WO2020037109A1

WO2020037109A1 - Processes for fluorination

Info

Publication number: WO2020037109A1
Application number: PCT/US2019/046627
Authority: WO
Inventors: Melanie S. Sanford; Sydonie D. SCHIMLER; James W. Ringer; Douglas Bland; Patrick R. MELVIN; Devin FERGUSON
Original assignee: Dow AgroSciences LLC; University of Michigan System
Current assignee: University of Michigan System; Corteva Agriscience LLC
Priority date: 2018-08-17
Filing date: 2019-08-15
Publication date: 2020-02-20
Anticipated expiration: 2021-02-17

Abstract

The present technology relates to fluorination reactions. Specifically, processes useful for making the fungicide compound, DFT are disclosed. More broadly, also disclosed herein are processes useful for deoxyfluorination at the α-aromatic position of a given compound.

Description

PROCESSES FOR FLUORINATION

1. BACKGROUND

[0001] Difluoropyridinyl triazolothione (DFT) is a potent fungicide compound. The known syntheses of DFT, and applicable intermediates thereof, currently employ traditional“fluorinating reagents” to affect fluorine atom transfer, but may not include all the advantages of other fluorine transfer reactions at scale.

[0002] A variety of methods may be used for the fluorination of

substituted aryl compounds. One method of fluorinating these types

compounds is to use single existing fluorine-delivery reagents to affect deoxyfluorination reactions. Known reagent include, but certainly are not limited to: phenylsulfur trifluoride, dialkylaminosulfur trifluorides, and bis(2- methoxyethyl)aminosulfur trifluoride. These reagents can be costly, and in certain reactions are inefficient in terms of yield, atom economy, and reaction rate; and may produce unwanted, toxic and/or difficult to handle by-products or impurities. Thus, it would most desirable to find processes of fluorination that are both efficient and obviate side-products.

[0003] Accordingly, there is a need in the field for better processes to synthesize fluorinated compounds, especially compounds having mono-fluoro and di-fluoro substitution -a to an aromatic functional group, i.e. in the benzylic position. Such processes will be advantageous in that they will improve the active’s impurity profile, lower commercial manufacturing costs and improve efficiency, atom economy.

2. SUMMARY

[0004] The structure of DFT is:

DFT is also known by its chemical name: 4-((6-(2-(2,4-difluorophenyl)- l, l-difluoro-2-hydroxy-3-(5-thioxo-4, 5-dihydro- 1H- 1, 2, 4-triazol- l- yl) propyl) pyridin-3 -yl) oxy) benzonitrile .

[0005] The synthesis of DFT is described in U.S. Patent Application No. 15/574,775, which is hereby incorporated by reference in its entirety.

[0006] The current disclosure describes a method of preparing

monoiluoromethyl or difluoromethyl substituted aromatic and heteroaromatic compounds by the deoxyfluorination of the corresponding aromatic or

heteroaromatic alcohol, ketone, aldehyde or ester. More specifically, the method employs 1, G-sulfonyldiimidazole (SDI), to create sulfuryl fluoride (SO2F2) in situ, along with fluoride anion to convert starting aromatic or heteroaromatic alcohol, aldehyde or ester into the monoiluoromethyl or difluoromethyl substituted product.

[0007] In one aspect, the disclosure provides for processes that affect fluorination in mild conditions. In some aspects, the mild conditions comprise room temperature with a low loading of an acid. In some aspects, the mild conditions comprise room temperature with a low loading of the Lewis acid, tetramethyl ammonium fluoride. In some aspects, the conditions comprise room temperature with the acid, hydrofluoric acid. In some aspects, the conditions comprise room temperature with the acid, hydrogen fluoride.

[0008] In some aspects, the disclosure provides for a process to make the difluoromethyl substituted heteroaromatic synthon for DFT. In such aspects for DFT, the substituted heteroaromatic part of the synthon is a pyridinyl moiety 3-aryloxy substituted (aryl ether) which itself is 4-substituted by a cyano functional group. In some such aspects, the DFT synthon is a 4-(pyridin-3- yloxy) benzonitrile group.

[0009] In a still further aspects, process to make DFT, or methods of manufacture of DFT, or a salt thereof, are provided. The present disclosure provides methods to arrive at the a-iluorinated pyridinyl compound which is a synthon in the synthesis of DFT. And it is presently contemplated that these methods can be extended into an otherwise distinct method or process to make (or manufacture) the entire DFT molecule made when the remaining

nucleophilic addition reactions, the synthetic steps of which is just one such example that are disclosed in the‘775 application, are employed to add in the difluorophenyl and triazolothione pieces for DFT.

3. DETAILED DESCRIPTION 3.1. Definitions

[0010] Various terms used in the specification and claims herein are defined as set forth below, unless otherwise specifically defined in this disclosure. All technical and scientific terms not defined herein have the meaning commonly understood by a person skilled in the art to which this invention belongs.

[OOl l] “Substantially purified or free of impurities” refers to a mixture in which one small organic molecule of interest far exceeds the amount of minerals, metal, and / or other small organic molecules as impurities, and at least 95% by dry weight is the small organic molecule of interest.

[0012] Fluoride salt” refers to a combination of a cation and fluoride anion. Typical fluoride salts include metal cations and so, some examples include, but are not limited to: sodium fluoride (NaF), potassium fluoride (KF), rubidium fluoride (RbF), cesium fluoride (CsF), potassium fluoride (KF), tetrabutyl ammonium fluoride, iron trifluoride (FeFa), manganese difluoride (MnFa), cobalt difluoride (C0F2), copper difluoride (CUF2) and calcium difluoride (CaF₂).

[0013] “Pg or protecting group” refers to any organic functional group which is a mask or as is traditional known in the art, is a group that“protects” a certain organic functional group with the ability to form that certain

functional group upon bond cleavage. Examples include, but are not limited to:

O

TMS, TBDMS, TBDPS, Ms, Ns, Tf, Fmoc, Boc, Cbz, Troc, Alloc, acetyl

including acetamide where R=methyl or trifluoroacetamide where

OH

R=trifluouromethyl, hydroxylamine (^/N\), Tr or trityl (-C(Ph)₃), benzylidene (

Arv H

il \

'^{/ l} lsT R

^/N\), hydrazinyl ( I ) where R also can be C(0)R’, benzoyl (-C(O)Ph), benzyl (-CFEPh), allyl, vinyl, Bu*, and Piv. These groups, generally, are trivial to put on and there are many primary references in the literature to follow for the synthesis techniques, including the Wutz reference disclosed herein, which can assist the skilled artisan if they should need troubleshooting. Also, the skilled artisan will note that the groups referenced herein as“R” are a variety of organic functional groups that are selected from the group consisting of:

alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl,

aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,

aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,

substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,

substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,

heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0014] As used herein, the term "salt" refers to salts which are suitable for use in agriculture, i.e. they affect humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio in agriculture. These salts are well known in the art. Salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate,

undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide,

carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl

sulfonate.

[0015] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH₂-), n-propyl (CH3CH₂CH₂-), isopropyl ((CH₃)₂CH-), n-butyl (CH3CH₂CH₂CH₂-), isobutyl ((CH₃)₂CHCH₂-), sec-butyl ((CH₃)(CH₃CH₂)CH-), f-butyl ((CH₃)₃C-), n-pentyl (CH3CH₂CH₂CH₂CH₂-), and neopentyl ((CFhJsCCFE-). C_x alkyl refers to an alkyl group having x number of carbon atoms.

[0016] “Alkenyl” refers to straight or branched hydrocarbyl groups having from 1 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of unsaturation (>C=C<). Such groups are exemplified, for example, by vinyl, allyl, and but-3-en- l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers. C_x alkenyl refers to an alkenyl group having x number of carbon atoms.

[0017] “Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C^º C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C^º CH), and propargyl (-CH2C^º CH). C_x alkynyl refers to an alkynyl group having x number of carbon atoms.

[0018] “Substituted alkyl” refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino,

aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,

aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,

substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio,

heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted

heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0019] In some embodiments, the substituted alkyl groups include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[0020] “Alkyl aryl” refers to an alkyl group having from 1 to 8, preferably 1 to 5, or more preferably 1 to 3 carbon atoms in length and is substituted specifically at any one of the carbons along the chain with an aryl group.

“Alkenyl aryl” refers to an alkenyl or alkene group having from 1 to 8, preferably 1 to 5, or more preferably 1 to 3 carbon atoms in length and is substituted specifically at any one of the carbons along the chain with an aryl group. The aryl group can include heteroatoms or not. Alkynyl aryl” refers to an alkynyl or alkyne group having from 1 to 8, preferably 1 to 5, or more

preferably 1 to 3 carbon atoms in length and is substituted specifically at any one of the carbons along the chain with an aryl group. The aryl group can include heteroatoms or not. [0021] “Cycloalkyl” or“Cyclyl alkyl” refers to a saturated or partially saturated, but not aromatic, group having from 3 to 10 ring carbon atoms and no heteroatoms. Cycloalkyl encompasses single ring systems.

[0022] Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,

aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,

substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,

heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0023] “Substituted alkynyl” refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,

aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,

substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to an acetylenic carbon atom.

[0024] “Ar” and/or“aryl” refers to any group which is aromatic. This group must be cyclic; and does not contain heteroatoms.

[0025] "Alkoxy" refers to the group -O-alkyl or the group -O-phenyl wherein the phenyl and alkyl are defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, f-butoxy,

sec-butoxy, and n-pentoxy.

[0026] "Substituted alkoxy" refers to the group -0-(substituted alkyl) or -0-(substituted phenyl) wherein substituted phenyl and alkyl are defined herein. Preferred substituted alkyl groups in -0-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[0027] “Acyl” refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-,

heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl,

substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,

substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and

substituted heterocyclic are as defined herein. Acyl includes the“acetyl” group CH₃C(0)-.

[0028] “Acylamino” refers to the groups - NR³⁰C(O)alkyl, -NR³⁰C(O)substituted

alkyl, -NR³⁰C(O)cycloalkyl, -NR³⁰C(O)substituted cycloalkyl, -N

R³⁰C(O) alkenyl, -NR³⁰C(O)substituted alkenyl, alkoxy, substituted

alkoxy- N R³⁰ C ( O ) alkynyl , -NR³⁰C(O)substituted

alkynyl, -NR³⁰C(O)aryl, -NR³⁰C(O)substituted

aryl, -NR³⁰C(O)heteroaryl, -NR³⁰C(O)substituted

heteroaryl, -NR³⁰C(O)heterocyclic, and -NR³⁰C(O)substituted heterocyclic wherein R³⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

heterocyclic and substituted heterocyclic are as defined herein.

[0029] “Aminoacyl” refers to the groups H-C(N)-, alkyl-C(N)-, substituted alkyl-C(N)-, alkenyl-C(N)-, substituted alkenyl-C(N)-, alkynyl-C(N)-, substituted alkynyl-C(N)-, cycloalkyl-C(N)-, substituted cycloalkyl-C(N)-, aryl-C(N)-, substituted aryl-C(N)-, heteroaryl-C(N)-, substituted heteroaryl-C(N)-,

heterocyclic-C(N)-, and substituted heterocyclic-C(N)-, wherein alkyl,

substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and

substituted heterocyclic are as defined herein.

[0030] “Acyloxy” refers to the groups alkyl-C(0)0-, substituted

alkyl-C(0)0-, alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl-C(0)0-, aryl-C(0)0-, substituted aryl-C(0)0-,

cyeloalkyl-C(0)0-, substituted cyeloalkyl-C(0)0-, heteroaryl-C(0)0-,

substituted heteroaryl-C(0)0-, heterocyelic-C(0)0-, and substituted

heterocyelic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and

substituted heterocyclic are as defined herein.

[0031] “Amino” refers to the group -NH2.

[0032] “Substituted amino” refers to the group -NR³¹R³² where R³¹ and R³² are independently selected from the group consisting of hydrogen, hydroxy, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and substituted sulfonyl and wherein R³¹ and R³² are optionally joined, together with the nitrogen bound thereto to form a

heterocyclic or substituted heterocyclic group, provided that R³¹ and R³² are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R³¹ is hydrogen and R³² is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R³¹ and R³² are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a

monosubstituted amino, it is meant that either R³¹ or R³² is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R³¹ nor R³² are hydrogen.

[0033] “Aminocarbonyl” refers to the group -C(0)NR³³R³⁴ where R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

heterocyclic and substituted heterocyclic are as defined herein.

[0034] “Aminoacyl carbonyloxy” refers to the group -C(NR³³)OR³⁴ where R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,

substituted cycloalkyl heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted

heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0035] “Aminothiocarbonyl” refers to the group -C(S)NR³³R³⁴ where R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,

substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted

[0036] “Aminocarbonylamino” refers to the group -NR³⁰C(O)NR³³R³⁴ where R³⁰ is hydrogen or alkyl and R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,

substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ are optionally joined together with the nitrogen bound thereto to form a

heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0037] “Aminothiocarbonylamino” refers to the group -NR³⁰C(S)NR³³R³⁴ where R³⁰ is hydrogen or alkyl and R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,

heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. [0038] “Aminocarbonyloxy” refers to the group -0-C(0)NR³³R³⁴ where R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,

[0039] “Aminosulfonyl” refers to the group -S0₂NR³³R³⁴ where R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

heterocyclic and substituted heterocyclic are as defined herein.

[0040] “Aminosulfonyloxy” refers to the group -0-S0₂NR³³R³⁴ where R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,

heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. [0041] “Aminosulfonylamino” refers to the group -NR³⁰-SO2NR³³R³⁴ where R³⁰ is hydrogen or alkyl and R³³ and R³⁴ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl,

[0042] “Amidino” refers to the group -C(=NR³⁵)NR³³R³⁴ where R³³, R³⁴, and R³⁵ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R³³ and R³⁴ are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

heterocyclic and substituted heterocyclic are as defined herein.

[0043] “Substituted aryl” refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,

heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted

heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, a monosaccharide (which may be covalently bonded to the aryl group thru any oxygen atom on the saccharide), and substituted alkylthio, wherein said substituents are defined herein.

[0044] “Aryloxy” refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

[0045] “Substituted aryloxy” refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.

[0046] “Arylthio” refers to the group -S-aryl, where aryl is as defined herein.

[0047] “Substituted arylthio” refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.

[0048] “Carbonyl” refers to the divalent group -C(O)- which is equivalent to -C(=0)-.

[0049] “Carboxy” or“carboxyl” or“carboxylate” refers to -COOH or salts thereof.

[0050] “Carboxyl ester” or“carboxy ester” refers to the

groups -C(0)0-alkyl, -C(0)0-substituted

alkyl, -C(0)0-alkenyl, -C(0)0-substituted

alkenyl, -C(0)0-alkynyl, -C(0)0-substituted

alkynyl, -C(O) O-aryl, -C(0)0-substituted

aryl, -C(O) O-cycloalkyl, -C(0)0-substituted

cycloalkyl, -C(O) O-heteroaryl, -C(0)0-substituted

heteroaryl, -C(0)0-heterocyelic, and -C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. [0051] “(Carboxyl ester)amino” refers to the

group -NR³⁰-C(O)O-alkyl, -NR³⁰-C(O)O-substituted

alkyl, -NR³⁰-C(O)O-alkenyl, -NR³⁰-C(O)O-substituted

alkenyl, -NR³⁰-C(O)O-alkynyl, -NR³⁰-C(O)O-substituted

alkynyl, -NR³⁰-C(O)O-aryl, -NR³⁰-C(O)O-substituted

aryl, -NR³⁰-C(O) O-cycloalkyl, -NR³⁰-C(O)O-substituted

cycloalkyl, -NR³⁰-C(O) O-heteroaryl, -NR³⁰-C(O)O-substituted

heteroaryl, -NR³⁰-C(O)O-heterocyclic, and -NR³⁰-C(O)O-substituted heterocyclic wherein R³⁰ is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

heterocyclic, and substituted heterocyclic are as defined herein.

[0052] “(Carboxyl ester)oxy” refers to the

group -0-C(0)0-alkyl, -0-C(0)0-substituted

alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted

alkenyl, -0-C(0)0-alkynyl, -0-C(0)0-substituted

alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted

aryl, -O-C(O) O-cycloalkyl, -0-C(0)0-substituted

cycloalkyl, -O-C(O) O-heteroaryl, -0-C(0)0-substituted

heteroaryl, -0-C(0)0-heterocyelic, and -0-C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0053] “Cyano” refers to the group -C^ºN.

[0054] “Cycloalkyl” refers to a saturated or unsaturated but nonaromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. C_x cycloalkyl refers to a cycloalkyl group having x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring saturated carbocyclic ring.“Substituted cycloalkyl” refers to a cycloalkyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, aminocarbonylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,

aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted

cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic,

heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0055] “Cycloalkyloxy” refers to -O-cycloalkyl.

[0056] “Substituted cycloalkyloxy” refers to -0-(substituted cycloalkyl).

[0057] “Cycloalkylthio” refers to -S-cycloalkyl.

[0058] “Substituted cycloalkylthio” refers to -S-(substituted cycloalkyl).

[0059] “Guanidino” refers to the group -NHC(=NH)NH2.

[0060] “Substituted guanidino” refers to -NR³⁶C(=NR³⁶)N(R³⁶)2 where each R³⁶ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R³⁶ groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R³⁶ is not hydrogen, and wherein said substituents are as defined herein.

[0061] “Halo” or“halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.

[0062] “Hydroxy” or“hydroxyl” refers to the group -OH. [0063] “Heteroaryl” refers to an aromatic group of from 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring ( e.g ., pyridinyl or furyl) or multiple condensed rings ( e.g ., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and / or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N 0), sulfinyl, or sulfonyl moieties. Preferred heteroaryls include 5 or 6 membered heteroaryls such as pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

[0064] “Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of

substituents defined for substituted aryl.

[0065] “Heteroaryloxy” refers to -O-heteroaryl.

[0066] “Substituted heteroaryloxy” refers to the group -0-(substituted heteroaryl) .

[0067] “Heteroarylthio” refers to the group -S-heteroaryl.

[0068] “Substituted heteroarylthio” refers to the group -S-(substituted heteroaryl) .

[0069] “Heterocycle” or“heterocyclic” or“heterocycloalkyl” or

“heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 2 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. C_x cycloalkyl or heterocycloalkyl refers to a group having x number of ring carbon atoms excluding the ring heteroatoms. Heterocycle encompasses single ring or multiple condensed rings, including fused, bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, sulfonyl moieties. [0070] “Substituted heterocyclic” or“substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0071] “Heterocyclyloxy” refers to the group -O-heterocycyl.

[0072] “Substituted heterocyclyloxy” refers to the group -0-(substituted heterocycyl) .

[0073] “Heterocyclylthio” refers to the group -S-heterocycyl.

[0074] “Substituted heterocyclylthio” refers to the group -S-(substituted heterocycyl) .

[0075] Examples of heterocycle and heteroaryl include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, dexahydroindole, dihydro pyridine, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, imidazolinone, piperidine, piperazine, indoline, phthalimide,

1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1, 1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0076] “Nitro” refers to the group -NO2.

[0077] “Oxo” refers to the atom (=0) or (-O ).

[0078] “Phthalimido” refers to the group

Phthalimide functional groups are well known in the art and can be generated by covalently bonding a nitrogen atom to a C6H₄(CO)2 group.

[0079] “Polyethylene glycol” refers to the group -0-(CH₂CH₂-0)_n-E, wherein E is either H or CH3, where n is between 2-20,000. [0080] “Spirocyclic ring system” refers to a ring system with two rings that has a single ring carbon atom in common to both rings. Herein used the term bicyclic can incorporate up to four heteroatoms in either ring.

[0081] “Bicyclic ring” or“Bicyclic ring system” refers to a ring system with two rings that has two ring carbon atoms in common, and which can located at any position along either ring. Herein used the term bicyclic ring system can incorporate up to four heteroatoms in either ring.

[0082] “Sulfinyl” refers to the divalent group -SO-.

[0083] “Sulfonyl” refers to the divalent group -S(0)₂-.

[0084] “Substituted sulfonyl” refers to the

group -S0₂-alkyl, -S0₂-substituted

alkyl, -SO2-OH, -S0₂-alkenyl, -S0₂-substituted

alkenyl, -S0₂-cycloalkyl, -S0₂-substituted

cylcoalkyl, -S0₂-aryl, -S0₂-substituted aryl, -S0₂-heteroaryl, -S0₂-substituted heteroaryl, -S0₂-heterocyclic, -S0₂-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-S0₂-, phenyl-S0₂-, and 4-methylphenyl-S0₂-. Preferred substituted alkyl groups on the substituted alkyl-S0₂- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

[0085] “Substituted sulfinyl” refers to the

group -SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted

alkenyl, -SO-cycloalkyl, -SO-substituted cylcoalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted

heteroaryl, -SO-heterocyclic, -SO-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfinyl includes groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on the substituted alkyl-SO- include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, dilluromethyl, fluoromethyl and the like.

[0086] “Sulfonyloxy” or“substituted sulfonyloxy” refers to the

group -OS0₂-alkyl, -OS0₂-substituted

alkyl, -OSO2-OH, -OS0₂-alkenyl, -OS0₂-substituted

alkenyl, -OS0₂-cycloalkyl, -OS0₂-substituted

cylcoalkyl, -OS0₂-aryl, -OS0₂-substituted

aryl, -OS0₂-heteroaryl, -OS0₂-substituted

heteroaryl, -OS0₂-heterocyclic, -OS0₂-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0087] “Substitution” or“substitution” or“substitutied” generally refers groups which are covalently bonded to an atom to replace a hydrogen atom.

The atom in this general context can be a carbon atom or a heteroatom, for example a nitrogen atom.

[0088] “Thioacyl” refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-,

heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl,

substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0089] “Mercapto” or“thiol” refers to the group -SH.

[0090] “Formyl” refers to the group -C(0)H.

[0091] “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring NH moiety and a ring =N moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. [0092] “Thiocarbonyl” refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[0093] “Thione” refers to the atom (=S).

[0094] “Alkylthio” refers to the group -S-alkyl wherein alkyl is as defined herein.

[0095] “Substituted alkylthio” refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein. Preferred substituted alkyl groups on -S-(substituted alkyl) include halogenated alkyl groups and particularly halogenated methyl groups such as trifluoromethyl, difluromethyl, fluoromethyl and the like.

3.2. Additional interpretational conventions

[0100] Generally, reference to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, ¹⁴C, ³²P and ³⁵S are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0101] Unless the specific stereochemistry is expressly indicated, all chiral, diastereomeric, and racemic forms of a compound are intended. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Racemic mixtures, and d or 1 enriched stereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0102] The compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.

[0103] Herein any substituted functional group is substituted at from one to three different positions, and those one to three substituting groups are capable of each independently being substituted at one to three positions, wherein any and each substituting group is independently selected from the group consisting of: halogen, hydroxyl, Ci-Cs alkyl, substituted Ci-Cs alkyl, Ci- Ce alkenyl, substituted Ci-Cs alkenyl, Ci-Cs alkynyl, substituted Ci-Cs alkynyl, acyl, acylamino, aminocarbonylamino, aminoacyl, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminoacyl carbonyloxy,

aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy,

aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, Ci-Cs alkoxy, substituted Ci-Cs alkoxy, C3-C7 aryl, substituted C3-C7 aryl, C3-C7 aryloxy, substituted C3-C7 aryloxy, C3-C7 arylthio, substituted C3-C7 arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, C₃-C₁₀ cycloalkyl, substituted C₃-C₁₀ cycloalkyl, C₃-C7 heterocycloalkyl, guanidino, substituted guanidino, C3-C7 heteroaryloxy, C3-C7 substituted heteroaryloxy, C3-C7 heteroarylthio, C₃-C7 substituted heteroarylthio, sulfonyl, substituted sulfonyl, sulfinyl, substituted sulfinyl, sulfonyloxy, substituted sulfonyloxy, thioacyl, alkylthio, substituted alkylthio, C₃-C7 heteroaryl, and substituted C₃-C7 heteroaryl.

[0104] Herein any and all heteroaryl and heterocycloalkyl substituents may contain up to four heteroatoms selected from the group consisting of: O, N, and S but may not contain the heteroatom-heteroatom bonds: O-O, O-S and S-S. It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves ( e.g ., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substituents is three.

That is to say that each of the above definitions is constrained by a limitation that each functional group is substituted (at from one to three positions) and that any and all of those substituent groups may be substituted one more time (at from one to three positions). [0105] It is understood that the definitions presented herein are not intended to include impermissible substitution patterns ( e.g ., methyl substituted with 5 fluoro groups) . Such impermissible substitution patterns are well known to the skilled artisan.

[0106] Throughout this application, the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology.

[0107] For the purposes of this specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, parameters, quantities, characteristics, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term “about” even though the term“about” may not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are not and need not be exact, but may be approximate and / or larger or smaller as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art

depending on the desired properties sought to be obtained by the presently disclosed subject matter. For example, the term“about,” when referring to a value can be meant to encompass variations of, in some aspects, ± 100% in some aspects ± 50%, in some aspects ± 20%, in some aspects ± 10%, in some aspects ± 5%, in some aspects ± 1%, in some aspects ± 0.5%, and in some aspects ± 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0108] As used herein and in the appended claims, singular articles such as “a,”“an” and“the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, including the upper and lower bounds of the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language ( e.g “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non- claimed element as essential.

[0109] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent“alkoxycarbonylalkyl” refers to the group (alkoxy)-C(0)-(alkyl)-.

3.3. Processes

[0110] In a first aspect, the disclosure provides for a process of fluorinating an aromatic a- hydroxy, keto, aldehyde or ester organic compound, the process comprising mixing the aromatic compound with SDI, tetramethyl ammonium fluoride, a fluoride salt and an acid (a Lewis acid or otherwise).

[0111] In some aspects, the disclosure provides for a total synthesis of DFT. In some aspects, the disclosure provides for a process of manufacturing DFT wherein the process returns an amount of DFT made is greater than or equivalent to five hundred (500) grams. In some aspects, the process of manufacturing DFT returns greater than or equivalent to one ( 1) kilogram of DFT.

3.3.1. Deoxyfluorination

[0112] Herein disclosed are processes for the deoxyfluorination of aromatic compounds. In some aspects, the present disclosure provides for processes that fluorinate a compound of formula II, as described herein, with sulfuryl fluoride.

In some aspects, the present disclosure provides for processes that make sulfuryl fluoride in situ by combining 1, G-thiocarbonyldiimidazole (SDI) and tetramethyl fluoride (N(CH₃)₄F). Accordingly, the present disclosure provides for processes that fluorinate a compound of formula II, as described herein, with I, G-thiocarbonyldiimidazole (SDI) and tetramethyl fluoride (N(CH₃)₄F).

[0113] In some aspects, the present disclosure provides for a process to make a compound of formula I:

I I i

, or a salt thereof, the process comprising

mixing the following compounds:

a) a compound of formula II: ¹¹ , or a salt thereof,

b) 1, G-thiocarbonyldiimidazole (SDI),

c) N(CH₃)₄F,

d) a fluoride salt; and

e) an acid,

wherein:

Y is hydrogen or fluorine;

each of U, J, E, Z, and T is independently selected from the group consisting of: CH, CR¹, and N, wherein up to 3 of U, J, E, Z, and T may be N; each R¹ is independently selected from the group consisting of: hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ substituted cycloalkyl, C₃-C₈ heterocycloalkyl, C₃-C₈ substituted heterocycloalkyl, C₃-C₇ heteroaryl, C₃-C₇ substituted heteroaryl, phenyl, substituted phenyl, cyano, and nitro;

and wherein any two R¹ groups may be covalently bonded together to form a cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl ring;

and wherein any and all heterocyclic groups contain up to three heteroatoms selected from the group consisting of: oxygen, sulfur and nitrogen.

[0114] A process to make a compound of formula III:

, or a salt thereof, the process comprising

mixing the following compounds:

a) a compound of formula IV: IV or a salt thereof,

b) I, G-thiocarbonyldiimidazole (SDI),

c) N(CH₃)₄F,

d) a fluoride salt; and

e) an acid,

wherein:

each of U, J, E, Z, and T is independently selected from the group consisting of: CH, CR¹, and N. wherein up to 3 of U, J, E, Z, and T may be N; each R¹ is independently selected from the group consisting of: hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-Cs cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C₃-C7 heteroaryl, C₃-C7 substituted heteroaryl, phenyl, substituted phenyl, cyano, and nitro;

R² is selected from the group consisting of: hydrogen, Ci-Cs alkyl, Ci- Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ substituted cycloalkyl, C₃- Cs heterocycloalkyl, C₃-C₈ substituted heterocycloalkyl, C₃-C7 heteroaryl, C₃- C7 substituted heteroaryl, phenyl, and substituted phenyl;

[0115] A process to make a compound of formula V:

, or a salt thereof, the process comprising mixing the following compounds:

a) a compound of formula VI:

, or a salt thereof, b) I, G-thiocarbonyldiimidazole (SDI),

c) N(CH₃)₄F,

d) a fluoride salt; and

e) an acid,

wherein:

m is from 0-4; each R¹ is independently selected from the group consisting of:

hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-C₈ cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C₃-C7 heteroaryl, C₃-C7 substituted heteroaryl, phenyl, substituted phenyl, cyano, and nitro;

[0116] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR¹ where R¹ is substituted amino.

[0117] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR¹ where R¹ is cyano.

[0118] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR¹ where R¹ is Ci-Cs substituted alkyl.

[0119] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR¹ where R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.

[0120] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, Z, and T is CH, E is CR¹ where R¹ is C₃-C7 heteroaryl. [0121] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is N, E is

N.

[0122] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is N, E is

N.

[0123] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is CR¹ where R¹ is substituted amino, E is N.

[0124] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is CR¹ where R¹ is cyano, E is N.

[0125] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, T, and Z is CH, J is CR¹ where R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy, E is N.

[0126] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR¹ where R¹ is substituted amino, E is N.

[0127] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR¹ where R¹ is C₃-C7 heteroaryl, E is N.

[0128] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR¹ where R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy, E is N.

[0129] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein each of U, J, and Z is CH, T is CR¹ where R¹ is cyano, E is N.

[0130] In one aspect, the disclosure provides a process for preparing a

O compound of formula I, as described herein, wherein E is N and X is

. In one aspect, the disclosure provides a process for preparing a compound of

OH formula I, as described herein, wherein E is CH and X is J

In one aspect, the disclosure provides a process for preparing a compound of

OH formula I, as described herein, wherein E is N and X isJ . In one aspect, the disclosure provides a process for preparing a compound of formula I, as

O described herein, wherein each of U, J, Z, and T is CH; E is N and X is ^k ^H . In one aspect, the disclosure provides a process for preparing a compound of formula I, as described herein, wherein each of U, J, Z, and T is CH; E is N and

OH

X isJ . In one aspect, the disclosure provides a process for preparing a compound of formula I, as described herein, wherein each of U, J and T is CH;

O JU

Z is N, E is N and X is H . i_n one aspect, the disclosure provides a process for preparing a compound of formula I, as described herein, wherein each of U,

OH

J and T is CH; Z is N, E is N and X is J

[0131] In some aspects, the disclosure provides for a process of to make a

O compound of formula I wherein Y is F, X i iss "J^UH , each of U, J, and Z is CH, and E is N.

[0132] In some aspects, the disclosure provides for a process of to make a

OH compound of formula I wherein Y is H, X is J , each of U, J, and Z is CH, and E is N. [0133] In some aspects, the disclosure provides for a process of to make a

OH compound of formula I wherein Y is H, X is J , each of U, Z, and J is CH, and E is N.

[0134] In some aspects, the disclosure provides for a process of to make a

OH compound of formula I wherein Y is H, X is J , each of U, J, E and Z is CH.

[0135] In some aspects, the disclosure provides for a process of to make a

O

NA

compound of formula I wherein Y is F, X is H , each of U, J, and Z is CH, and E is N.

[0136] In some aspects, the disclosure provides for a process of to make a

O compound of formula I wherein Y is F, X is v H _? each of U, Z, and J is CH, and E is N.

[0137] In some aspects, the disclosure provides for a process of to make a

O compound of formula I wherein Y is H, X is v H , each of U, J, E and Z is CH.

[0138] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl.

[0139] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR¹ where R¹ is substituted amino.

[0140] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR¹ where R¹ is cyano.

[0141] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR¹ where R¹ is Ci-Cs substituted alkyl.

[0142] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR¹ where R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.

[0143] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, Z, and T is CH, E is CR¹ where R¹ is C3-C7 heteroaryl.

[0144] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, J, and Z is CH, T is N, E is N.

[0145] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is N, E is N.

[0146] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is CR¹ where R¹ is substituted amino, E is N.

[0147] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is CR¹ where R¹ is cyano, E is N.

[0148] In some aspects, the disclosure provides for a process of to make a compound of formula III or V wherein R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, each of U, T, and Z is CH, J is CR¹ where R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy, E is N.

[0149] In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 1. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 3. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 4.

[0150] In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 1, R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.

[0151] In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and one R¹ is amino or substituted amino. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is C3-C7 heteroaryl or C3-C7 substituted heteroaryl, and one R¹ is amino or substituted amino. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is phenyl or substituted phenyl, and one R¹ is amino or substituted amino.

[0152] In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and one R¹ is halogen while the other R¹ is cyano. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is Ci-Cs alkyl or Ci-Cs substituted alkyl or Ci-Cs alkenyl or Ci-Cs substituted alkenyl, and one R¹ is halogen while the other R¹ is amino or substituted amino. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is C3-C8 heterocycloalkyl or C3-C8 substituted heterocycloalkyl, and one R¹ is halogen while the other R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.

[0153] In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is C3-C8 heterocycloalkyl or C3-C8 substituted heterocycloalkyl, and one R¹ is Ci-Cs alkyl or Ci-Cs substituted alkyl while the other R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy. In some aspects, the disclosure provides for a process of to make a compound of formula V wherein m is 2, R² is Ci-Cs alkyl or Ci-Cs substituted alkyl, and one R¹ is carboxy ester while the other R¹ is Ci-Cs alkoxy or Ci-Cs alkyl.

[0154] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein E is N, each of U, J, and T is CH, and Z is CR¹ where R¹ is selected from the group consisting of: hydrogen, halogen, carboxy ester, amino, substituted amino, hydroxyl, Ci-Cs alkyl, Ci-Cs

substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, and cyano.

[0155] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein E is N, each of U, T, and Z is CH, and J is CR¹ where R¹ is selected from the group consisting of: hydrogen, halogen, amino, substituted amino, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, and cyano.

[0156] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein E is N, each of T, J, and Z is CH, and U is CR¹ where R¹ is selected from the group consisting of: hydrogen, halogen, carboxy ester, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C3-C7 heteroaryl, C3-C7 substituted heteroaryl, phenyl, and substituted phenyl.

[0157] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is hydrogen fluoride.

In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is hydrofluoric acid. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is formic acid. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is p-toluenesulfonic acid. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the organic acid is trifluoroacetic acid.

[0158] In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the fluoride salt is potassium fluoride. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the fluoride salt is tetramethylammonium fluoride. In some aspects, the disclosure provides for a process of to make a compound of formula I, III, or V wherein the fluoride salt is sodium fluoride.

[0159] In some aspects, the disclosure provides a process substantially as shown in Example 1.

3.3.2. DFT Total syntheses

[0160] In a first aspect, the disclosure provides for a total synthesis of DFT. Herein disclosed are processes to make DFT, or methods of manufacture of DFT, or a salt thereof, where the process of method comprises: fluorination of a ethyl 2-(5-(4-cyanophenoxy)pyridin-2-yl)-2-oxoacetate derivative using

tetramethylammonium fluoride, 1, G-thiocarbonyldiimidazole (SDI), a fluoride salt and an acid; nucleophilic addition to the fluorinated ethyl 2-(5-(4- cyanophenoxy)pyridin-2-yl)-2-oxoacetate derivative product with a 1,3- difluorobenzene nucleophile; and nucleophilic addition to the fluorinated ethyl 2-(5-(4-cyanophenoxy)pyridin-2-yl)-2-oxoacetate- l,3-difluorobenzyl derivative with a triazole or triazolothione nucleophile.

[0161] In some aspects, the disclosure provides for a process to make DFT, or method of manufacture of DFT, or a salt thereof, the process comprising:

reacting

to make

, wherein Metal is a metal or metalloid that makes a nucleophilic organometallic reagent of the difluoro compound, and wherein R¹ is selected from the group consisting of:

hydrogen, halogen, amino, substituted amino, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Ce substituted alkynyl, C₃-C7 heteroaryl, C₃-C7 substituted heteroaryl, phenyl, and substituted phenyl;

reacting

trimethylsulfoxonium iodide to make

-triazole to make DFT, or a salt thereof.

[0162] In some aspects, the disclosure provides for a process to make DFT, or method of manufacture of DFT, or a salt thereof, the process comprising:

, a metal or metalloid that makes a nucleophilic organometallic reagent of the difluoro compound, and wherein R¹ is selected from the group consisting of:

hydrogen, halogen, amino, substituted amino, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-C7 heteroaryl, C₃-C7 substituted heteroaryl, phenyl, and substituted phenyl;

reacting

make

salt thereof, wherein Metal is a metal or metalloid that makes a nucleophilic

organometallic reagent of the difluoro compound.

[0163] In some aspects, the disclosure provides for processes where the Metal or metalloid is selected from the group consisting of: magnesium, lithium, copper, zinc, and boron.

[0164] In some aspects, the disclosure provides for a process of

manufacturing DFT wherein the process returns an amount of DFT made is greater than or equivalent to five hundred (500) grams. In some aspects, the process of manufacturing DFT returns greater than or equivalent to one ( 1) kilogram of DFT. In some aspects, the disclosure provides for a process of manufacturing DFT wherein the process returns five hundred (500) grams or one ( 1) kg of DFT where the amount of each of the staring materials, i.e.

, , trimethylsulfoxonium iodide, and 1H- 1,2,4- triazole is such that it corresponds with the amounts needed based on the reaction stoichiometry and % yield disclosed in the addition reactions disclosed in the Examples section herein, and assuming that any following steps, if needed, are nearly quantitative, i.e. any deprotection and/or reduction and/or

acylation reactions needed to go from

the way to DFT are

-80%, -85%, -90%, or -95% in yield; and therefore the amount of each of the starting material compounds may be calculated or adjusted according to the expected yield, as described above, from those reactions.

[0165] In some aspects, the disclosure provides a process substantially as shown below:

3.3.3. Conditions

[0166] In some aspects, the disclosure provides a process for preparing the compounds disclosed herein by deoxyfluorination reactions, the process

comprising: mixing a compound of formula II:

, or a salt thereof, X, U,

E, J, Z, T as defined herein, and N(CH3)₄F in one chamber of a two-chamber reaction vessel; I, G-thiocarbonyldiimidazole (SDI), a fluoride salt, and an acid are mixed in the other chamber; the contents of both chambers are allowed to mix separately, each for over 2 hours.

[0167] In some aspects, the mixtures are stirred in each reaction chamber. In some aspects, a mixture is stirred in one chamber.

[0168] In some aspects, the mixing of the contents of both chambers occurs at room temperature. In some aspects, the mixing of the contents of both

chambers occurs initially at -78°C, -25°C, 0°C, 5°C, 10°C, or 15°C and then the mixture is allowed to warm to room temperature or above. In some aspects, the mixing of the contents of both chambers occurs at 30°C. In some aspects, the mixing of the contents of both chambers occurs from 20- 120°C. In some aspects, the mixing of the contents of both chambers occurs at 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, or 120°C for 2 hours or more. In some aspects, the mixing of the contents of both chambers occurs for 2 hours, and some aspects, for 3 hours. In some aspects, the mixing of the contents of both chambers occurs for 4 hours. In some aspects, the mixing of the contents of both chambers occurs for 6 hours or for 8 hours. In some aspects, the mixing of the contents of both chambers occurs for 12 hours.

[0169] In some aspects, the mixing of the contents of one of the chambers occurs at 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, or 120°C.

[0170] In some aspects, aprotic organic solvent is mixed in the reaction chamber containing the compound of formula II and N(CH3)₄F. In some aspects, aprotic organic solvent is mixed both chambers. In some aspects, aprotic organic solvent is mixed in the reaction chamber containing the 1, 1'- thiocarbonyldiimidazole (SDI), the fluoride salt, and the acid. [0171] In some aspects, the aprotic organic solvent is the same in both chambers. In some aspects, the aprotic organic solvent is different in each chamber. Regardless, there is no limitation on the identity of which aprotic organic solvent may be used in each of the chambers, i.e. one can mix and match among aprotic solvents and even use one or more aprotic organic co- solvents in any one or both chambers. In some aspects, the aprotic organic solvent is acetonitrile (ACN). In some aspects, the aprotic organic solvent is tetrahydrofuran (THF). In some aspects, the aprotic organic solvent is 2-methyl - tetrahydrofuran (2-methyl THF).

[0172] In some aspects, the disclosure provides a process on an industrial scale comprising a-iluorination of an aromatic compound with 1, 1’- sulfonyldiimidazole (SDI) and tetramethylammonium fluoride (N(CH3)₄F), where deoxyfluorination of the aromatic or heteroaromatic alcohol, ketone, aldehyde or ester provides the corresponding monoiluoromethyl or difluoromethyl substituted aromatic compound. In some aspects, the disclosure provides a process on an industrial scale comprising the synthesis of DFT, wherein a- iluorination of a 4-(pyridin-3-yloxy)benzonitrile derivative provides a product that is a synthon for DFT. That product is then used in the total synthesis at an industrial scale with difluorophenyl and triazolothionyl derivatives to make DFT.

[0173] In some aspects, the disclosure provides a process for preparing the solvate of any one of the product or reactant compounds disclosed herein. Such solvates may have desirable properties such as enhanced solubility or even less impurities, e.g. minute amounts of regio-isomers can be present even in commercial shelf-reagents and preparing a solvate of such a reagent or when purifying a product may be advantageous.

3.3.4. Exemplary deoxyfluorination procedure

[0174] In some aspects, the fluorination process is affected by a general methodology, such an exemplary method is specifically demonstrated where benzaldehyde, SDI, KF, formic acid, DMF solvent and Me₄NF are mixed at room temperature. Next, ether as an aprotic extraction solvent is added and the compound is extracted in the organic layer three (3) times. The combined organic layers are washed with water, dried with MgS0₄, filtered and the solvent is removed in vacuo. The resulting mixture is purified by either flash or HPLC chromatography.

[0175] In one aspect, an exemplary fluorination process is carried out where SDI and the fluoride salt, in the above case, KF, are mixed separately from the aromatic compound of formula II, IV, or VI and Me₄NF. The acid, in the above case, formic acid, is added to the SDI/KF mixture. The aprotic solvent, in the above case, DMF is added to the compound of formula II, IV, or VI/ Me₄NF mixture. Then the two mixtures are mixed together at room temperature. An extraction solvent is added after some time, the organic layers taken and the combined organic layer washed with water, dried and chromatographed.

3.3.5. General methods to make and use the synthons

[0176] Synthons described herein for the total synthesis of DFT are prepared from readily available commercial starting materials using the following general methods and procedures to the skilled artisan, e.g. those synthetic

transformations described in the references already cited in this application.

[0177] Briefly, aromatic compounds can be functionalized with the desired or appropriate R¹ group by electrophilic aromatic substitution reactions. For example benzyl derivatives can be functionalized by reacting the benzyl derivative with an electrophilic partner in the presence of a Lewis acid. In one particular example, if say one wanted to have a ketone substituent in a certain position on a benzyl moiety, the skilled artisan could purchase a functionalized benzene with a Cl group at the 2- position and use a Lewis acid like AlCh to put on an acid chloride electrophile onto the ring. Alternatively, one can purchase an aromatic starting compound from a vendor such as bromo- benzene and like, which already have one or more functional groups on them. From there, if the stereoelectronics are such that an electrophilic substitution reaction is not feasible, one might look to nucleophilic aromatic substitution. In such a case one might react say, bromo benzene with a Grignard, alkoxy or amine nucleophile to create the desired electron donating substituent on the aromatic ring where it is desired. Such reactions are known and are facile. Of course the skilled artisan can use primary texts, journal articles, and other materials to look up and employ specific desired reactions and conditions.

Specific examples of the general methodologies useful are shown below:

[0178] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from

commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA), CombiChem (SAN DIEGO, CA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1- 15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,

Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0179] It will also be appreciated that where typical process conditions ( i.e reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given to make these compounds, minor modifications to these process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactant or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures as long as the reagents stay the same.

[0180] Additionally, as will be apparent to those skilled in the art,

conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Herein it is understood that amino, keto, thio, hydroxyl, and any other necessary protecting groups and their methods of deprotection are known in the art, such as those described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, which is incorporated in its entirety along with the references cited therein.

4. EXAMPLES

[0181] The following synthetic and biological examples are offered to illustrate this the present technology and are not to be construed in any way as limiting the scope of this the present technology. Unless otherwise stated, all

temperatures are in degrees Celsius.

[0182] The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used ( e.g ., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0183] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry,

recombinant DNA techniques and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd Edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Agricultural Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3^rd Ed. (Plenum Press) Vols A and B( 1992), and Organic Reactions, Volumes 1- 40 (John Wiley, and Sons, 1991).

[0184] The present technology is further understood by reference to the following examples, which are intended to be purely exemplary of the present technology. The present technology is not limited in scope by the exemplified embodiments, which are intended as illustrations of single aspects of the present technology only. Any methods that are functionally equivalent are within the scope of the present technology. Various modifications of the present technology in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures.

Such modifications fall within the scope of the appended claims.

[0185] In the examples below, the following abbreviations have the following meanings. +If an abbreviation is not defined, it has its generally accepted meaning.

aq. = aqueous

LC-MS = liquid chromatography-mass spectrometry

MS = mass spectrometry

THF = tetrahydrofuran

NaHCOa = sodium bicarbonate

DIEA = diisopropylethylamine

MS = mass spectrometry

NaH = sodium hydride

o/n = overnight

HATU = l-[Bis(dimethylamino) methylene]- 1H- 1,2,3- trl zolo[4,5-b]pyridinium 3-oxid

hexailuorophosphate

r.t. = room temperature

LAH = lithium aluminum hydride

DCM = dichloromethane

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

equiv. = equivalent

EtOAc = ethyl acetate

EtOH = ethanol

g = gram

h = hours

HC1 = hydrochloric acid

HPLC = high-performance liquid chromatography

HO Ac = acetic acid

M = molar MeOH = methanol

mg milligrams

mL milliliters

mmol millimols

mp melting point

m/z mass to charge ratio

NaCl sodium chloride

Na₂C0₃ sodium carbonate

NMR nuclear magnetic resonance

NaOH sodium hydroxide

Na₂S0₄ sodium sulfate

TLC thin layer chromatography

UV ultraviolet

wt % weight percent

mM micromolar

4.1. EXAMPLE 1: Fluorination syntheses

General experimental details:

[0186] Final compounds were confirmed by HPLC/MS analysis and

determined to be > 90%. H and ¹³C NMR spectra were recorded in CDCW (residual internal standard CHCW = d 7.26), DMSO-cfe (residual internal standard CD3SOCD₂H = d 2.50), methanol-c^ (residual internal standard CD₂HOD = d 3.20), or aceton e-cfe (residual internal standard CD3COCD₂H = d 2.05). The chemical shifts (d) reported are given in parts per million (ppm) and the coupling constants ( are in Hertz (Hz) . The spin multiplicities are reported as s = singlet, bs = broad singlet, bm = broad multiplet, d = doublet, t = triplet, q = quartet, p = pentuplet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, tt = triplet of triplet, and m = multiplet.

[0187] HPLC-MS analysis was carried out with gradient elution. Medium pressure liquid chromatography (MPLC) was performed with silica gel columns in both the normal phase and reverse phase.

[0188] Standard Reaction Conditions/ Experimental Procedures Aldehyde-Fluorination Reactions

Chamber A: 2 equiv SDI, 4 equiv KF

Formic Acid

Chamber B: 4 equiv Me₄NF, DMF

rt, 4 h

For isolated compounds: In a nitrogen-filled glovebox, benzaldehyde (0.2 mmol) and Me₄NF (74.4 mg, 0.8 mmol) were added to Chamber B of the two- chamber reaction vessel equipped with a magnetic stir-bar. 1, 1’- sulfonyldiimidazole (79.2 mg, 0.4 mmol) and KF (46.4 mg, 0.8 mmol) were added to Chamber A equipped with a magnetic stir-bar. The vessel was removed from the glovebox, formic acid (0.4 mL) was added to Chamber A, and the mixture was allowed to stir at room temperature for 5 minutes. Anhydrous iV,iV-dimethylformamide ( 1.0 mL) was added to Chamber B and the reaction was allowed to stir for 4 hours at room temperature. The reaction vessel was opened and ether (5 mL) was added to Chamber B, which was then transferred to a separatory funnel. The organic layer was washed with water ( 15 mL, 5X), dried with MgS0₄, filtered and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel chromatography using hexane and ethyl acetate.

For NMR yields: In a nitrogen-filled glovebox, benzaldehyde (0.2 mmol) and Me₄NF (74.4 mg, 0.8 mmol) were added to Chamber B of the two-chamber reaction vessel equipped with a magnetic stir-bar. I, G-sulfonyldiimidazole (79.2 mg, 0.4 mmol) and KF (46.4 mg, 0.8 mmol) were added to Chamber A equipped with a magnetic stir-bar. The vessel was removed from the glovebox, formic acid (0.4 mL) was added to Chamber A, and the mixture was allowed to stir at room temperature for 5 minutes. Anhydrous lV,lV-dimethylformamide ( 1.0 mL) was added to Chamber B and the reaction was allowed to stir for 4 hours at room temperature. Following the completion of the reaction, Chamber B was diluted with DCM (2.0 mL) and 4-fluoroanisole was added as an internal standard. The reaction mixture was analyzed by ¹⁹F NMR spectroscopy. The yields of difluoromethyl product are determined from the average of two runs.

l-bromo-4-(diiluoromethyl)benzene ( la). The reaction was performed using the standard conditions described above with 4-bromobenzaldehyde (37.0 mg, 0.2 mmol). Product la was obtained as a colorless oil (35.2 mg, 85%). The H, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for CzHsB^, 205.9543; found 205.9550. The isolated yield reported is the average of two runs (76% and 80%).

4-(diiluoromethyl)- l, r-biphenyl ( lb). The reaction was performed using the standard conditions described above with 4-phenylbenzaldehyde (37.2 mg, 0.2 mmol). Product lb was obtained as a white solid (27.0 mg, 66% yield, mp = 77.8 C). The H, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for Ci₃HioF₂, 204.0751; found 204.0750. The isolated yield reported is the average of two runs (67% and 65%).

l-iodo-4-(diiluoromethyl)benzene ( lc). The reaction was performed using the standard conditions described above with 4-iodobenzaldehyde (46.4 mg, 0.2 mmol). Product lc was obtained as a colorless oil (39.0 mg, 76%). Ή NMR (500 MHz, CDCb):□ 7.80 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.60 (t, J = 56.3 Hz, 1H). ⁱsC^H} NMR ( 125 MHz, CDCb): 137.89, 133.88, 127.24 (t, J = 6.0 Hz), 1 14. 19 (t, J = 239. 1 Hz), 97. 10. ¹⁹F NMR (471 MHz, CDCb): - 1 1 1.4 (d, J = 56.3 Hz). HRMS El (m/z): [M]+ calcd for C7H5IF₂, 253.9404; found 253.9400. The isolated yield reported is the average of two runs (71% and 81%).

l-chloro-4-(difluoromethyl)benzene ( Id). The reaction was performed using the standard conditions described above with 4-chlorobenzaldehyde (28.0 mg, 0.2 mmol). Product Id was obtained as a colorless oil ( 14.6 mg, 45%). The Ή, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for C7H5CIF2, 162.0048; found 162.0045. The isolated yield reported is the average of two runs (44% and 45%).

l-(diiluoromethyl)-2-methylbenzene ( le). The reaction was performed using the standard conditions described above with o-tulualdehyde (24.0 mg, 0.2 mmol). Product le was obtained as a colorless oil ( 15.6 mg, 55%). H NMR (500 MHz, CDCb): 7.46 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 6.72 (t, J = 55.5 Hz, 1H), 2.40 (s, 3H). ^C^H} NMR ( 125 MHz, CDCb): 136.20, 132.2, 130.99, 130.54, 125.94, 125.74 (t, J = 7.4 Hz), 1 14.41 (t, J = 237.8 Hz), 18.47. ¹⁹F NMR (471 MHz, CDCb): - 1 13. 10. HRMS El (m/z): [M]+ calcd for C₈H₈F₂, 142.0594; found 142.0593. The isolated yield reported is the average of two runs (56% and 54%) . Due to the high volatility of le (bp = 155 C), the isolated product could not be separated completely from ethyl acetate (<5%).

l-(diiluoromethyl) -2 -isopropylbenzene ( If). The reaction was performed using the standard conditions described above with 2-isopropylbenzaldehyde (29.8 mg, 0.2 mmol). Product If was obtained as a colorless oil ( 19.7 mg, 58%).

NMR (500 MHz, CDCb): 7.51 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.86 (t, J = 55.5 Hz, 1H), 3.27 (sept, J = 6.8 Hz, 1H), 1.29 (d, J = 6.8 Hz, 6H). ^C^H} NMR (125 MHz, CDCb): 147.51, 130.90, 130.85, 126.04, 125.87, 125.74 (t, J = 7.4 Hz), 1 14.06 (t, J = 55.5 Hz), 28.64, 24.02. ¹⁹F NMR (471 MHz, CDCb): - 1 10.32 (d, J = 54.0 Hz). HRMS El (m/z): [M]+ calcd for CioH_l2F₂, 170.0907; found 170.0905. The isolated yield reported is the average of two runs (62% and 54%).

l-(diiluoromethyl)-2,6-dimethylbenzene ( lg). The reaction was performed using the standard conditions described above with 2,6-dimethylbenzaldehyde (26.8 mg, 0.2 mmol). Product lg was obtained as a colorless oil ( 16.0 mg, 51%).

NMR (500 MHz, CDCh): 7.21 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.5 Hz, 2H), 6.98 (t, J = 54.3 Hz, 1H), 2.47 (s, 6H). ^C^H} NMR ( 125 MHz, CDCh): 137.03, 130.29, 129. 16, 1 14.46 (t, J = 236. 1 Hz), 19.46. ¹⁹F NMR (471 MHz, CDCh): - 1 1 1.97 (d, J = 54.3 Hz). HRMS El (m/z): [M]+ calcd for C₉H_l0F₂, 156.0751;

found 156.0752. The isolated yield reported is the average of two runs (50% and 52%).

2 -(diiluoromethyl)- 1, 1’-biphenyl ( lh). The reaction was performed using the standard conditions described above with 2-phenylbenzaldehyde (36.4 mg, 0.2 mmol). Product lh was obtained as a colorless oil (29.3 mg, 72%). The H, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for Ci₃H_l0F₂, 204.0751, found 204.0759. The isolated yield reported is the average of two runs (70% and 74%).

4-(diiluoromethyl)-benzonitrile ( li). The reaction was performed using the standard conditions described above with 4-formylbenzonitrile (26.2 mg, 0.2 mmol). Product li was obtained as a colorless oil (25.2 mg, 82%). The Ή, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for C₈H₅NF₂, 153.0390; found 153.0396. The isolated yield reported is the average of two runs (80% and 84%) .

Methyl 4-(diiluoromethyl)benzoate ( lj). The reaction was performed using the standard conditions described above with methyl 4-formylbenzoate (32.8 mg, 0.2 mmol). Product lj was obtained as a white solid (36.0 mg, 97%, mp = 89.2 C). The H, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for C9H8O2F2, 186.0492; found 186.0490. The isolated yield reported is the average of two runs (97% and 97%).

4-(diiluoromethyl)-phenyl- l-pyrrolidinyl methanone ( lk). The reaction was performed using the standard conditions described above with 4- (pyrrolidinylcarbonyl)-benzaldehyde (40.6 mg, 0.2 mmol). Product lk was obtained as a colorless oil (38.7 mg, 86%, mp = 89.2 C). Ή NMR (500 MHz, CDCb): 7.57 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 6.64 (t, J = 56.3 Hz, 1H), 3.63 (t, J = 6.9 Hz, 2H), 3.37 (t, J = 6.9 Hz, 2H), 1.95 (pent, J = 6.6 Hz,

2H), 1.87 (pent, J = 6.6 Hz, 2H). ^C^H} NMR ( 125 MHz, CDCb): 168.65,

139.59, 135.54 (t, J = 22.4 Hz), 127.41, 125.58 (t, J = 6. 1 Hz), 1 14. 18 (t, J = 239.4 Hz), 49.50, 46.20, 26.36, 24.41. ¹⁹F NMR (471 MHz, CDCb): - 1 1 1.59 (t, J = 56.3 Hz). HRMS El (m/z): [M]+ calcd for Ci2H_l3NOF₂, 225.0965; found

225.0965. The isolated yield reported is the average of two runs (85% and 87%).

l-[4-(difluoromethyl)phenyl]- lH-pyrrole ( 11). The reaction was performed using the standard conditions described above with 4-( lH-pyrrol- l- yl)benzaldehyde (34.2 mg, 0.2 mmol). Product 11 was obtained as a colorless oil ( 10.4 mg, 27%,). m NMR (500 MHz, CDCb): 7.97 (d, J = 2. 1 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.75 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.27 (s, 1H), 6.68 (t, J = 56.4 Hz, 1H), 6.50 (s, 1H). ^C^H} NMR (125 MHz, CDCb): 141.65, 126.93 (t, J = 6. 1 Hz), 126.76, 1 18.99, 1 14.25 (t, J = 238.8 Hz), 108.21. ¹⁹F NMR (471 MHz, CDCb): - 1 10.39 (d, J = 56.5 Hz). HRMS El (m/z): [M]+ calcd for CnH₉NF₂, 193.0703; found 193.0705. The isolated yield reported is the average of two runs (25% and 30%).

l-(diiluoromethyl)-4-( l, 1-dimethylethyl) benzene ( lm). The reaction was performed using the standard conditions described above with 4-( l, l- dimethylethyl)benzaldehyde (32.4 mg, 0.2 mmol). Product lm was obtained as a colorless oil ( 17.0 mg, 46%). The Ή, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for C nH_l4F2, 184. 1064; found 184. 1061. The isolated yield reported is the average of two runs (47% and 45%).

2-[4-(diiluoromethyl)phenyl]-pyridine ( In). The reaction was performed using the standard conditions described above with 4-(2- pyridinyl)benzaldehyde (36.6 mg, 0.2 mmol). Product In was obtained as a colorless oil (32.4 mg, 79%,). NMR (500 MHz, CDCb): 8.70 (dt, J = 4.5 & 1.3 Hz, 1H), 8.06 (d, J = 7.8 Hz, 2H), 7.73 - 7.79 (m, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.26 - 7.30 (m, 1H), 6.69 (t, J = 56.5 Hz, 1H). ^C^H} NMR ( 125 MHz, CDCb): 156.32, 149.83, 141.68, 136.88, 134.69 (t, J = 22.4 Hz), 127. 17, 125.97 (t, J = 6. 1 Hz), 122.67, 120.75, 1 14.59 (t, J = 238.9 Hz). ¹⁹F NMR (471 MHz, CDCb): - 1 10.89 (d, J = 56.5 Hz). HRMS El (m/z): [M]+ calcd for C_I2H₉NF₂, 205.0703; found 205.0700. The isolated yield reported is the average of two runs (77% and 81%).

2 -(dilluoromethyl) pyridine ( lo). The reaction was performed using the standard conditions described above with 2-pyridinecarboxaldehyde (21.4 mg, 0.2 mmol). Product lo was obtained as a colorless oil ( 14.2 mg, 55%). The H, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for C₆H₅NF₂, 129.0390; found 129.0387. The isolated yield reported is the average of two runs (50% and 60%) .

2 -(dilluoromethyl) -3 -methoxypyridine ( lp). The reaction was performed using the standard conditions described above with 3-methoxy-2- pyridinecarboxaldehyde (27.4 mg, 0.2 mmol). Product lp was obtained as a colorless oil (28.5 mg, 90%,). NMR (500 MHz, CDCh): 8.25 (d, J = 4.5 Hz,

1H), 7.36 - 7.38 (m, 1H), 7.31 (d, J = 8.5 Hz, 1H), 6.89 (t, J = 54.3 Hz, 1H), 3.89 (s, 3H). ¹³C{ⁱH} NMR ( 125 MHz, CDCh): 154. 19, 141. 10 (d, J = 4.7 Hz), 126.52 (d, J = 28.8 Hz), 1 18.90 (d, J = 27. 1 Hz), 1 13.33, 1 1 1.47 (t, J = 234.6 Hz),

55.60. ¹⁹F NMR (471 MHz, CDCh): - 1 19.46 (d, J = 54.4 Hz). HRMS El (m/z): [M]+ calcd for C7H7NOF₂, 159.0496; found 159.0499. The isolated yield reported is the average of two runs (90% and 90%) .

2-(diiluoromethyl)-6-methylpyridine ( lq). The reaction was performed using the standard conditions described above with 6-methyl-2- pyridinecarboxaldehyde (24.2 mg, 0.2 mmol). Product lq was obtained as a colorless oil (24.0 mg, 80%,). NMR (500 MHz, CDCh): 7.71 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 6.4 Hz, 1H), 6.59 (t, J = 55.6 Hz, 1H), 2.59 (s, 3H). ⁱsC^H} NMR ( 125 MHz, CDCh): 158.60, 152.20, 137.35, 125.05, 1 17.02 (t, J = 3.3 Hz), 1 14.03 (t, J = 240.4 Hz), 24.23. ¹⁹F NMR (471 MHz, CDC ): - 1 15.79 (d, J = 55.6 Hz). HRMS El (m/z): [M]+ calcd for C7H7NF₂, 143.0547; found 143.0547. The isolated yield reported is the average of two runs (78% and 82%). Due to the high volatility of lq (bp = 150 C), the isolated product could not be separated completely from ethyl acetate (<3%).

5-bromo-2-(diiluoromethyl)pyridine ( lr). The reaction was performed using the standard conditions described above with 5-bromo-2- pyridinecarboxaldehyde (37.2 mg, 0.2 mmol). Product lr was obtained as a colorless oil (34.0 mg, 82%,). NMR (500 MHz, CDCb): 8.38 (s, 1H), 7.96 (t, J = 7.2 Hz, 1H), 7.05 (d, J = 8.5 Hz), 6.72 (t, J = 55.7 Hz, 1H). ^C^H} NMR ( 125 MHz, CDCb): 145.90 (d, J = 16.2 Hz), 138.69 (d, J = 8.7 Hz), 128.21, 1 12.70 (t, J = 239.5 Hz), 1 10.22, 109.92. ¹⁹F NMR (471 MHz, CDCb): - 1 15.62 (d, J = 55.6 Hz). HRMS El (m/z): [M]+ calcd for C₇H₄BrNF₂, 206.9495; found 206.9494. The isolated yield reported is the average of two runs (78% and 86%).

5-iluoro-2-(diiluoromethyl)pyridine ( Is). The reaction was performed using the standard conditions described above with 5-nitro-2- pyridinecarboxaldehyde (30.4 mg, 0.2 mmol), providing Is in 80% yield as determined by ¹⁹F NMR spectroscopic analysis of the crude reaction mixture. The identity of the product was further confirmed by GCMS analysis ( m/z = 147). The yield reported is the average of two runs (76% and 84%).

3 -(diiluoromethyl) pyridine ( It). The reaction was performed using the standard conditions described above with 3-pyridinecarboxaldehyde (21.4 mg,

0.2 mmol). Product It was obtained as a colorless oil ( 17.0 mg, 66%). The H,

¹³C and ¹⁹F NMR spectra were consistent with those published in the literature.

HRMS El (m/z): [M]+ calcd for CeHsNFa, 129.0390; found 129.0392. The isolated yield reported is the average of two runs (50% and 60%) . Due to the high volatility of It (bp = 165 C), the isolated product could not be separated completely from ethyl acetate (< 10%).

3-chloro-4-(difluoromethyl)pyridine ( lu). The reaction was performed using the standard conditions described above with 3-chloro-4- pyridinecarboxaldehyde (28.3 mg, 0.2 mmol), providing lu in 34% yield as determined by ¹⁹F NMR spectroscopic analysis of the crude reaction mixture. The identity of the of the product was further confirmed by GCMS analysis (m/z = 163). The yield reported is the average of two runs (33% and 35%).

2 -(diiluoromethyl) quinoline ( lv). The reaction was performed using the standard conditions described above with 2-quinolinecarboxaldehyde (31.4 mg, 0.2 mmol). Product lv was obtained as a white solid (32. 1 mg, 90%). The Ή,

¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for Ci₀H₇NF₂, 179.0547; found 179.0549. The isolated yield reported is the average of two runs (90% and 90%) .

4-(diiluoromethyl)quinoline ( lw). The reaction was performed using the standard conditions described above with 4-quinolinecarboxaldehyde (31.4 mg, 0.2 mmol). Product lw was obtained as a white solid (34.5 mg, 96%). Ή NMR (500 MHz, CDCh): 9.00 (d, J = 4.3 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.77 (t, J = 8.3 Hz, 1H), 7.64 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 4.3 Hz, 1H), 7. 14 (t, J = 54.6 Hz, 1H). ^C^H} NMR ( 125 MHz, CDCh): 149.96, 148.59, 137.76, 130.40, 129.89, 127.78, 124. 10, 123.25, 1 17.91 (t, J = 7.6 Hz), 1 13.26 (t, J = 240.3 Hz). ¹⁹F NMR (471 MHz, CDCh): - 1 15.06 (d, J = 54.6 Hz). HRMS El (m/z): [M]+ calcd for C₁₀H7NF₂, 179.0547; found 179.0545. The isolated yield reported is the average of two runs (95% and 97%).

4-(diiluoromethyl)isoquinoline ( lx). The reaction was performed using the standard conditions described above with 4-isoquinolinecarboxaldehyde (31.4 mg, 0.2 mmol). Product lx was obtained as a white solid (31.7 mg, 89%). H NMR (500 MHz, CDCb): 9.32 (s, 1H), 8.63 (s, 1H), 8. 17 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.79 (t, J = 8.2 Hz, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.04 (t, J =

54.5 Hz, 1H). ¹³C{¹H} NMR ( 125 MHz, CDCb): 156.00, 141.64 (t, J = 9.4 Hz), 132. 14, 131.66, 128.41, 127.91, 123.42, 123.25, 123. 14, 1 15.05 (t, J = 238.5 Hz). ¹⁹F NMR (471 MHz, CDCb): - 1 1 1.03 (d, J = 54.4 Hz). HRMS El (m/z): [M]+ calcd for C10H7NF2, 179.0547; found 179.0544. The isolated yield reported is the average of two runs (90% and 88%) .

l-[(dipropylamino)sulfonyl]-4-(diiluoromethyl)benzene ( ly). The reaction was performed using the standard conditions described above with probenecid benzaldehyde (53.8 mg, 0.2 mmol). Product ly was obtained as a colorless oil (47.8 mg, 82%). NMR (500 MHz, CDCb): 7.89 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 6.69 (t, J = 54.5 Hz, 1H), 3.09 (t, J = 7.7 Hz, 4H), 1.56 (sext, J =

7.6 Hz, 4H), 0.87 (t, J = 7.4 Hz, 6H). ¹³^H} NMR ( 125 MHz, CDCb): 142.59, 137.91, 127.42, 126.31 (t, J = 6. 1 Hz), 1 13.59 (t, J = 240.2 Hz), 50.00, 21.99, 1 1. 14. ¹⁹F NMR (471 MHz, CDCb): - 1 12.54 (d, J = 56.0 Hz). HRMS El (m/z):

[M]+ calcd for Ci₃HigN0₂SF₂, 291. 1 105; found 291. 1 104. The isolated yield reported is the average of two runs (84% and 80%) .

6-(4-methoxy-3-tricyclo[3.3. 1 ljdee- I-ylphenyl)-2- (diiluoromethyljngiphthalene ( lz). The reaction was performed using the standard conditions described above with adapalene benzaldehyde (80.0 mg, 0.2 mmol). Product lz was obtained as a white solid (34.0 mg, 42%, mp = 301C). NMR (500 MHz, CDCh): 7.98 (t, J = 21.2 Hz, 3H), 7.94 (d, J = 23.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.81 (t, J = 56.5 Hz, 1H), 3.91 (s, 3H), 2. 19 (s, 6H), 2. 1 1 (br, 3H), 1.81 (s, 6H). ^C^H} NMR (125 MHz, CDCh): 158.80, 140.53, 138.97, 134.70, 132.60, 131.28, 128.96, 128.83, 126.62, 125.92, 125.67, 124.86, 122.32 (t, J = 4.8 Hz), 1 15. 10 (t, J = 238.3 Hz), 1 12.08, 55. 16, 40.60, 37. 19, 37. 12, 29. 10. ¹⁹F NMR (471 MHz, CDCh): - 109.65 (d, J = 56.5 Hz).

HRMS El (m/z): [M]+ calcd for C₂₈H₂₈0F₂, 418.2108; found 418.2101. The isolated yield reported is the average of two runs (37% and 47%).

Alcohol-Fluorination Reactions

H Chamber A: 2 equiv SDI, 4 equiv KF

Formic Acid

Chamber B: 4 equiv Me₄NF, DMF

rt, 4 h

For isolated compounds: In a nitrogen-filled glovebox, benzyl alcohol (0.2 mmol) and Me₄NF (74.4 mg, 0.8 mmol) were added to Chamber B of the two- chamber reaction vessel equipped with a magnetic stir-bar. 1, 1’- sulfonyldiimidazole (79.2 mg, 0.4 mmol) and KF (46.4 mg, 0.8 mmol) were added to Chamber A equipped with a magnetic stir-bar. The vessel was removed from the glovebox, formic acid (0.4 mL) was added to Chamber A, and the mixture was allowed to stir at room temperature for 5 minutes. Anhydrous lV,lV-dimethylformamide ( 1.0 mL) was added to Chamber B and the reaction was allowed to stir for 4 hours at room temperature. The reaction vessel was opened and ether (5 mL) was added to Chamber B, which was then transferred to a separatory funnel. The organic layer was washed with water (5 x 15 mL), dried with MgS0₄, filtered, and the solvent was removed under reduced pressure. The crude reaction mixture was purified by silica gel chromatography

(hexanes:ethyl acetate eluent).

For NMR yields: In a nitrogen-filled glovebox, benzyl alcohol (0.2 mmol) and Me₄NF (74.4 mg, 0.8 mmol) were added to Chamber B of the two-chamber reaction vessel equipped with a magnetic stir-bar. I, G-sulfonyldiimidazole (79.2 mg, 0.4 mmol) and KF (46.4 mg, 0.8 mmol) were added to Chamber A equipped with a magnetic stir-bar. The vessel was removed from the glovebox, formic acid (0.4 mL) was added to Chamber A, and the mixture was allowed to stir at room temperature for 5 minutes. Anhydrous !V,lV-dimethylformamide ( 1.0 mL) was added to Chamber B and the reaction was allowed to stir for 4 hours at room temperature. Following the completion of the reaction, Chamber B was diluted with DCM (2.0 mL) and 4-fluoroanisole was added as an internal standard. The reaction mixture was analyzed by ¹⁹F NMR spectroscopy. The yields of monoiluoromethyl product are represented as the average of two runs.

4-(fluoromethyl)- l, r-biphenyl ( la). The reaction was performed using the standard conditions described above with biphenyl-4-methanol (36.8 mg, 0.2 mmol). Product la was obtained as a white solid (33.0 mg, 89% yield, mp =

62. 1 C). The Ή, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for Ci3HnF, 186.0845; found 186.0853. The isolated yield reported is the average of two runs (90% and

88%) .

l-bromo-4-(fluoromethyl)-benzene ( lb). The reaction was performed using the standard conditions described above with 4-bromobenzyl alcohol (36.8 mg, 0.2 mmol). Product lb was obtained as a colorless oil (37.4 mg, 88% yield). The Ή, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for CyHeFBr, 187.9637; found

187.9645. The isolated yield reported is the average of two runs (90% and

86%) .

l-chloro-4-(fluoromethyl)-benzene ( lc). The reaction was performed using the standard conditions described above with 4-chlorobenzyl alcohol (28.5 mg, 0.2 mmol). Product lc was obtained as a colorless oil (26.0 mg, 90% yield). The H, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for C7H6FCI, 144.0142; found 144.0143. The isolated yield reported is the average of two runs (90% and 90%) .

4-(fluoromethyl)-benzonitrile ( Id). The reaction was performed using the standard conditions described above with 4- (hydroxymethyl) benzonitrile (26.6 mg, 0.2 mmol). Product Id was obtained as a colorless oil (23.2 mg, 86% yield) The Ή, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for CsHeFN, 135.0484; found 135.0489. The isolated yield reported is the average of two runs (87% and 85%).

2-(isopropyl)- l-(iluoromethyl)benzene ( le). The reaction was performed using the standard conditions described above with 2-(isopropyl)- l-

(hydroxymethyl) benzene (30.0 mg, 0.2 mmol). Product le was obtained as a colorless oil (26.2 mg, 86% yield). Ή NMR (500 MHz, CDCb): 7.33 - 7.37 (m,

3H), 7.20 - 7.23 (m, 1H), 5.52 (d, J = 48.2 Hz, 2H), 3.22 (sept, J = 6.8 Hz, 1H),

1.28 (d, J = 6.9 Hz, 6H). ¹³C NMR ( 125 MHz, CDCb): 147.99 (d, J = 3.3 Hz), 132.70 (d, J = 15.6 Hz), 129.57 (d, J = 3.5 Hz), 129.40 (d, J = 7.4 Hz), 125.80 (d, J = 1.4 Hz), 125.56 (d, J = 2.0 Hz), 83.59 (d, J = 165.0 Hz), 28.94, 23.95. ¹⁹F NMR (471 MHz, CDCh): -203.70 (t, J = 48.2 Hz). HRMS El (m/z): [M]+ calcd for CioHi3F, 152. 1001; found 152. 1005. The isolated yield reported is the average of two runs (89% and 84%) .

2 -methyl- l-(fluoromethyl) benzene ( If). The reaction was performed using the standard conditions described above with 2-(methyl)- l- (hydroxymethyl) benzene (24.4 mg, 0.2 mmol). Product If was obtained as a colorless oil ( 16.9 mg, 68% yield) NMR (500 MHz, CDCh): 7.31 (d, J = 7.6 Hz, 1H), 7.24 - 7.29 (m, 1H), 7.21 (t, J = 7.2 Hz, 2H), 5.47 (d, J = 47.9 Hz, 2H), 2.37 (s, 3H). ¹³C NMR ( 125 MHz, CDCh): 136.89 (d, J = 2.3 Hz), 134.27 (d, J = 7.8 Hz), 130.37 (d, J = 1.3 Hz), 129.08 (d, J = 4.2 Hz), 128.65 (d, J = 8.0 Hz), 125.98 (d, J = 1.2 Hz), 83.86 (J = 164.2 Hz), 18.58. ¹⁹F NMR (471 MHz, CDCh): -209. 17 (t, J = 48.4 Hz). HRMS El (m/z): [M]+ calcd for C₈H₉F, 124.0688;

found 124.0662. The isolated yield reported is the average of two runs (70% and 66%).

l-( l, l-dimethylethyl)-4-(fluoromethyl)benzene ( lg). The reaction was performed using the standard conditions described above with 1-( 1, 1- dimethylethyl)-4-(hydroxymethyl)benzene (32.8 mg, 0.2 mmol). Product lg was obtained as a colorless oil (24.3 mg, 73% yield). H NMR (500 MHz, CDCh):

7.42 (d, J = 8. 1 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.40 (d, J = 48.3 Hz, 2H), 1.33 (s, 9H).¹³C NMR ( 125 MHz, CDCh): 151.92, 133.25 (d, J = 8.2 Hz), 127.62 (d, J = 3.6 Hz), 125.52 (d, J = 1.2 Hz), 125.26, 85.20 (d, J = 163.4 Hz), 34.65, 31.28. ¹⁹F NMR (471 MHz, CDCh): -204.45 (t, J = 47.4 Hz). HRMS El (m/z): [M]+ calcd for CnHieF, 166. 1 158; found 166. 1 163. The isolated yield reported is the average of two runs (74% and 72%).

l-(fluoromethyl) naphthalene ( lh). The reaction was performed using the standard conditions described above with 1-naphthalene methanol (31.6 mg, 0.2 mmol). Product lh was obtained as a colorless oil (25.6 mg, 80% yield). The Ή, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for C₁₁H₉F, 160.0688; found 160.0695. The isolated yield reported is the average of two runs (76% and 84%).

2 -(iluoromethyl) pyridine ( li). The reaction was performed using the standard conditions described above with 2-pyridine methanol (21.8 mg, 0.2 mmol). Product li was obtained as a colorless oil (9. 1 mg, 41% yield). H NMR (500 MHz, CDCh): 8.58 (d, J = 1.6 Hz, 1H), 7.76 (t, J = 4.7 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.25 (obscured by residual solvent peak, 1H), 5.54 (d, J = 49.0 Hz, 2H). ¹³C NMR ( 125 MHz, CDCh): 156.47 (d, J = 2.3 Hz), 149.21, 136.85,

123.00, 120.48 (d, J = 2.2 Hz), 85.08 (d, J = 164.0 Hz). ¹⁹F NMR (471 MHz, CDCh): -221. 14 (t, J = 48.2 Hz). HRMS El (m/z): [M]+ calcd for C₆H₆FN,

1 1 1.0484; found 1 1 1.0480. The isolated yield reported is the average of two runs (43% and 39%). Due to the high volatility of li (bp = 145 C), the isolated product could not be separated completely from ethyl acetate (<5%). The yield of li as determined by ¹⁹F NMR spectroscopic analysis of the crude reaction mixture was determined to be 94%.

4-(fluoromethyl)pyridine ( lj). The reaction was performed using the standard conditions described above with 4-pyridine methanol (21.8 mg, 0.2 mmol), providing lj in 89% yield as determined by ¹⁹F NMR spectroscopic analysis of the crude reaction mixture. The identity of the of the product was further confirmed by GCMS analysis ( m/z = 1 1 1). The yield reported is the average of two runs (89% and 88%) .

2 -(iluoromethyl) quinoline ( lk). The reaction was performed using the standard conditions described above with 2-quinoline methanol (31.4 mg, 0.2 mmol). Product lk was obtained as a colorless oil (32. 1 mg, 90% yield). The H, ¹³C and ¹⁹F NMR spectra were consistent with those published in the literature. HRMS El (m/z): [M]+ calcd for CioHsFN, 161.0641; found 161.0645. The isolated yield reported is the average of two runs (88% and 92%).

2,6-bis(iluoromethyl)pyridine ( 11). The reaction was performed using the standard conditions described above with 2,6-bis(hydroxymethyl)pyridine (28.6 mg, 0.2 mmol). Product 11 was obtained as a colorless oil (9.2 mg, 32% yield).

NMR (500 MHz, CDCh): 7.81 (t, J = 5.6 H, 1H), 7.41 (d, J = 7.6 Hz, 2H), 5.51 (d, J = 48.9 Hz, 4H). ¹³C NMR ( 125 MHz, CDCh): 155.91 (d, J = 3.4 Hz), 137.73, 1 19.82 (d, J = 2.2 Hz), 84.87 (d, J = 165.0 Hz). ¹⁹F NMR (471 MHz, CDCh): - 221.32 (t, J = 48.7 Hz). HRMS El (m/z): [M]+ calcd for C₇H₇F₂N, 143.0547; found 143.0543. The isolated yield reported is the average of two runs (32% and 32%). The yield of 11 as determined by ¹⁹F NMR spectroscopic analysis of the crude reaction mixture was determined to be 92%.

l-[(dipropylamino)sulfonyl]-4-(fluoromethyl)benzene ( lm). The reaction was performed using the standard conditions described above with probenecid benzyl alcohol (54.6 mg, 0.2 mmol). Product lm was obtained as a colorless oil (48.6 mg, 89%). Ή NMR (500 MHz, CDCh): 7.82 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 7.3 Hz, 2H), 5.49 (d, J = 48.8 Hz, 2H), 3.07 (t, J = 5.6 Hz, 4H), 1.55 (sext, J = 6.0 Hz, 4H), 0.87 (t, J = 5.5 Hz, 6H). ^C^H} NMR ( 125 MHz, CDCb): 140.68 (d, J = 8.7 Hz), 140.30 (d, J = 1.2 Hz), 127.33, 127.07 (d, J = 8.2 Hz), 83.99 (d, J = 165.5 Hz), 50.00, 22.00, 1 1. 16. ¹⁹F NMR (471 MHz, CDCb): -213.44 (t, J = 47.6 Hz). HRMS El (m/z): [M]+ calcd for Ci₃H₂oN0₂SF, 273. 1 199; found 273. 1200. The isolated yield reported is the average of two runs (86% and 92%).

6-(4-methoxy-3-tricydo[3.3. 1. l]dec l-ylphenyl)-2- (fluoromethyl) naphthalene ( In). The reaction was performed using the standard conditions described above with adapalene benzyl alcohol (80.2 mg, 0.2 mmol). Product In was obtained as a white solid (41.6 mg, 42%, mp = 304 - 306 C).

NMR (500 MHz, CDCb): 8.00 (s, 1H), 7.91 (t, J = 6.5 Hz, 2H), 7.84 (s, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.60 (d, J = 1.2 Hz, 1H), 7.51 (dd, J = 5.5 & 3.2 Hz, 2H), 7.01 (d, J = 7.0 Hz, 1H), 5.60 (d, J = 45.6 Hz, 2H), 3.91 (s, 3H), 2.20 (s,

6H), 2. 1 1 (br, 3H), 1.81 (br, 6H). ^C^H} NMR ( 125 MHz, CDCb): 158.66,

139.62, 138.90, 133.74, 133.27, 133. 14, 132.91, 131.88, 128.60, 128.41, 126.59 (d, J = 4.3 Hz), 126.22, 125.89, 125.59, 125.33 (d, J = 2.3 Hz), 124.84, 1 12.08, 85.49 (d, J = 164.0 Hz), 55. 16, 40.62, 37. 14, 29. 12. ¹⁹F NMR (471 MHz, CDCb): -206. 14 (t, J = 48.0 Hz). HRMS El (m/z): [M]+ calcd for C₂₈H₂₉OF, 400.2202; found 400.2200. The isolated yield reported is the average of two runs (40% and 44%) .

Keto-Fluorination Reactions

Q Chamber A: 2.0 equiv SDI, 4.0 equiv KF

Formic Acid

Chamber B: 4.0 equiv Me₄NF, DMF

rt, 4 h

In a nitrogen-filled glovebox, ethyl 2-pyridine glyoxylate ( 179.2 mg, 1.0 mmol) and Me₄NF (372.6 mg, 4.0 mmol) were added to Chamber B of the two- chamber reaction vessel, which was also equipped with a magnetic stir-bar. I, G-Sulfonyldiimidazole (396.0 mg, 2.0 mmol) and KF (232.0 mg, 4.0 mmol) were added to Chamber A, which was also equipped with a magnetic stir-bar. The vessel was removed from the glovebox, formic acid ( 1.0 mL) was added to Chamber A, and the mixture was allowed to stir at room temperature for 5 min. Anhydrous !V,lV-dimethylformamide (2.5 mL) was added to Chamber B, and the reaction was allowed to stir for 4 h at room temperature. Diethyl ether (25 mL) was added to Chamber B, and this mixture was then transferred to a

separatory funnel. The organic layer was washed with water (5 x 50 mL) and then dried over MgS0₄, and the solvent was removed under reduced pressure. The crude reaction mixture was purified by chromatography of silica gel (0% -> 30% ethyl acetate in hexanes; R_F = 0.51) to afford ethyl 2- pyridinediiluoroacetate as a colorless oil ( 165.0 mg, 82% yield). H NMR (500 MHz, CDCb): 8. 13 (d, J = 4.7 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.90 (t, J = 4.7 Hz, 1H), 3.85 (q, J = 7. 1 Hz, 2H), 0.81 (t, J = 7. 1 3H). ¹⁹F NMR (471 MHz, CDCb): -105.92 (s).

Chamber A: 2.0 equiv SDI, 4.0 equiv KF

Formic Acid

Chamber B: 4.0 equiv Me₄NF, DMF

rt, 4 h

In a nitrogen-filled glovebox, ethyl 2-oxo-2-phenylacetate ( 17.8 mg, 0. 1 mmol) and Me₄NF (37.2 mg, 0.4 mmol, 4.0 equiv) were added to Chamber B of the two-chamber reaction vessel, which was also equipped with a magnetic stir- bar. I, G-Sulfonyldiimidazole (39.6 mg, 0.2 mmol) and KF (23.2 mg, 0.4 mmol) were added to Chamber A, which was also equipped with a magnetic stir-bar. The vessel was removed from the glovebox, formic acid (0.2 mL) was added to Chamber A, and the mixture was allowed to stir at room temperature for 5 min. Anhydrous !V,lV-dimethylformamide (0.5 mL) was added to Chamber B, and the reaction was allowed to stir for 24 h at room temperature. Chamber B was then diluted with dichloromethane (2.0 mL), and 4-fluoroanisole was added as an NMR standard. The reaction mixture was analyzed by ¹⁹F NMR spectroscopy; the yield of the iluorinated product was 60% compared to the internal

standard. Ch b A

yield: 62%

Same general procedure (though differing amounts of reagents) as above.

4.2. EXAMPLE 2: Classic fluorination reaction failure

Classic fluorination with perfluoro- l-butanesulfonyl fluoride gives no product.

In a nitrogen-filled glovebox, ethyl 2-pyridine glyoxylate ( 179.2 mg, 1.0 mmol) and Me₄NF (372.6 mg, 4.0 mmol) were added to the reaction vessel, which was also equipped with a magnetic stir-bar. Perfluoro- l-butanesulfonyl fluoride (PBSF, 2.0 mmol) was added. Anhydrous tetrahydrofuran (THF) (2.5 mL) was added and the reaction was allowed to stir for 24 h at room

temperature. Diethyl ether (25 mL) was added and this mixture was then transferred to a separatory funnel. The organic layer was washed with water (5 x 50 mL) and then dried over MgS0₄, and the solvent was removed under reduced pressure. The crude reaction mixture afford no product, ethyl 2- pyridinedifluoroacetate as a colorless oil (0% yield) .

[0189] While some embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compounds of the present technology or salts, agricultural

compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and

embodiments.

[0190] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0191] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms“comprising,” “including,”“containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology.

Additionally, the phrase“consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase“consisting of’ excludes any element not specified.

[0192] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present technology. This includes the generic description of the present technology with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0193] All publications, patent applications, issued patents, and other documents (for example, journals, articles and/or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0194] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

[0195] While the invention has been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0196] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

WE CLAIM

1. A process to make a compound of formula I:

I I I

, or a salt thereof, the process comprising

mixing the following compounds:

f) a compound of formula II: II or a salt thereof,

g) I, G-thiocarbonyldiimidazole (SDI),

h) N(CH₃)₄F,

i) a fluoride salt; and

j) an acid,

wherein:

Y is hydrogen or fluorine;

each of U, J, E, Z, and T is independently selected from the group consisting of: CH, CR¹, and N, wherein up to 3 of U, J, E, Z, and T may be N; each R¹ is independently selected from the group consisting of: hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs

substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ substituted cycloalkyl, C₃-C₈ heterocycloalkyl, C₃-C₈ substituted heterocycloalkyl, C₃-C7 heteroaryl, C₃-C7 substituted heteroaryl, phenyl, substituted phenyl, cyano, and nitro; and wherein any two R¹ groups may be covalently bonded together to form a cycloalkyl, heterocycloalkyl, heteroaryl, or phenyl ring;

2. The process of claim 1 wherein Y is F and E is CR¹ where R¹ is C3-C8 heterocycloalkyl.

3. The process of claim 1 Y is F and wherein Z is CR¹ where R¹ is Ci-Cs substituted alkoxy.

4. The process of claim 1 Y is H and wherein Z is CR¹ where R¹ is

substituted amino.

5. The process of claim 1 wherein Y is F and T is CR¹ where R¹ is Ci-Cs alkyl and U is CR¹ where R¹ is substituted alkylthio.

6. The process of claim 1 wherein Y is H and Z is CR¹ where R¹ is C3-C8 substituted heterocycloalkyl, U is CR¹ where R¹ is hydroxy, and J is CR¹ where R¹ is C₃-C7 substituted heteroaryl.

7. A process to make a compound of formula III:

, or a salt thereof, the process comprising

mixing the following compounds:

f) a compound of formula IV: IV , or a salt thereof, g) I, G-thiocarbonyldiimidazole (SDI),

h) N(CH₃)₄F,

i) a fluoride salt; and

j) an acid,

wherein:

each of U, J, E, Z, and T is independently selected from the group consisting of: CH, CR¹, and N. wherein up to 3 of U, J, E, Z, and T may be N; each R¹ is independently selected from the group consisting of:

hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs

substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-C₈ cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C₃-C7 heteroaryl, C₃-C7 substituted heteroaryl, phenyl, substituted phenyl, cyano, and nitro;

8. The process of claim 7 wherein R² is hydrogen.

9. The process of claim 7 wherein R² is Ci-Cs alkyl.

10. The process of claim 7 wherein R² is Ci-Cs substituted alkynyl.

1 1. The process of claim 7 wherein E is CR¹ where R¹ is Ci-Cs alkyl; and R² is Ci-Cs alkyl.

12. The process of claim 7 wherein Z is CR¹ where R¹ is Ci-Cs substituted alkoxy, U is CR¹ where R¹ is carboxylate, J is CR¹ where R¹ is Cl, T is CR¹ where R¹ is hydroxyl; and R² is CH₃.

13. A process to make a compound of formula V:

, or a salt thereof, the process comprising mixing the following compounds:

f) a compound of formula VI:

, or a salt thereof, g) I, G-thiocarbonyldiimidazole (SDI),

h) N(CH₃)₄F,

i) a fluoride salt; and

j) an acid,

wherein:

m is from 0-4;

each R¹ is independently selected from the group consisting of: hydrogen, halogen, carboxy ester, carboxylate, amino, substituted amino, hydroxyl, thiol, alkylthio, substituted alkylthio, Ci-Cs alkoxy, Ci-Cs substituted alkoxy, Ci-Cs alkyl, Ci-Cs substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C₃-C₈ cycloalkyl, C3-C8 substituted cycloalkyl, C3-C8 heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C₃-C7 heteroaryl, C₃-C7 substituted heteroaryl, phenyl, substituted phenyl, cyano, and nitro; R² is selected from the group consisting of: hydrogen, Ci-Cs alkyl, Ci- Ce substituted alkyl, Ci-Cs alkenyl, Ci-Cs substituted alkenyl, Ci-Cs alkynyl, Ci-Cs substituted alkynyl, C3-C8 cycloalkyl, C3-C8 substituted cycloalkyl, C3- Cs heterocycloalkyl, C3-C8 substituted heterocycloalkyl, C3-C7 heteroaryl, C3- C7 substituted heteroaryl, phenyl, and substituted phenyl;

14. The process of claim 13 wherein m is 2.

15. The process of claim 13 wherein m is 2 and one R¹ is Ci-Cs alkoxy or Ci-Cs substituted alkoxy.

16. The process of any one of claims 1- 15 wherein the acid is an

organic acid, and that organic acid is p-toluene sulfonic acid.

17. The process of any one of claims 1- 15 wherein the acid is formic acid.

18. The process of any one of claims 1- 17 wherein the fluoride salt is potassium fluoride.

19. The process of any one of claims 1- 17 wherein the the fluoride salt is sodium fluoride.

20. The process of any one of claims 1- 19 wherein the amount of the organic acid is 5 mol% based on the amount of compound II, compound IV or compound VI.

21. The process of any one of claims 1-20 wherein the mixing occurs under conditions further comprising an aprotic organic solvent.

22. The process of claim 21 wherein the solvent is dimethylformamide (DMF).

23. The process of any one of claims 1-22 wherein the mixing occurs under conditions further comprising room temperature or about 21°C.

24. The process of any one of claims 7-23 wherein compound III or

OMe OMe

compound V is selected from the group consisting of:

25. The process of any one of claims 7-24 wherein compound IV or compound VI is selected from the group consisting of:

26. A process to make DFT, or method of manufacture of DFT, or a salt thereof, the process comprising:

reacting

to make

, wherein Metal is a metal or metalloid that makes a nucleophilic organometallic reagent of the difluoro compound;

reacting

trimethylsulfoxonium iodide to make

-triazole to make DFT, or a salt thereof.

27. The process of any one of claims 1-26 wherein the process further comprises an aprotic organic solvent.

28. The process of claim 27 wherein the solvent is dimethylformamide (DMF).

29. The process of claim 27 wherein the solvent is dimethyl sulfoxide (DMSO).