction was heated to 25±°C and stirred for 1 hour at the new temperature. Samples for IPC were taken until the content of NDI-012080-2 was 0. Reaction was cooled to 0-10 °C before the addition of isopropylamine (315.9 g, 4eq). Reaction was again warmed to 25±5 °C and stirred for 1 hour at the new temperature with samples taken for IPC until the content of Compound 2.2 was 0. H2O (9.0L, 20 V) was added followed by concentrated HC1 (111.3ml, 4.0eq), dropwise, at 0-25 °C. Reaction was stirred for 2 hours at 0~25 °C, filtered, and the resulting filter cake washed with water (896ml, 2V) and then with ceric ammonium nitrate (896ml, 2V). Obtained 442g of Compound 3.1 (purity: 98.8%, yield: 87.9%) as an off-white solid.

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PCT/US2018/020728 [00247] Example 5.4: Preparation of N-isopropyl-2-(l-(2-(2-methoxyphenyl)-2 oxoethyl)-5-methyl-2,4-dioxo-6-(2H-1,2,3-triazol-2-yl)-1,4-dihydrothieno [2,3-d] pyrimidin3(2H)-yl)-2-methylpropanamide(compound 4.1)

N-isopropyl-2-(1 -(2-(2methoxyphenyl)-2-oxoethyl)-5methyl-2,4-dioxo-6-(2H-1,2,3triazol-2-yl)-1,4dihydrothieno[2,3-d]pyrimidin3(2H)-yl)-2methylpropanamide

MW: 524.29 [00248] Compound 3.1 (430g, 1.0 eq) and N-methyl-2-pyrrolidone (2.2 L, 5 V) were added in that order to a reactor and stirred at 20±5 °C until the solid dissolved. Compound 1.1 (282.6 g, 1.08 eq) and then K2CO3 (5.51G, 3 eq) were added before stirring an additional 2 hours at 25± 5 °C. Samples for IPC were taken until the content of Compound 3.1 was 3.1%. H2O (4.3L, 10V) was added and the reaction mixture was filtered. The filter cake was slurried with water (4.3L, 10V) twice and with petroleum ether (4.3L, 10V) once before drying under vacuum at 40±5°C to obtain 642.8 g of Compound 4.1 (Purity: 97.2%, QNMR: 79.2%, yield: 85%).

[00249] Example 5.5: Preparation of (R)-2-(l-(2-hydroxy-2-(2methoxyphenyl)ethyl)-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3d]pyrimidin-3(2H)-yl)-N-isopropyl-2-methylpropanamide (compound 5.1)

(R)-2-(1-(2-hydroxy-2-(2-methoxyphenyl)ethyl)-5-methyl2,4-dioxo-6-(2/7-1,2,3-triazol-2-yl)-1,4-dihydrothieno[2,3a(]pyrimidin-3(2/7)-yl)-A/-isopropyl-2-methylpropanamide

MW: 526.61

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PCT/US2018/020728 [00250] Compound 4.1 (645.0 g, 1.0 eq) was added to a reactor containing tetrahydrofuran (1.9L, 3.0v) at 20-25 °C. Triethylamine (20.0eq) was added at 20-25 °C. RuCl[(S,S)-Ts-dpen](p-cymene) (10% w/w) was added at the same temperature followed by formic acid (20.0 eq), dropwise, at 20-25°C. Reaction was stirred at 20-30°C for 4 days and sampled for HPLC until the content of Compound 4.1 was no more than 3.0%. Reaction product was concentrated to 4~5v under vacuum at 35±5 °C and then added, dropwise, into water (12.0L, -20.0V). Reaction was filtered and washed with water (2.5L, 4.0 V) and then slurried with MTBE/heptane (1:1, 4.0L). Slurry was filtered and washed with heptane (2.5L, 4.0V) to obtain 430.0 g of Compound 5.1 as an off-white solid (purity: 96.3%).

[00251] Example 5.6: Preparation of (R)-2-(l-(2-(2-cyanoethoxy)-2-(2methoxyphenyl)ethyl)-5-methyl-2,4-dioxo-6-(2H-l,2,3-triazol-2-yl)-l,4-dihydrothieno[2,3d]pyrimidin-3(2H)-yl)-N-isopropyl-2-methylpropanamide (compound 1-193).

6.1 (Final Product)

Formula 1-193

MW: 579.23 [00252] Compound 5.1 (130.0 g, 1.0 eq) was added to a reactor containing tetrahydrofuran (1.3L, 10.0V) and then cooled to -5~0°C. A 50% KOH solution in water (130.0 ml, 1.0V) followed by acrylonitrile (260.0 ml, 2.0v) were added and the reaction mixture was stirred for 20h at -5~0°C. Samples were taken for HPLC until the content of NDI-012080-5 was no more than 5.0%. Ethyl acetate (1.3L, 10.0V) was then added. The organic phase was separated, collected, and washed with 20% NaCl (650.0ml, 5.0V) twice before it was concentrated under vacuum at 35±5 °C. Concentrate was slurried with isopropyl alchohol (650.0 ml, 5.0 V) and then re-crystallized with isopropyl alcohol to obtain 61.0 g of the final product (compound 1-193) as an off-white solid (purity: 98.7%).

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PCT/US2018/020728 [00253] When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles a, an, the and said are intended to mean that there are one or more of the elements. The terms comprising, including and having are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[00254] In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

[00255] As various changes could be made in the above processes without departing from the scope of the invention, it is intended that all matter contained in the above shall be interpreted as illustrative and not in a limiting sense.

Claims

WHAT IS CLAIMED IS:

A process for preparing a stereomerically enriched compound of Formula V-l or V-2-F:

Formula V-l

Formula V-2-F or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-l or V-2-F, respectively; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3; and

R² is hydrogen or F.
2. A process for preparing a stereomerically enriched compound of Formula V-3, V-4-F, or

V-4-F-la:

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Formula V-4-F-la or a salt thereof, the process comprising contacting a compound of Formula IV-3, IV-4-F, or

IV-4-F-la:

Formula IV-3

Formula IV-4-F

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Formula IV-4-F-1 a or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-3, V-4-F, or V-4-F-la, respectively; wherein:

R¹ is 2H-l,2,3-triazol-2-yl or-C(O)OCH₂CH₃; and

R² is hydrogen or F.
3. A process for preparing a stereomerically enriched compound of Formula V-5, V-6-F, or

V-6-F-la:

Formula V-6-F-la

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IV-6-F-la or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-5, V-6-F, or V-6-F-la, respectively; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3; and

R² is hydrogen or F.
4. A process for preparing a stereomerically enriched compound of Formula V-7-F or V-7-

F-la:

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Formula V-7-F

Formula V-7-F-la or a salt thereof, the process comprising contacting a compound of Formula IV-7-F or IV-7-Fla:

Formula IV-7-F Formula I V-l-F-la or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-7-F or V-7-F-la; wherein: R¹ is 2H- l,2,3-triazol-2-yl or -C(O)OCH₂CH₃.
5. The process of claim 1 wherein the process further comprises a step of preparing the compound of Formula IV-1 or IV-2-F:

Formula IV-1

Formula IV-2-F or a salt thereof, the step comprising contacting a compound of Formula II-l or II-2:

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Η

Formula II-l

H

Formula II-2 or a salt thereof, with a compound of Formula III:

Formula III or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-1 or IV-2-F; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3;

R² is hydrogen or F; and

X is Cl, Br, or I.
6. The process of claim 2 wherein the process further comprises a step of preparing the compound of Formula IV-3, IV-4-F or IV-4-F-la:

Formula IV-3

Formula IV-4-F

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Formula IV-4-F-1 a

Formula II-4-la or a salt thereof, with a compound of Formula III:

Formula III or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-3, IV-4-F or IV-4-F-la; wherein:

R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH₂CH₃;

R² is hydrogen or F; and

X is Cl, Br, or I.
7. The process of claim 3 wherein the process further comprises a step of preparing the compound of Formula IV-5,IV-6-F or IV-6-F-la:

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Formula IV-6-F-1 a or a salt thereof, the step comprising contacting a compound of Formula 11-5,11-6 or II-6-la:

H

Formula II-5

H

Formula II-6

H

Formula II-6-la or a salt thereof, with a compound of Formula III:

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Formula III or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-5,IV-6-F or IV-6-F-la; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3;

R² is hydrogen or F; and

X is Cl, Br, or I.
8. The process of claim 4 wherein the process further comprises a step of preparing the compound of Formula IV-7-F or IV-l-F-la:

Formula IV-l-F-la

Formula IV-7-F or a salt thereof, the step comprising contacting a compound of Formula II-7 or II-7-la:

H H

Formula II-7 Formula II-7-la or a salt thereof, with a compound of Formula III-F:

Formula III-F

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PCT/US2018/020728 or a salt thereof, in the presence of a base in an alkylation zone comprising a reaction medium, thereby providing the compound or salt of Formula IV-7-F or IV-l-F-la; wherein:

R¹ is 2H-l,2,3-triazol-2-yl or-C(O)OCH₂CH₃; and

X is Cl, Br, or I.
9. A process for preparing a stereomerically enriched compound of Formula 1-020,1-074,

1-064,1-014,1-184,1-211,1-212, or 1-213:

1-020 1-074

1-064

1-014 1-184

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1-211

1-212 1-213 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-5-F:

Formula V-5-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-5-F:

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Formula VI-5-F or a salt thereof; and reacting the compound or salt of Formula VI-5-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, ethylene glycol, (S)-3-hydroxy-2methylpropanenitrile, (R)-3-hydroxy-2-methylpropanenitrile, and 3-hydroxy-2,2dimethylpropanenitrile, thereby providing the stereomerically enriched compound or salt of

Formula 1-020,1-074,1-064,1-014,1-184,1-211,1-212, or 1-213; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3.
10. A process for preparing a stereomerically enriched compound of Formula 1-082 or 1-171:

1-082 1-171 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-6-T-F:

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Formula V-6-T-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-6-T-F:

Formula VI-6-T-F or a salt thereof;

reacting the compound or salt of Formula VI-6-T-F with methoxy ethanol, thereby providing the stereomerically enriched compound or salt of Formula 1-082; and separating the compound or salt of Formula 1-082, thereby providing the stereomerically enriched compound or salt of Formula 1-171.
11. A process for preparing a stereomerically enriched compound of Formula 1-020,1-074, 1-014,1-211,1-212, or 1-213:

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1-211 1-212

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PCT/US2018/020728 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-l-F:

Formula V-l-F or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-l-F:

Formula VI-l-F or a salt thereof;

reacting the compound or salt of Formula VI-l-F with an alcohol selected from the group consisting of isopropanol, methoxyethanol, (S)-3-hydroxy-2-methylpropanenitrile, (R)-3hydroxy-2-methylpropanenitrile, and 3-hydroxy-2,2-dimethylpropanenitrile thereby providing a stereomerically enriched compound of Formula VII-l-T-F-1, VII-1 -I-1-2. VII-l-P-F-1, VII-1T-F-3, VII-l-T-F-4, or VII-l-T-F-5:

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VII-l-T-F-1

VII-l-T-F-2

CH₃

VII-l-T-F-3

VII-l-T-F-4

VII-l-T-F-5 or a salt thereof;

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PCT/US2018/020728 treating the compound or salt of Formula VII-l-T-F-1, VII-l-T-F-2, VII-l-P-F-1, VIIl-T-F-3, VII-l-T-F-4, or VII-l-T-F-5 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-l-T-F-1, VIII-l-T-F-2, VIII-l-P-F1, VIII-l-T-F-3, VIII-l-T-F-4, or VIII-l-T-F-5:

VIII-l-T-F-2

VIII-l-P-F-1

VIII-l-T-F-3

VIII-l-T-F-4

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VIII-l-T-F-5 or a salt thereof; and forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-020,1-074,1-014,1-211,1-212, or 1-213; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH3.
12. A process for preparing a stereomerically enriched compound of Formula 1-082 or 1-171:

1-082 1-171 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-2-T-F:

Formula V-2-T-F

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PCT/US2018/020728 or a salt thereof, with methanesulfonic anhydride in the presence of a base in a mesylation zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VI-2-T-F:

Formula VI-2-T-F or a salt thereof;

reacting the compound or salt of Formula VI-2-T-F with methoxy ethanol, thereby providing a stereomerically enriched compound of Formula VII-2-T-F-2:

VII-2-T-F-2 or a salt thereof;

treating the compound or salt of Formula VII-2-T-F-2 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-2-T-F-2:

VIII-2-T-F-2

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PCT/US2018/020728 or a salt thereof;

forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-082; and separating the compound or salt of Formula 1-082, thereby providing the stereomerically enriched compound or salt of Formula 1-171.
13. A process for preparing a stereomerically enriched compound of Formula 1-208,1-206,

1-193

1-095

1-192

1-191

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1-234 1-231

1-233

1-181 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-l:

Formula V-l or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-1-4:

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Formula VII-1-4 or a salt thereof;

treating the compound or salt of Formula VII-1-4 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-1-4:

Formula VIII-1-4 or a salt thereof; and forming an amide with an amine selected from the group consisting of ethylamine and isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-208,1-206,1-193,1-095,1-192,1-191,1-234,1-231,1-233, or I181; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH₃; and

R² is hydrogen or F.
14. A process for preparing a stereomerically enriched compound of Formula 1-211,1-212,

1-262,1-263,1-258,1-259, or 1-213:

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1-213 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-l-F:

Formula V-l-F or a salt thereof, with an alkenyl compound of CH2=C(CH3)CN in the presence of a base in a

Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-l-F-5:

Formula VII-l-F-5 or a salt thereof;

treating the compound or salt of Formula VII-l-F-5 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-l-F-5:

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Formula VIII-l-F-5 or a salt thereof;

forming an amide with isopropylamine in an amide formation zone, thereby providing a compound of Formula 1-211/212,1-262/263, or 1-258/259:

Formula 1-211/212 Formula 1-262/263

1-258/259 or a salt thereof; and separating the compound or salt of Formula 1-211/212,1-262/263, or 1-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211,1-212,1-262,1-263, 1-258, or 1-259; or reacting the compound or salt of Formula 1-211/212 with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-213; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH₃.

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15. A process for preparing a stereomerically enriched compound of Formula 1-205,1-220 or

1-229:

1-205

1-220 1-229 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-2-F:

Formula V-2-F or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-2-F-4:

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Formula VI1-2-1-4 or a salt thereof;

treating the compound or salt of Formula VII-2-F-4 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-2-F-4:

or a salt thereof; and forming an amide with an amine selected from the group consisting of isopropylamine and 7V-methylisopropylamine in an amide formation zone, thereby providing a compound of Formula I-205-RR/RS, I-220-RR/RS, or I-229-RR/RS:

I-205-RR/RS

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PCT/US2018/020728 or a salt thereof; and separating the compound or salt of Formula I-205-RR/RS, I-220-RR/RS, or 1-229RR/RS, thereby providing the stereomerically enriched compound or salt of Formula 1-205,1220, or 1-229; wherein:

R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH₂CH₃.
16. A process for preparing a stereomerically enriched compound of Formula 1-285:

1-285 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-l-E-F:

Formula V-l-E-F

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PCT/US2018/020728 or a salt thereof, with an alkenyl compound of CH2=CHSO2CH3 in the presence of a base in a

Michael-addition zone comprising a reaction medium, thereby providing a stereomerically enriched compound of Formula VII-l-E-F-6:

Formula VII-l-E-F-6 or a salt thereof, treating the compound or salt of Formula VII-l-E-F-6 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of VIII-l-E-F-6:

Formula VIII-l-E-F-6 or a salt thereof; and forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-285.
17. A process for preparing a stereomerically enriched compound of Formula 1-208,1-206, 1-234, or 1-231:

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1-234

1-231 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-3:

Formula V-3 or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-208,1-206,1-234, or 1-231; wherein:

R¹ is 2H-l,2,3-triazol-2-yl or-C(O)OCH₂CH₃; and

R² is hydrogen or F.
18. A process for preparing a stereomerically enriched compound of Formula 1-193,1-095,

1-192,1-191,1-233, or 1-181:

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1-233 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-5:

Formula V-5

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PCT/US2018/020728 or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-193,1-095,1-192,1-191,1-233, or 1-181; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH₃; and

R² is hydrogen or F.
19. A process for preparing a stereomerically enriched compound of Formula 1-211,1-212,

1-262,1-263,1-258,1-259, or 1-213:

1-211 1-212

1-262 1-263

1-258 1-259

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1-213

Formula V-5-F or a salt thereof, with an alkenyl compound of CH2=C(CH3)CN in the presence of a base in a

Michael-addition zone comprising a reaction medium, thereby providing a compound of

Formula 1-211/212,1-262/263, or 1-258/259:

Formula 1-211/212

Formula 1-262/263

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1-258/259 or a salt thereof; and separating the compound or salt of Formula 1-211/212,1-262/263, or 1-258/259, thereby providing the stereomerically enriched compound or salt of Formula 1-211,1-212,1-262,1-263, 1-258, or 1-259; or reacting the compound or salt of Formula 1-211/212 with methyl halide in the presence of base in a methylation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-213; wherein:

R¹ is 2H-l,2,3-triazol-2-yl, 1-pyrazolyl, or-C(O)OCH2CH₃;.
20. A process for preparing a stereomerically enriched compound of Formula 1-220:

1-220 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-6-E-F:

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Formula V-6-E-F or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a

Michael-addition zone comprising a reaction medium, thereby providing a compound of

Formula I-220-RR/RS:

I-220-RR/RS or a salt thereof; and separating the compound or salt of Formula I-220-RR/RS, thereby providing the stereomerically enriched compound or salt of Formula 1-220.
21. A process for preparing a stereomerically enriched compound of Formula 1-205 or 1-229:

1-205 1-229 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-7-F:

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Formula V-7-F or a salt thereof, with an alkenyl compound of CH2=CHCN in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing a compound of Formula I-205-RR/RS or I-229-RR/RS:

I-229-RR/RS separating the compound or salt of Formula I-205-RR/RS or I-229-RR/RS, thereby providing the stereomerically enriched compound or salt of Formula 1-205 or 1-229; wherein:

R¹ is 2H-l,2,3-triazol-2-yl or -C(O)OCH₂CH₃.
22. A process for preparing a stereomerically enriched compound of Formula 1-285:

1-285 or a salt thereof, the process comprising:

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PCT/US2018/020728 contacting a stereomerically enriched compound of Formula V-5-E-F:

Formula V-5-E-F or a salt thereof, with an alkenyl compound of CH2=CHSO2CH3 in the presence of a base in a Michael-addition zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-285.
23. A process for preparing a stereomerically enriched compound of Formula 1-064:

or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-l-T-F:

Formula V-l-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium;

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PCT/US2018/020728 reacting the product with a compound of XCH2C(O)OR3 in the α-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-l-T-F-7:

Formula VII-l-T-F-7 or a salt thereof;

treating the compound or salt of Formula VII-l-T-F-7 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-l-T-F-7:

Formula VIII-l-T-F-7 or a salt thereof;

forming an amide with isopropylamine in an amide formation zone, thereby providing a stereomerically enriched compound of Formula IX-l-T-F-7:

Formula IX-l-T-F-7 or a salt thereof; and

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PCT/US2018/020728 contacting the compound or salt of Formula IX-l-T-F-7 with a reducing agent in a reduction zone, thereby providing the stereomerically enriched compound or salt of Formula I064;

wherein: X is Cl or Br, and R³ is selected from the group consisting of methyl and ethyl.
24. A process for preparing a stereomerically enriched compound of Formula 1-089 or 1-090:

1-090 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-2-T-F:

Formula V-2-T-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium;

reacting the product with a compound of XCH2C(O)OR³ in the α-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-2-T-F-7:

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Formula VII-2-T-F-7 or a salt thereof;

treating the compound or salt of Formula VII-2-T-F-7 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-2-T-F-7:

Formula VIII-2-T-F-7 or a salt thereof;

forming an amide with A'-methylisopropylamine in an amide formation zone, thereby providing a stereomerically enriched compound of Formula IX-2-T-F-7:

Formula IX-2-T-F-7 or a salt thereof;

contacting the compound or salt of Formula IX-2-T-F-7 with a reducing agent in a reduction zone, thereby providing a compound of Formula I- 1-089/090:

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1-089/090 or a salt thereof; and separating the compound or salt of Formula 1-089/090, thereby providing the stereomerically enriched compound or salt of Formula 1-089 or 1-090;

wherein: X is Cl or Br, and R³ is selected from the group consisting of methyl and ethyl.
25. A process for preparing a stereomerically enriched compound of Formula 1-251:

1-251 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-l-E-F:

Formula V-l-E-F or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium;

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PCT/US2018/020728 reacting the product with a compound of XCH2CN in the α-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-l-E-F-8:

Formula VII-l-E-F-8 or a salt thereof;

treating the compound or salt of Formula VII-l-E-F-8 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-l-E-F-8:

Formula VIII-l-E-F-8 or a salt thereof;

forming an amide with isopropylamine in an amide formation zone, thereby providing the stereomerically enriched compound or salt of Formula 1-251;

wherein: X is Cl or Br.
26. A process for preparing a stereomerically enriched compound of Formula 1-246:

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PCT/US2018/020728 or a salt thereof, the process comprising contacting a stereomerically enriched compound of

Formula V-8-T-F:

or a salt thereof, with a strong deprotonating agent in an α-alkylation zone comprising a reaction medium;

reacting the product with a compound of XCH2C(O)OR₃ in the α-alkylation zone, thereby providing a stereomerically enriched compound of Formula VII-8-T-F-7:

Formula VII-8-T-F-7 or a salt thereof;

treating the compound or salt of Formula VII-8-T-F-7 with an acid in a deprotection zone, thereby providing a corresponding carboxylic acid compound of Formula VIII-8-T-F-7:

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Formula VIII-8-T-F-7 or a salt thereof;

forming an amide with isopropylamine in an amide formation zone, thereby providing a stereomerically enriched compound of Formula IX-8-T-F-7:

Formula IX-8-T-F-7 or a salt thereof; and contacting the compound or salt of Formula IX-8-T-F-7 with a reducing agent in a reduction zone, thereby providing the stereomerically enriched compound or salt of Formula I246;

wherein X is Cl or Br, and R³ is selected from the group consisting of methyl and ethyl.
27. A process for preparing a stereomerically enriched compound of Formula 1-323:

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PCT/US2018/020728 or a salt thereof, the process comprising:

contacting a stereomerically enriched compound of Formula V-3-T-F:

Formula V-3-T-F or a salt thereof, with acetic anhydride or acetyl chloride in the presence of a base in an acetylation zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula 1-323.
28. A process for preparing a stereomerically enriched compound of Formula 1-189:

1-189 or a salt thereof, the process comprising:

separating a compound of Formula V-7-T-F:

Formula V-7-T-F

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PCT/US2018/020728 or a salt thereof, thereby providing the stereomerically enriched compound or salt of Formula I189
29. A process for preparing a stereomerically enriched compound of Formula V-6-T-F-la (I-

400):

V-6-T-F-la (1-400) or a salt thereof, the process comprising contacting a compound of Formula IV-6-T-F-la:

Formula IV-6-T-F-1 a or a salt thereof, with a hydrogen source in the presence of a chiral organometallic catalyst in an asymmetrical reduction zone comprising a reaction medium, thereby providing the stereomerically enriched compound or salt of Formula V-6-T-F-la (1-400).