Processes related to preparation of triazole derivatives

Abstract

This disclosure provides processes for preparation of substituted triazole compounds of Formula X:

Description

PROCESSES RELATED TO PREPARATION OF TRIAZOLE DERIVATIVES BACKGROUND

[0001] This disclosure relates to processes to prepare triazole derivatives and intermediates thereof having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda.

[0002] Triazole oxathiazolidine ureas of specific interest have been disclosed in WO 2021 / 011722 A1.

[0003] The protection of crops from insects and nematodes which inhibit crop growth is a constantly recurring problem in agriculture. To help combat this problem, researchers in the field of synthetic chemistry have produced an extensive variety of chemicals and chemical formulations effective in controlling of such insects and nematodes. Chemical insecticides and nematicides of many types have been disclosed in the literature and a large number is in commercial use. However, there remains a need for compositions and methods that are effective for controlling undesirable insects and nematodes and methods to prepare such. SUMMARY

[0004] In one aspect, this disclosure provides processes to make and use compounds of Formula One:wherein Ar1and Ar2are substituted aryl or heteroaryl groups. In a particular aspect, Ar1and Ar2are substituted phenyl groups.

[0005] This disclosure also provides processes to make and use compounds having the following formula X: NX where R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, - (C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and A is selected from the group consisting of -F, -Cl, -CF3, -(C1-C4) alkyl, -(C1- C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F. DETAILED DESCRIPTION

[0006] Examples provided herein are not exhaustive and should not be construed as limiting. It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular molecule to which it is attached. These definitions are only to be used for the purposes of this disclosure.

[0007] The term “alkyl” means an acyclic, saturated, branched, or unbranched, substituent consisting of carbon and hydrogen, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl.

[0008] The term "halogen" or "halo" or derivative terms such as “halide” refers to one or more halogen atoms, defined as F, Cl, Br, and I.

[0009] The term “ambient pressure” refers to pressures from about 80 kilopascals (kPa) to about 105 kPa.

[0010] The term “ambient temperature” or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C.

[0011] The term “catalyst” refers to any substance that increases the rate of a reaction without itself being consumed.

[0012] “Continuous flow”, “flow”, “continuous formation”, “continuous process”, or other derivative terms as used herein means methods that produce a minimum amount of a reactive intermediate at any given time and provide reduced cycle times in comparison to conventional methods. For example, U.S. Patent 9,145,428 B2 describes methods and systemsusing continuous flow. Processes disclosed herein can be conducted according to conventional batch processes or continuous flow processes.

[0013] All references, including publications, patent applications, and patents, referred to herein are incorporated by reference herein to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety.

[0014] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (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. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. 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, 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 invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. The processes disclosed herein can be carried out by combining the components in any order. For example, in some instances, the reagents can be added sequentially in any order. In some other instances, the reagents can be added simultaneously. Compounds can be isolated as the free base form ((HA)n, where n = 0) or corresponding salt ((HA)n, where n = 1 or 2) using standard techniques known in the art such aspH adjustments, wherein A is the counterion of an inorganic acid. The products and / or intermediates disclosed herein can be isolated using standard techniques in the art (such as crystallization, or filtration of the solvents to recover solid material) or carried into the next step without any isolation.

[0015] Throughout the disclosure, reference to compounds of the present disclosure is read as also including all regioisomers, structural isomers, geometrical isomers, rotational isomers, tautomers, and stereoisomers, for example diastereomers, enantiomers, and mixtures thereof.

[0016] The compounds of the disclosure may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage e.g., restriction resulting from the presence of a ring or a double bond. Accordingly, any cis / trans and E / Z isomers are expressly included in the present disclosure.

[0017] The compounds of the disclosure may also be present in multiple tautomeric forms. Where one or more tautomeric forms exist, the disclosure expressly includes all such tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented.

[0018] The compounds of the present disclosure may exist in an amorphous solid form or as an oil. The compounds of the present disclosure may exist in one or more crystalline or polymorphic forms. All crystalline forms and polymorphs of the compounds of the disclosure are expressly included in the present disclosure.

[0019] A molecule, X, having the following formula: N and processes to make andded. The molecule X may be useful in a process to prepare compounds of formula Z shown below:N OSNON N R4where R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, -OCH2CF3and - OCH2F; A is selected from the group consisting of -F, -Cl, -CF3, -(C1-C4) alkyl, -(C1-C4)alkoxy, - CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; R3is selected from the group consisting of -(C1-C4)alkyl, -(C1-C4)alkoxy, -CH3, - CH2CH3, -OCH3, and -OCH2CH3; and R4is selected from the group consisting of -CH2OCH2CH3, -CH2OCH2CF3, - CH2OCH2CH2F, -CH2OCH2CHF2, -OCF3, -OCH2CH2CH3, -OCH2CH2CF3and -OCH2CF3. Particular examples of compounds of formula Z are illustrated below: FFF N F FFFF N ONF F F F F F F6Z5

[0020] Compounds of formula Z have pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda.

[0021] In one aspect, this disclosure provides a process for the preparation of a compound of Formula One: N ArN 1 NAr2ecomprising the step of: a. reacting a compound of Formula Two: H N (HA)nAr1NH2Formula Two b. with a compound of Formula Three: NH (HA)nFormula Three in the presence of a formate source, an appropriate solvent and optionally, in the presence of an optional base. In this example, (HA)n is an appropriate acid addition salt. In some aspects, the base is an organic base. In some aspects, the base is an inorganic base. In some instances, Ar1and Ar2can be the same. In some other instances, Ar1and Ar2can be different. In some specific instances, Ar1and Ar2are substituted aryl or heteroaryl groups. In some particular instances, Ar1and Ar2are substituted phenyl groups. In some instances, Formula Two and Formula Three can be neutral forms as shown. In some other instances, Formula Two and Formula Three can becorresponding acid salts. In some instances, the solvent is a polar, protic solvent. In some other instances, the solvent is a polar, aprotic solvent. In some other instances, the solvent is a non- polar, aprotic solvent. In some instances, the solvent can be a mixture of solvents selected from at least two of the following a) polar, protic solvent, b) polar, aprotic solvent and c) non-polar, aprotic solvent. In some instances, compounds of Formula Four can be observed as intermediates. Accordingly, compounds of Formula Four are within the scope of the processes disclosed herein. In some instances, compounds of Formula Four are isolated and in some other instances the intermediates are further reacted without any isolation to produce compounds of Formula One. NH H (HA)nN A N Ar2Four

[0022] In some instances, the compound of Formula One is a compound having Formula X: N N N R2wherein:R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1- C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; R2is selected from the group consisting of -NH2, -NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F, and I; and A is selected from the group consisting of -F, -Cl, -CF3, -(C1-C4) alkyl, -(C1- C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F.

[0023] In some instances, the compound of Formula X is a compound of Formula X1:N N N NH2wherein R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; and A is H, F or Cl.

[0024] In some particular instances, R1is -OCF3and A is F.

[0025] In some instances, the compound of Formula X is a compound of Formula Xa: F F F N R2wherein R2is selected from thth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F, and I.

[0026] In some instances, the compound of Formula X is a compound of Formula Xb: F F N R2wherein R2is selected from the group consisting of -NH2, -NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F, and I.

[0027] In some instances of the disclosed processes, the compound of Formula Three is a compound of Formula 3.1: NH OR R2A (HA)n3.1 wherein R is -(C1-C4)alkyl;A is H, F or Cl; and R2is selected from the group consisting of -NH2, -NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F, and I.

[0028] In some specific instances, the compound of Formula Two is a compound of Formula 2.1: H N NH2R1 (HA)n2.1

[0029] where R1is selectedfrom the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F.

[0030] In some aspects, the compound of Formula X is selected from any of the following compounds: N N N NN N N N N NO N NHCClwhere R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, - (C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; and A is H, F or Cl.

[0031] In certain aspects, the compounds of Formula X are selected from the following compounds: N NX10 X11 N N 3 t12F N F N H N H N F N F N

[0032] US 9604942B2 discloses a process for the preparation of certain 1,3- diaryltriazoles of Formula I. Ar2N N R N 1R2Ar1Formula I wherein R1is a (C1-C6) haloalkoxy, and R2is -NO2, -COOH or -CO-O-(C1-C6)alkyl. The R2groups are electron withdrawing groups and the aryl groups, both Ar1and Ar2, are mono- substituted. The process involves the condensation reaction between the hydrazine II and alkoxyimidate salt III (Scheme 1). In step a, haloalkoxyhydrazine II is reacted with arylalkoxyimidate III to produce intermediate iminohydrazine IV. Step a is carried out in a weakly alkaline heterocyclic solvent such as pyridine, lutidine or mixtures thereof, or in a non- basic, polar, aprotic solvent such as acetonitrile or THF in the presence of organic or inorganicbase. Examples of organic bases are pyridine and trialkylamines. Examples of inorganic bases are alkali carbonates such as sodium carbonate and potassium carbonate. The addition of hydrazine is carried out at lower temperatures (preferably from about 0 ℃ to about -5 ℃) and raised to 25 ℃ following the addition. In step b, the intermediate iminohydrazine IV is cyclized using a formate source such as formic acid, formate esters or orthoesters to afford the diaryltriazoles of Formula I. Weakly alkaline heterocyclic solvents such as pyridine, lutidine or mixtures thereof, or a non-basic, polar, aprotic solvent such as acetonitrile or THF have been used. An organic or inorganic base is also used in step b. NHNH2HN H R2polar, aprotic solvent N R2ce R2ormua Scheme 1 Triazoles of Formula I can be used to prepare the compounds of Formula Z. This involves converting the R2groups (-COOH, CO-O(C1-C6)alkyl, -NO2) to corresponding amines (-NH2). For example, when R2is -COOH, a Curtius rearrangement generated the corresponding amine(NH2). When R2is -NO2, it is reduced with an appropriate reducing agent to generate the corresponding amine (-NH2).

[0033] The following are processes related to the preparation of X and Z.

[0034] Scheme 2 shows the general process for the preparation of Z (WO 2021 / 011722A1) via the reaction between a compound of formula X1 and a compound of formula Y1. Y1 is prepared from a compound of formula Y, wherein L is a leaving group, for example, halides such as -Cl, -Br, -I, - or sulfonates such as OSO2C6H4Me, OSO2Ph, -OSO2Me. SOL S O R N4HNN N 3Scheme 2

[0035] One aspect of the processes disclosed herein is the synthesis of compounds of Formula X using polar aprotic solvent and a base such as pyridine. In some instances, pyridine can also be used as the solvent. In comparison to US 9604942B2, the compounds of Formula X consist of different substitution patterns. For example, a compound of Formula X can be synthesized using the process shown below (Scheme 3).

[0036] NH N NHNH2N + ORpolar, aprotic solvent,N R2

[0037] A further aspect of the disclosure herein is an improvement of the process illustrated in Scheme 3.

[0038] Scheme 4 shows a general process for the preparation of X according to one aspect of the disclosure herein. Rpolar prooticrsolventHN NHNH22H N R22Scheme 4

[0039] Accordingly, hydrazine 2.1 is reacted with alkoxyimidate 3.1 in a polar protic solvent in the presence of an optional base. The polar, protic solvent is selected from the groupconsisting of methanol, ethanol, propanol, isopropanol, and butanol. In some instances, hydrazine 2.1 is reacted with alkoxyimidate 3.1 in a non-polar aprotic solvent in the presence of an optional base. The non-polar, aprotic solvent is selected from the group consisting of aromatic or aliphatic solvents such as toluene, xylenes, anisole, hexanes, heptanes, or cyclohexane. In some instances, the solvent can be a mixture of solvents selected from at least two of the following a) polar, protic solvent b) polar, aprotic solvent and c) non-polar, aprotic solvent. The optimal ratio of these solvents can be achieved by a skilled person in the art using the guidelines in this disclosure. For example, if the inorganic bases is not soluble in a apolar, aprotic solvent, a polar protic solvent or a polar protic solvent or mixtures thereof can be added to the solvent mixture. The concentration of the reaction can vary from 0.1 Molar to 2.0 Molar. The base is an inorganic or organic base. In some aspects, the organic base is selected from sodium acetate, potassium acetate, lithium acetate. The amount of base used can vary from 0 to 100 molar equivalents. The disclosure provides a process wherein the amount of base used is between 1 and 5 molar equivalents. The disclosure provides a process wherein the amount of base used is about 2 molar equivalents. The reaction is conducted at a temperature from about - 10 to 100 °C, preferably around room temperature. Once the reaction is completed, the intermediate 4.1 is condensed with a formate source to generate X. Suitable formate sources include formic acid, formate esters, amidines and orthoesters. Specific examples include formic acid, methyl formate, ethyl formate, amidine, trimethyl orthoformate and triethyl orthoformate. The disclosure provides a process wherein the amount of formate source used is between about 1 and about 10 molar equivalents. The intermediate 4.1 can be isolated but is typically carried forward to the next step without isolation, and the final condensation with a formate source is carried out in the same polar, protic solvent or non-polar, aprotic solvent. The reaction is conducted at a temperature from about 20 to about 120 °C.The process shown in Scheme 3 has several advantages. First, the use of polar, protic solvent or non-polar, aprotic solvent enables efficient reactivity of the reactants 2.1, 3.1 and organic base. Additionally, X can be precipitated out in crystalline form directly from the reaction medium, without a need for further purification. In this way, X is obtained in high yield and in high purity. In some cases, this process enables thecrude solution of X to be carried directly into the subsequent downstream steps, whereby the isolation of X is averted.Synthesis of 2.1

[0040] 2.1, a hydrazine, can be synthesized from 2a or 2b (Scheme 5). 2a and 2b are either commercially available or can be synthesized using known methods. R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, - CH2F, -CF3, -OCF3, -OCF2H, -OCH2CF3and -OCH2F. In some aspects, hydrazine 2.1 can be prepared from 2a, where R6is -NH2as depicted in Scheme 5. Compounds of formula 2a can be treated with an organic nitrite or inorganic nitrite salt in the presence of an acid to generate an intermediate diazonium salt of formula 2.2, which can be subsequently treated with a reductant to produce the hydrazine of formula 2.1. In a specific embodiment, the nitrite is sodium nitrite (NaNO2), in some other embodiments, the nitrite is t-butyl nitrite (tBuONO). Suitable acids include HCl, HBr, HI, H2SO4, TFA, HNO3, H3PO4, methanesulfonic acid, toluenesulfonic acid or mixtures thereof. The resulting diazonium intermediate is reduced with a suitable reducing agent. The reducing agent is selected from the group consisting of tin(II) chloride (SnCl2), ascorbic acid, and sodium sulfite (Na2SO3). The reaction can be carried out in water, or polar solvents including acetonitrile, ethanol, methanol, formic acid, acetic acid or mixtures thereof. The reactions are carried out at a temperature from about -10 to about 100 ℃. The reactions can be conducted in batch, continuous flow or a combination thereof. If desired, the hydrazine 2.1 can be obtained as a salt or a free base ((HA)n, where n= 0, 1, or 2) with pH adjustments known in the art.

[0041] In some aspects, 2.1 can be synthesized from 2b, where R6is a halogen (Scheme 5). 2b is either commercially available or can be synthesized using known methods. R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1- C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, -OCH2CF3and -OCH2F. In such an instance, the halide is converted to the aryl hydrazine using a ligand-supported copper(I) salt as a catalyst in the presence of an inorganic base and a phase transfer catalyst in a suitable solvent. Suitable copper(I) salts include CuCl, CuBr, CuI or Cu2O. Ligands can be selected from any chelating ornon-chelating nitrogen-based ligand such as pyridine derivatives or bisamides (e.g., N1, N2- bis(2,6-dimethylphenyl)oxalamide (BMPO). Inorganic bases include K3PO4, Na2CO3, K2CO3, NaHCO3, or KHCO3. Suitable phase transfer catalysts include a quaternary ammonium salts such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride or tetraethylammonium bromide. Suitable solvents can be selected from the group consisting of water, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and mixtures thereof. The reaction can be carried out at a temperature from about 20 ℃ to about 100 ℃. X R N26acid, reductant nitrite NH2A)nScheme 5 Synthesis of 3.1

[0042] Compounds of formula 3.1 can be prepared via the general synthetic process as shown in Scheme 6.

[0043] In some aspects, a compound of the formula 3.2 can be prepared from the substituted phenyl derivative 3a, where A is selected from the group consisting of H, F or Cl.In aspecific embodiment, A is either F or Cl. In another specific embodiment, A is F. 3a is either commercially available or can be synthesized according to the known methods. In some aspects of the process, F is converted to R2. In some specific embodiments, R2and F are the same, such that the conversion of F to R2is not necessary. In such an instance, 3a is the same as 3.2 and is subjected to imidoylation with a suitable alcohol under acidic conditions to make the corresponding alkoxyimidate 3.1. In the alternative, 3a is converted to 3.2, and a subsequent imidoylation reaction under acidic conditions with a suitable alcohol generated alkoxyimidate salt 3.1.

[0044] In some aspects, a compound of the formula 3.2 can be prepared from the substituted phenyl derivative 3b, where A is selected from the group consisting of H, F or Cl. In a specific embodiment, A is either F or Cl. In another specific embodiment, A is F. 3b is either commercially available or can be synthesized according to known methods. In some aspects of the process, the -NH2group is converted to R2. In some specific embodiments, R2is NH2, such that the conversion of NH2to R2is not necessary. In such an instance, 3b is the same as 3.2 and is subjected to the imidoylation reaction with a suitable alcohol under acidic conditions to make the corresponding alkoxyimidate 3.1. In the alternative, 3b is converted to 3.2, and a subsequent imidoylation reaction under acidic conditions with a suitable alcohol generated alkoxyimidate salt 3.1. A general synthetic process is shown in Scheme 6. nucleophile F solvent optionally base R2AScheme 6

[0045] General reaction conditions for converting 3a to 3.2 are below: Any nitrogen nucleophile, for example, a cyanate salt, phthalimide, sodium phthalimide, potassium phthalimide, benzylamine, methyl carbamate, or ammonia can be used. In some specific embodiments the cyanate salt can be potassium cyanate or sodium cyanate. The solvent can be selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, acetonitrile, benzonitrile, N-methyl-2-pyrrolidone, water and mixtures thereof. Optionally, an inorganic base such as K3PO4, Na2CO3, K2CO3, NaHCO3or KHCO3can be used. Optionally, a phase transfer catalyst can be used such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride or tetraethylammonium bromide. The reaction is carried out at a temperature of about 20 ℃ to about 150 ℃.

[0046] General reaction conditions for converting 3b to 3.2 are below: The NH2group can be protected with any protecting group such as a phthalimide, carbamate, or amide. In some embodiments the protecting group can be installed by using anhydrides, chloroformates, carbonates, acyl halides or ketones. In some embodiments, the protecting group can be installed with phthalic anhydride, methyl chloroformate, ethyl chloroformate, dimethyl carbonate, diethyl carbonate, trichloroacetyl chloride, or hexachloroacetone. Suitable solvents include aromatic hydrocarbons, acids, ketones, esters, ethers, nitriles and halogenated C1-C4alkyls. Specific examples are toluene, acetic acid, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, and dichloromethane and mixtures thereof. Optionally, inorganic bases (K3PO4, Na2CO3, K2CO3, NaHCO3or KHCO3) or organic bases (amine bases such as triethylamine) can be used. Optionally, a phase transfer catalyst can be used such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride or tetraethylammonium bromide. The reaction is carried out at a temperature of about 0 ℃ to about 150 ℃.

[0047] General conditions for converting 3.2 to 3.1 are below: 3.2 where R2is -NH2, - NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F, and I is reacted with an alcohol (e.g, methanol, ethanol, propanol, isopropanol, or butanol) in the presence of an acid such as HCl, HBr, HI, trifluoroacetic acid, or toluenesulfonic acid in a solvent selected from the group consisting of dichloromethane, ethyl acetate, propyl acetate, butyl acetate, toluene, xylenes, methanol, ethanol, propanol, isopropanol, butanol or mixtures thereof at a temperature of about 0 ℃ to about 50 ℃. In some embodiments, the acid is added as a gas. In some cases, the acid is HCl and is added as a gas. In other embodiments, the acid is generated in situ from an acyl halide and alcohol. In some embodiments, the acid generated in situ is HCl from acetyl chloride and ethanol. The process can be carried out by combining the components in any order. 3.1 is isolated as the corresponding salt (HA)n, where n = 1 or 2. If desired, the imidate 3.1 can be obtained as the free base ((HA)n, where n = 0) with pH adjustments. In some instances, 3.1 can be carried into the next step without any isolation.

[0048] Synthesis of X1

[0049] X is subjected to appropriate conditions to prepare compounds of Formula X1 by converting the R2group to -NH2functionality using conditions known in the literature (T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999, 550-555, 740-743) (Scheme 7). N conditions N N N N N NH2Scheme 7

[0050] In a specific embodiment, a compound of formula X1 can be prepared from a compound of formula X2, when R2is -NPhth, with a deprotecting agent to reveal the -NH2functionality (Scheme 8a). Suitable deprotecting agents include hydrazine, ethanolamine, diaminoethane, HBr, sodium hydroxide, potassium hydroxide, ammonia, ammonium hydroxide, and alkoxides such as sodium methoxide and sodium ethoxide. Suitable solvents include aromatic hydrocarbons, acids, ketones, esters, ethers, nitriles, halogenated C1-C4 alkyls, alcohols, aliphatic and water. Specific examples include toluene, xylenes, acetic acid, acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, anisole, acetonitrile, dichloromethane, methanol, ethanol, propanol, butanol, hexane, heptane, cyclohexane, water and mixtures thereof.N deprotection N N N N N NPhth NH2Scheme 8a

[0051] In another embodiment, a compound of formula X1 can be prepared from a compound of formula X3, when R2is -NO2, by reduction to reveal the -NH2functionality (Scheme 8b). Reduction of the -NO2group can be achieved under a variety of conditions (Org. Process Res. Dev.2018, 22, 4, 430–445) including in the presence of a catalyst, such as palladium on carbon or Raney nickel, and hydrogen source such as hydrogen gas or ammonium formate. In some other instances, where R2is a functional group such as -Cl, -Br or -I, it can be converted to the -NH2group with a suitable nitrogen nucleophile such as ammonia in the presence of a copper catalyst such as CuCl, CuBr, CuI or Cu2O and any chelating or non- chelating ligand. In some other instances, where R2is F, a compound of formula X1 can be prepared by nucleophilic displacement of the fluoride with a nitrogen nucleophile such as ammonia or ammonium hydroxide. In some other instance, where R2is NHCOCl3, NHCO2Me, or NHCO2Et, the protecting group can be removed by using a deprotecting reagent such as sodium hydroxide, potassium hydroxide, HCl or HBr. N reduction N N N H23Scheme 8b

[0052] In certain aspects, disclosed herein is a process for the preparation of compound of Formula Xa: N N N R2The process comprising the steps of: reacting a compound of Formula 2.1.1 or an salt thereof: H N NH2)nwith a compound of Formula 3.1.1 or a salt thereof: NH )n

[0053] where R2is selected from the group consisting of -NH2, -NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F, and I; and R is a –(C1-C4)alkyl, in a polar, protic solvent; apolar protic solvent or an apolar, aprotic solvent in the presence of an optional base. The polar, protic solvent is selected from methanol, ethanol, propanol, isopropanol, or butanol. In some aspects, the solvent is a non-polar, aprotic solvent. In some instances, the solvent can be a mixture of solvents selected from at least two of the following a) polar, protic solvent, b) polar, aprotic solvent and c) non-polar, aprotic solvent. The optional base can be an organic base such as sodium acetate, potassium acetate, or lithium acetate.

[0054] 2.1.1 can be prepared by converting aniline 2a.1 to the corresponding diazonium salt using a nitrite source under acidic conditions, followed by a reduction using an appropriate reducing agent (Scheme 9a). 2.1.1 can also be prepared by converting an aryl halide 2b.1 under metal-mediated conditions (Scheme 9b). NH2nitrite, then NHNH2FCO(HA) redun3 ction F3COScheme 9a NHNH X2NH2NH2F3CO (HA)n

[0055] Compounds of Formula 3.1.1 can be prepared from compounds of Formula 3.2.1 under acidic conditions with a (C1-C4) alcohol (ROH) as shown in Scheme 10, where R2is selected from the group consisting of -NH2, -NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F, and I and R is a –(C1-C4)alkyl. NH CN R H i OR A)n10

[0056] Compounds of Formula 3.2.1 are either commercially available or can be prepared from 3a.1 and 3b.1 (Scheme 11). For example, 3a.1 can be reacted with a suitable nitrogen nucleophile such as ammonia, a cyanate salt, or a phthalimide salt. In some aspects, pthalimide can be used as a nitrogen nucleophile in the presence of a base. Bases can be organic or inorganic bases such as amines, alkoxides, carbonates and / or bicarbonates. In some aspects, it is preferrable to use a phase transfer catalyst. In some aspects, the phase transfer catalyst can be a tetraalkylammonium halide such as tetramethylammonium bromide, tetramethylammoniumchloride, tetraethylammonium bromide, tetraethylammonium chloride, tetrabutylammonium bromide, or tetrabutylammonium chloride. In other aspects, compounds of Formula 3.2.1 can be prepared from 3b.1 with a suitable protecting group such as a phthalimide, carbamate, or amide. In some embodiments the protecting group can be installed by using anhydrides, chloroformates, carbonates, acyl halides or ketones. nucleophile F solvent optionally base optionally phase transfer cat NC F R2F

[0057] In certain aspects of the processes disclosed herein, the compounds of Formula One are selected from the following compounds:

[0058] F F F F F N F NN N N N N NHCOM N NHCOEtF F F N F N ON O N, ing to the Scheme 12. In some aspects, compounds of Formula X11 to X18 can be converted to X10 and compounds of Formula X20 to X27 can be converted to X19 to install the -NH2group. H NH N solvent NH2 +ROformate source X27

[0060] In some aspects, the base is an organic base. In some aspects, the base is an inorganic base. In some instances, the compounds of Formula 2.1.1, the compounds of Formula 2.1.2 and the compounds of Formula 3.1.1 can be neutral forms. In some other instances, the compounds of Formula 2.1.1, the compounds of Formula 2.1.2 and the compounds of Formula 3.1.1 can be the corresponding acid salts. In some instances, the solvent is a polar, protic solvent. In some instances, the polar, protic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and butanol. In some other instances, the solvent is a polar, aprotic solvent. In some instances, the polar, aprotic solvent is selected from the group consisting of acetonitrile, dimethyl carbonate and tetrahydrofuran. In some instances, the solvent is a non-polar, aprotic solvent. In some instances, the non-polar, aprotic solvent is selected fromthe group consisting of aromatic or aliphatic solvents such as toluene, xylenes, anisole, hexanes, heptanes, or cyclohexane.

[0061] In certain aspects of the processes disclosed herein, the compounds of Formula Three, compounds of Formula 3.2 and compounds of Formula Four are selected from the following compounds: NH2NH2H NH N HN N 3 Me3.1.1.5 4.1.1.5 NHCO2Et NHCO2Et H NH Et3.1.1.11In light of the above disclosure, following further details are provided: d1. A process for the preparation of a compound of Formula X: N N N R2comprising the steps of: 1a. reacting a compound of Formula 2.1 or salt thereof: H N NH2)nFormula 2.1 1b. with a compound of Formula 3.1 or a salt thereof: NH R )nFormula 3.1 in the presence of a formate source, a solvent, and optionally a base;wherein: R is -(C1-C4)alkyl; R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and A is H, F or Cl. d2. The process according to d1, wherein the solvent is a polar, protic solvent or an aprotic, polar solvent. d3. The process according to any of d1-d2, wherein: the formate source is selected from the group consisting of formic acid, formate esters, amidine and orthoesters; the polar, protic solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, and butanol; and the base is sodium acetate, potassium acetate or lithium acetate. d4. The process according to any of d1-d3, wherein the compound of Formula 2.1 is a compound of Formula 2.1.1 or 2.1.2: H H N FNHN 2FNH2)n2.1.1 2.1.2. d5. The process according to any of d1-d3, wherein the compound of Formula 3.1 is a compound of Formula 3.1.1:NH OR )nwherein R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and R is –(C1-C4)alkyl. d6. The process according to d1, wherein the compound of Formula X is a compound of Formula Xa or Xb: N N N 2 R2Xb wherein R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I. d7. The process according to any of d1-d6, wherein the compound of Formula 2.1 is prepared by: a. converting an aniline of Formula 2a to a diazonium salt of Formula 2.2:cid, nitrite, solvent N .X NH2a2Rwhereinrion of an inorganic acid; ab. reducing the diazonium salt of Formula 2.2 to a hydrazine of Formula 2.1: H N .X 2 reductant N NH2A)ng p consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and - OCH2F. d8. The process according to d1, wherein the compound of Formula 3.1 is prepared by: converting a compound of Formula 3.2 to a compound of Formula 3.1: R2 ROH, acid(HA)nR2Awherein R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; R is –(C1-C4)alkyl; A is H, F or Cl; andX is the counterion of an inorganic acid. d9. The process according to any of d1-d8, for the preparation of a compound of Formula Xa: N N N R2comprising the steps of: a. reacting a compound of Formula 2.1.1: H N F NH F2)nb. with a compound of Formula. . NH RO R2wherein R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and R is a –(C1-C4)alkyl; in a polar, protic solvent in the presence of an optional base selected from the group consisting of sodium acetate, potassium acetate, and lithium acetate. d10. The process according to d9, wherein the compound of Formula Xa is selected from the group consisting of:N N N a. b. ; c. d. 3; e. ;N N N f. 5; g. h. d i. d11. Acompound(s) of Formula X, N N R2wherein R1 is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and A is selected from the group consisting of -H, -F, -Cl, -CF3, -(C1-C4) alkyl, -(C1- C4)alkoxy. d12. The compound according d11, wherein the compound of Formula X is Xa: N N F N R2wherein R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I.

[0062] Starting materials, reagents, and solvents that were obtained from commercial sources were used without further purification. Anhydrous solvents were purchased were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Some melting points were obtained using a Thermal Analysis (TA) Q2500 DSC instrument. After loading the sample in the sample pan, the DSC instrument is heated and the resulting heat flow into (endotherm) or out of (exotherm) the sample is measured via comparison to a blank reference cell. Some DSC data was collected on a TA Instruments Discovery DSC equipped with a 50-position auto-sampler. A 2.45 mg sample in a Tzero hermetic aluminum pan, was heated at 10 °C / min from -10 °C to 250 °C. A purge of dry nitrogen at 50 mL / min was maintained over the sample run time. Molecules are given their known names, named according to the naming program within ChemDraw (version 21.0.0.28 (21)), IUPAC guidelines or using conventional naming rules.1H NMR spectral data are in ppm (δ) and were recorded at 400 MHz or 500 MHz;13C NMR spectral data are in ppm (δ) and were recorded at 126 MHz; and19F NMR spectral data are in ppm (δ) and were recorded at 376 or 471 MHz, unless otherwise stated.

[0063] In the examples below, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. AcOH = acetic acid aq. = aqueous Boc = tert-butyloxycarbonyl Boc2O = di-tert-butyl dicarbonate DCM = dichloromethaneDMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide DSC = differential scanning calorimetry equiv = equivalent EtOAc = ethyl acetate EtOH = ethanol g = gram h = hours HCl = hydrochloric acid HPLC = high-performance liquid chromatography IPA = isopropanol iPrOAc = isopropyl acetate KOH = potassium hydroxide kPa = kilopascals LCMS = liquid chromatography mass spectrometry M = molar MeCN = acetonitrile MEK = methyl ethyl ketone MeOH = methanol mg = milligrams min = minutesmL = milliliters mmol = millimoles mp = melting point MS = mass spectrometry m / z = mass to charge ratio N = normal N2= nitrogen (gas) NaCl = sodium chloride Na2CO3= sodium carbonate NaHCO3= sodium bicarbonate NMR = nuclear magnetic resonance NaOH = sodium hydroxide Na2SO4= sodium sulfate NH3= ammonia o / n = overnight Phth = phthalimide psi = pounds per square inch rpm = revolutions per minute RT = room temperature t-BuOH = tert-butanol THF = tetrahydrofuranTLC = thin layer chromatography UV = ultraviolet wt % = weight percent μM = micromolar The following examples are for illustration purposes and are not to be construed as limiting.

[0064] Synthesis of compounds of Formula One.

[0065] Example 1a (synthesis of compound X10) via two-step procedure from ethyl 4-amino-3-fluorobenzimidate hydrochloride: F F H2

[0066] To a vial equipped with a magnetic stir bar and nitrogen inlet was added (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (261 mg, 1.14 mmol) in pyridine (4.57 mL, 0.250 M). The reaction mixture was cooled to 0 °C before ethyl 4-amino-3-fluorobenzimidate hydrochloride (250 mg, 1.143 mmol) was added portion wise over 1 min. The mixture was allowed to warm to room temperature and continue stirring overnight. After stirring for 16 h, the dark purple solution was transferred to a separatory funnel with DCM (20 mL) and water (20 mL). The organic layer was collected, and the aqueous layer was back-extracted with DCM (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude mixture which was purified by column chromatography to yield the desired product, 4-amino-3-fluoro-N’-(4-(trifluoromethoxy)phenyl)benzimidohydrazide.

[0067] To a vial equipped with a magnetic stir bar and nitrogen inlet was added 4- amino-3-fluoro-N’-(4-(trifluoromethoxy)phenyl)benzimidohydrazide (70 mg, 0.21 mmol). Formic acid (0.70 mL, 18 mmol, 0.31 M) was added and the reaction was heated to 100 °C and stirred overnight. After 16 h the reaction mixture was cooled to room temperature and poured into water (15 mL) and diluted with EtOAc (30 mL) and a solution of saturated sodium bicarbonate (15 mL). The organic layer was collected, and the aqueous layer was back-extracted with EtOAc (20 mL). combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude mixture which was purified by column chromatography (0-100%EtOAc / hexanes), yielding a purple solid, N-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H- 1,2,4-triazol-3-yl)phenyl)formamide (31 mg, 0.085 mmol).

[0068] The purple solid was then charged to a vial equipped with a magnetic stir bar and nitrogen inlet. EtOH (0.314 mL, 0.1 M) and a 1 M solution of sodium hydroxide (31.4 µL, 0.031 mmol) were added and the reaction was stirred at 75 °C for 16 h. The reaction was cooled to room temperature and transferred to a separatory funnel with EtOAc (20 mL), water (20 mL), and a saturated solution of sodium bicarbonate (10 mL). The organic layer was collected, and the aqueous layer was back-extracted with EtOAc (15 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude mixture which was purified by column chromatography (0-100% EtOAc / hexanes), yielding the desired product as a light brown solid, 2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (7.0 mg, 0.021 mmol, 26% over 2 steps): Analytical data matched that from example 1b below.

[0069] Example 1b (synthesis of compound X10) via phthalimide deprotection: Into a 500 mL 2-neck round bottom flask equipped with a stir bar, thermocouple, and reflux condenser were added 2-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3- yl)phenyl)isoindoline-1,3-dione (5.0 g, 10.7 mmol) and EtOH (21.4 mL) and the flask was flushed with N2. In a separate flask, sodium hydroxide (5.12 g, 128 mmol) was dissolved in water (21.4 mL). The NaOH solution was added to the reaction flask and stirred at 84 °C for 23 h. The reaction mass was cooled to room temperature and 100 mL of water was slowly added with stirring to induce precipitation of product. The solids were collected by filtration, washed with additional water, and dried in a vacuum oven (50 °C) overnight to yield 2-fluoro-4-(1-(4- (trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline as a white solid (3.58 g, 10.6 mmol, 99% yield):1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.89 – 7.69 (m, 4H), 7.47 – 7.33 (m, 2H), 6.85 (t, J = 8.6 Hz, 1H), 3.93 (br, 2H);19F NMR (376 MHz, CDCl3) δ -58.02, -135.33; ESIMS m / z 339.1 ([M+H]+).

[0070] Example 1c (synthesis of compound X10) via phthalimide deprotection: To a 250 mL jacketed reactor with an overhead stirrer, a nitrogen inlet and a condenser was added 2- (2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)isoindoline-1,3-dione (10.0 g, 21 mmol), toluene (100 mL) and premixed sodium hydroxide (12.8 g, 320 mmol) in water (60 mL). The mixture was heated to 80 °C and the reaction was monitored for conversion by HPLC analysis. The reactor was cooled to 50 °C and the mixture was transferred to a separation funnel. The phases were separated. The organic layer was washed with water (50 mL) and the phases were separated. The organic toluene layer was concentrated to ~50 mL under reduced pressure. The mixture was agitated, and heptane (~100 mL) was slowly added. The mixture was stirred for ~10 mins, then chilled in an ice-water bath before filtration. The solid was filtered, washed with heptane (10 mL) and dried to give a light brown solid 2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4- triazol-3-yl)aniline (6.8 g, 20 mmol, 94 % yield): Analytical data matched that from above.

[0071] Example 1d (synthesis of compound X10) via nitro reduction: To a Parr™ bottle was added Pd(OH)2 / C (100 mg, 0.007 mmol), which was wetted with EtOH (5 mL). A slurry of 3-(3-fluoro-4-nitrophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (2.2 g, 6.0 mmol) in EtOH (30 mL, 0.15 M) was added slowly to the reaction mixture. EtOAc (10 mL) was then added, and the bottle was added to the Parr™ shaker, purged with nitrogen, pressurized with hydrogen (40 psi, 276 kPa), and shaken for 4 hours. Upon completion the vessel was purged and backfilled with nitrogen. The reaction mixture was then filtered through a pad of Celite®, washed with EtOAc (20 mL), and concentrated to give the desired product as an off-white solid, 2- fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (1.82 g, 5.38 mmol, 90% yield): Analytical data matched that from above.

[0072] Example 1e (synthesis of compound X10) via trichloroacetyl deprotection: A vial equipped with a magnetic stir bar and nitrogen inlet was charged with 2,2,2-trichloro-N-(2- fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetamide (242 mg,0.500 mmol) in MeOH (10 mL). HCl (6 N HCl, 7.5 mL, 45 mmol) was then added and the reaction was heated to 90 °C and stirred overnight. After 20 h the reaction was sampled and showed high conversion by HPLC analysis. The reaction was cooled to room temperature to form a suspension. The reaction was cooled to 0-5 °C in an ice water bath and filtered through a fritted funnel, by transferring with a minimal amount of MeOH (2 mL) and water (2 mL). The cake was dried to give 70 mg of desired product. The filtrate contained product and was concentrated to remove MeOH, resulting in a suspension that was filtered and washed with water (5 mL) to give a second crop of solid product. The second crop of solid was dried in a vacuum oven overnight and contained an additional 80 mg of desired product after drying. Two crops of solids were combined to give 150 mg of the desired product as a light brown solid, 2-fluoro-4-(1- (4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline hydrochloride (150 mg, 0.40 mmol, 80% yield):1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.07 – 8.00 (m, 2H), 7.67 – 7.57 (m, 4H), 6.86 (t, J = 8.8 Hz, 1H), 5.58 (br, 2H);19F NMR (471 MHz, DMSO-d6) δ -56.97, -134.99; LCMS / UPLC-MS (ESIMS) m / z 339.1 ([M+H]+).

[0073] Example 1f (synthesis of compound X10) via Ullmann coupling with ammonia from aryl bromide: A 30 mL pressure reactor equipped with a stir bar was charged with 3-(4-bromo-3-fluorophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (500 mg, 1.24 mmol), potassium carbonate (516 mg, 3.73 mmol), copper(I) oxide (1.78 mg, 0.012 mmol) and ammonium hydroxide (28-30% NH3, 14.7 mL). The reactor was sealed, pressurized to 50 psi (345 kPa) with nitrogen and purged three times. Then the reactor was pressure tested with nitrogen to 200 psi (1379 kPa) and then heated to 140 °C. After 18 h, the reaction was cooled to room temperature, to give a biphasic mixture that was transferred to a separatory funnel. The organic layer was collected, dried over sodium sulfate and concentrated to give a dark oil. The crude material was purified by column chromatography (0-100% EtOAc / hexanes) to afford the desired product as a brown solid, 2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3- yl)aniline (114 mg, 0.337 mmol, 27.1% yield): Analytical data matched that from above.

[0074] Example 1g (synthesis of compound X10) via SNAr displacement with ammonia: A 30 mL pressure reactor equipped with a stir bar was charged with 3-(3,4- difluorophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (250 mg, 0.73 mmol) and water (2 mL). The reactor was purged with N2and then gaseous ammonia (5.3 g, 0.31 mol) was condensed into the reactor by cooling the reactor with dry ice and acetone. The reactor was sealed, heated to 200 °C, and stirred for 18 h. After 18 h, the reaction mixture was cooled to room temperature, vented of ammonia, diluted with MeOH (15 mL), and sampled by UPLC to reveal 88% conversion to X10 by UPLC area percent.

[0075] Example 1h (synthesis of compound X10) via Ullmann coupling from aryl iodide: A 30 mL pressure reactor equipped with a stir bar was charged with 3-(3-fluoro-4- iodophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (500 mg, 1.1 mmol), potassium carbonate (462 mg, 3.34 mmol), copper(I) oxide (1.59 mg, 0.011 mmol) and ammonium hydroxide (28-30% NH3, 14.7 mL). The reactor was sealed, pressurized to 50 psi (345 kPa) with nitrogen and purged three times. Then the reactor was pressure tested with nitrogen at 200 psi 1379 kPa) and then heated to 140 °C. After 20 h, the reaction was cooled to room temperature and diluted with EtOAc (15 mL) to give a biphasic mixture that was transferred to a separatory funnel. The layers were separated and the organic layer was collected. The aqueous layer was back-extracted with EtOAc (15 mL) and the organic layers were combined, dried over sodium sulfate, and concentrated to give a brown oil. The crude material was purified by column chromatography (0-100% EtOAc / hexanes), to afford the desired product as a brown solid, 2- fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (185 mg, 0.547 mmol, 49.1% yield): Analytical data matched that from above.Example 1i (synthesis of compound X10) via compound X11: To a pressure reactor equipped with overhead stirrer and temperature probe were added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (3.28 g, 14.3 mmol), compound 3.1.1.2 (5.0 g, 14.3 mmol), sodium acetate (2.35 g, 17.2 mmol) and ethanol (29 mL).The reactor was sealed, and the headspace was purged by filling and venting with N2three times. Nitrogen pressure was set to 100 psi and the reaction was stirred for 2 h at 21 °C before it was depressurized. Triethyl orthoformate (3.58 mL, 3.19 g, 21.5 mmol) was added, the reactor was sealed, the headspace purged as above. Nitrogen pressure was set to 100 psi and the reaction temperature was increased to 100 °C. The reaction was stirred for 18 h, and then cooled to 20 °C and depressurized. A solution of sodium hydroxide was prepared by dissolving NaOH (5.72 g, 143 mmol) in water (29 mL). This solution was added to the reaction mass at room temperature. The reactor was sealed and the headspace purged with N2as above. Nitrogen pressure was set to 100 psi and the reaction was stirred at 100 °C for 18 h. The reaction was cooled to 20 °C and water (30 mL) was added. The resulting solids were collected by filtration, washed with additional water (70 mL) and dried in a vacuum oven (~50 °C) to afford 2-fluoro-4-(1-(4- (trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (3.8 g, 80% yield) as a tan solid: mp = 99 – 103 °C; Analytical data matched that from above.

[0076] Example 1j (synthesis of compound X10) via butyl imidiate: To a reactor equipped with an overhead stirrer and temperature probe were added (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (2.72 g, 84.5 wt% purity, 10 mmol), butyl 4- (1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (3.92 g, 95 wt% purity, 10 mmol, 1 equiv), sodium acetate (1.65 g, 98.5 wt% purity, 20.1 mmol) and n-butanol (29 mL). The reactor was sealed and the headspace was purged by filling and venting with N2three times. The reaction was stirred for 6 h at 21 °C. Triethyl orthoformate (2.5 mL, 15.1 mmol, 1.5 equiv) was added, the reactor was sealed, and the headspace purged as above. The reaction mixture was heated 78 °C and stirred for 18 h before being cooled to 20 °C. A solution of sodium hydroxide was prepared by dissolving NaOH (4 g, 100 mmol, 10 equiv) in water (16.3 mL). This solution was added to the reaction mass from above at room temperature. The reactor was sealed, the headspace purged with N2as above, heated to 78 °C and stirred for 18 h. After cooling, the phases were separated. Heptanes (60 mL) was added to the organic phase and the mixture was split into two portions. One portion (46.6 g) was concentrated and to the resulting residue wasadded 10% aqueous NaOH and toluene. The phases were separated and the organic layer was washed with 10% aqueous NaOH. The organic phase was concentrated and dried in a vacuum oven at 20 °C to yield X10 as a reddish brown solid (1.2 g, 74 wt%, 44.3% isolated yield after accounting for purity and splitting of feed). Analytical data matched that from above.

[0077] Example 1k (synthesis of compound X11): F F F N ONth To a 100 mL reactor equippure probe, and nitrogen inlet were added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (3.28 g, 14.3 mmol, 1 equiv), ethyl 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (5.0 g, 14 mmol, 1 equiv), sodium acetate (2.35 g, 28.7 mmol, 2 equiv) and ethanol (28.7 mL, 0.5 M). The reaction mass was stirred at room temperature for 2 h. Triethyl orthoformate (14.3 mL, 86.0 mmol, 6 equiv) was added, the temperature was increased to 79 °C, and the mixture was stirred for 16 h, until complete conversion by HPLC was observed. The reaction was cooled to room temperature and the solids were collected by filtration and washed with ~10 mL each of EtOH and water. The solids were dried overnight in a vacuum overnight (50 °C) to yield 5.2 g of the desired product as a white solid (75%).1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.17 – 8.08 (m, 2H), 8.00 (dd, J = 5.5, 3.1 Hz, 2H), 7.89 – 7.75 (m, 4H), 7.49 (t, J = 7.7 Hz, 1H), 7.46 – 7.35 (m, 2H);19F NMR (376 MHz, CDCl3) δ -58.00, -117.73.

[0078] Example 1l (synthesis of compound X11): To a 100 mL reactor equipped with a mechanical stirrer, temperature probe, and nitrogen inlet were added (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (3.28 g (purity corrected for moisture content), 14.34 mmol, 1 equiv), ethyl 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidatehydrochloride (5 g, 14.34 mmol, 1 equiv), sodium acetate (2.4 g, 28.7 mmol, 2 equiv) and toluene (46 g, 500 mmol, 35 equiv). The reaction mass was stirred for 3 h at 20 to 25 °C before it was sampled by HPLC to confirm conversion to the intermediate. Triethyl orthoformate (3.6 mL, 3.2 g, 21.5 mmol, 1.5 equiv) was added, the temperature was increased to 78 °C and the reaction was stirred for 18 h. The in-pot yield of compound X11 was determined by HPLC analysis using benzanilide as an internal standard (75% in-pot yield).

[0079] Example 1m (synthesis of compound X12): F F F N O2To a vial equipped with a mags added 3- fluoronitrobenzimidate hydrochloride (500 mg, 2.01 mmol) in pyridine (4.02 mL, 0.5 M). The vial was placed in an ice bath and stirred at 0 °C before (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (552 mg, 2.41 mmol) was added, and the mixture was stirred for 5 min. The ice bath was removed, and the mixture was warmed to room temperature and stirred for 15 h, after which the resulting red solution was extracted with DCM (20 mL) and water (20 mL). The organic layer was collected, and the aqueous layer was back-extracted with DCM (20 mL, x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude mixture that was purified by column chromatography (0-100% EtOAc / hexanes) to yield the desired product as a dark green solid, 3-fluoro-4-nitro-N’-(4- (trifluoromethoxy)phenyl)benzimidohydrazine (516 mg, 1.44 mmol, 72% yield).

[0080] To a vial equipped with a magnetic stir bar and nitrogen inlet was added 3- fluoro-4-nitro-N’-(4-(trifluoromethoxy)phenyl)benzimidohydrazine (500 mg, 1.40 mmol). Formic acid (4.55 mL, 119 mmol, 0.307 M) was added, and the mixture was heated to 100 °C and stirred for 16 h before the reaction mixture was cooled to room temperature and poured into water (15 mL). Solids were collected by filtration and dried in a vacuum oven overnight toprovide the desired product as a peach-orange solid, 3-(3-fluoro-4-nitrophenyl)-1-(4- (trifluoromethoxy)phenyl)-1H-1,2,4-triazole (396 mg, 1.08 mmol, 77% yield):1H NMR (500 MHz, CDCl3) δ 8.62 (s, 1H), 8.22 – 8.10 (m, 4H), 7.87 – 7.78 (m, 3H), 7.45 – 7.40 (m, 3H);19F NMR (471 MHz, CDCl3) δ -58.00, -116.44 (m).

[0081] Example 1n (synthesis of compound X13): N O N N CCl3A three-neck round bottom, nitrogen inlet, and temperature probe was charged with ethyl 3-fluoro-4-(2,2,2-trichloroacetamido)benzimidate hydrochloride (3.2 g, 8.8 mmol) and pyridine (35.2 mL) and cooled to 0 °C in an ice bath to give a suspension. (4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (2.41 g, 10.6 mmol) was added, and the reaction mixture was stirred and slowly warmed to 10 °C over 2 h. After 2 h, full conversion of starting material was observed by HPLC analysis. A reflux condenser was added to the flask, triethyl orthoformate (2.2 mL, 13 mmol) was added, and the reaction mixture was heated to 100 °C. After 2 h, the reaction was sampled and showed full conversion by HPLC analysis. The reaction mixture was cooled to 0-5 °C in an ice bath, poured into chilled water (75 mL), cooled in an ice bath, and stirred. Additional water was added to reach a total volume of 125 mL. After stirring for 15 min, the suspension was filtered, washed with additional water (25 mL) and dried in a vacuum oven to give a light brown solid as the desired product, 2,2,2- trichloro-N-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acetamide (4.23 g, 7.87 mmol, 90% yield, 90% purity by AUC):1H NMR (400 MHz, CDCl3) δ 8.74 (br, 1H), 8.57 (s, 1H), 8.41 (t, J = 8.2 Hz, 1H), 8.10 – 8.05 (m, 1H), 8.02 (dd, J = 11.6, 1.9 Hz, 1H), 7.84 – 7.76 (m, 2H), 7.40 (d, J = 8.5 Hz, 2H);19F NMR (376 MHz, CDCl3) δ -58.02, -130.15; LCMS / UPLC-MS (ESIMS) m / z 485.0 ([M+H]+), 483.2 ([M+H]-).

[0082] Example 1o (synthesis of compound X15): N O N N O N To a vial equipped with aadded ethyl 4- ((ethoxycarbonyl)amino)-3-fluorobenzimidate hydrochloride (0.500 g, 1.72 mmol), sodium acetate (0.282 g, 3.44 mmol) and ethanol (2.50 mL, 0.688 M). To the solution was added (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (0.393 g, 1.72 mmol) and reaction was stirred at 25 °C. After 1 h, conversion appeared complete by UPLC analysis, triethyl orthoformate (0.43 mL, 2.6 mmol) was then added, and the reaction mixture was heated to 80 °C overnight. The next day, DI water (15 mL) was then added to the solution and filtered. Solids were collected then washed with additional DI water (50 mL) to give a pink solid that was dried in a vacuum oven at 40 °C overnight to give the desired product ethyl (2-fluoro-4-(1-(4- (trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate (0.603 g, 85% yield), as a pink solid:1H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 8.24 (t, J = 8.3 Hz, 1H), 7.97 (dt, J = 8.5, 1.3 Hz, 1H), 7.90 (dd, J = 12.0, 1.8 Hz, 1H), 7.82 – 7.73 (m, 2H), 7.42 – 7.35 (m, 2H), 6.94 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H);19F NMR (471 MHz, CDCl3) δ -58.02, - 132.59.

[0083] Example 1p (synthesis of compound X16): N N Br A three neck round bottom flas, gen inlet, and temperature probe was charged with 4-bromo-3-fluorobenzonitrile (2.5 g, 12.5 mmol) and EtOH (19.1 mL) and the reaction mass was cooled to 0-5 °C in an ice bath. Acetyl chloride (17.8 mL, 250 mmol) was added over 2 h at 0-5 °C before the reaction was warmed to 20 °C and stirred for 20 h. After 20h, the reaction was sampled, and conversion of starting material appeared complete by NMR spectroscopy. The reaction was sparged with nitrogen into a base trap and concentrated to give an off-white solid that was dried overnight and used in the next step without further purification.

[0084] A three neck round bottom flask equipped with a magnetic stir bar, nitrogen inlet, and temperature probe was charged with ethyl 4-bromo-3-fluorobenzimidate hydrochloride (3.53 g, 12.5 mmol) in pyridine (19.1 mL), and the reaction was cooled to 0-5 °C in an ice bath to give a suspension. (4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (3.14 g, 13.7 mmol) was added and the reaction mixture was stirred. After 1 h in the ice bath, the flask was removed, and the reaction mixture was warmed to room temperature. After 2 h, triethyl orthoformate (3.1 mL, 18.7 mmol) was added in one portion and the reaction mixture was heated to 100 °C for 1 h. After 1 h, the reaction was cooled to 0-5 °C in an ice bath and then poured into water (100 mL). The resulting suspension was stirred for 10 minutes in an ice bath and the solids were collected by filtration and washed with water to give a dark black solid. The solid was dried in a vacuum oven to give a black solid as the desired product, 3-(4-bromo-3-fluorophenyl)-1-(4- (trifluoromethoxy)phenyl)-1H-1,2,4-triazole (4.45 g, 11.07 mmol, 89% yield):1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 7.96 (dd, J = 9.5, 1.8 Hz, 1H), 7.87 (dd, J = 8.3, 1.9 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.71 – 7.62 (m, 1H), 7.46 – 7.36 (m, 2H);19F NMR (471 MHz, CDCl3) δ -58.01, - 106.72; LCMS / UPLC-MS (ESIMS) m / z 404.0 ([M+H]+).

[0085] Example 1q (synthesis of compound X16): To a vial equipped with a magnetic stir bar and a nitrogen inlet was added 4-bromo-3- fluorobenzonitrile (0.500 g, 1.77 mmol), (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (0.404 g, 1.77 mmol) and ethanol (3.50 mL, 0.506 M). The reaction was then cooled to 0 ℃ and allowed to stir for ~ 10 minutes. Sodium acetate (0.290 g, 3.54 mmol) was then added and upon complete addition, the ice bath was immediately removed, and the solution was allowed to warm to room temperature. Upon complete conversion, triethyl orthoformate (0.393 g, 2.66 mmol) was added, and the reaction mixture was heated to 75 °C and stirred overnight. Full conversion wasobserved by HPLC analysis, and the reaction was cooled to room temperature and poured into water (25.0 mL). The mixture was cooled in an ice bath and stirred for 0.5 h to induce precipitation of solids. Solids were collected by filtration and washed with excess water and dried in a vacuum oven at 40 °C overnight to give the desired product as a red solid, 3-(4-bromo- 3-fluorophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (0.701 g, 1.74 mmol, 88% purity, 86% yield):1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 7.96 (dd, J = 9.4, 1.9 Hz, 1H), 7.87 (dd, J = 8.3, 1.9 Hz, 1H), 7.83 – 7.76 (m, 2H), 7.65 (dd, J = 8.3, 7.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H);19F NMR (471 MHz, CDCl3) δ -58.02, -106.73.

[0086] Example 1r (synthesis of compound X17): N N N F A three neck round bottom flasbar, temperature probe, reflux condenser and nitrogen inlet was charged with ethyl 3,4-difluorobenzimidate hydrochloride (7.9 g, 36 mmol) and pyridine (143 mL, 0.25 M) and placed in an ice bath, and the reaction mixture was stirred at 0-5 °C. (4-(Trifluoromethoxy )phenyl)hydrazine hydrochloride (9.78 g, 42.8 mmol) was added and the mixture was stirred for 30 min. The mixture was warmed to room temperature over 2 h. After stirring for 2.5 h, a reflux condenser was added, triethyl orthoformate (8.9 mL, 54 mmol) was added, and the reaction mixture was heated to 100 °C and stirred for 2 h. Full conversion was observed by HPLC and the reaction was cooled to room temperature, poured into water (150 mL), and stirred. Additional water was added (150 mL) after 5 min. The mixture was cooled in an ice bath and stirred for 1 h to induce precipitation of solids. Solids were collected by filtration and washed with water (75 mL) to give a greenish-brown solid that was dried in a vacuum oven to give the desired product as a brown solid, 3-(3,4-difluorophenyl)-1-(4- (trifluoromethoxy)phenyl)-1H-1,2,4-triazole (11.32 g, 33.2 mmol, 93%):1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H), 8.01 (ddd, J = 11.2, 7.7, 2.1 Hz, 1H), 7.97 – 7.90 (m, 1H), 7.80 – 7.71 (m,2H), 7.46 – 7.36 (m, 2H), 7.28 – 7.25 (m, 1H);19F NMR (471 MHz, CDCl3) δ -58.02 (s), -135.96 (d, J = 20.8 Hz), -137.20 (d, J = 20.9 Hz); GCMS (EIMS) m / z 341.2.

[0087] Example 1s (synthesis of compound X17): To a 100 mL glass reactor equipped with a mechanical stirrer, temperature probe, and nitrogen inlet was charged with ethyl 3,4-difluorobenzimidate hydrochloride (3.18 g, 14.3 mmol), sodium acetate (2.35 g, 28.7 mmol) and ethanol (29.0 mL, 0.493 M). To the solution was added (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (3.28 g, 14.3 mmol) and reaction was stirred 25 °C for 15 minutes at which point full conversion was observed by UPLC / HPLC analysis. After stirring for 15-20 minutes, triethyl orthoformate (3.58 mL, 21.5 mmol) was added, and the reaction mixture was heated to 75 °C and stirred for 16 h. Full conversion was observed by HPLC analysis and the reaction was cooled to room temperature and poured into water (150 mL). The mixture was cooled in an ice bath and stirred for 0.5 h to induce precipitation of solids. Solids were collected by filtration and washed with water (100 mL) to give a red-orange solid that was dried in a vacuum oven at 40 °C overnight to give the desired product 3-(3,4- difluorophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (11.3 g, 33.2 mmol, 86%) as a reddish-brown solid:1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.06 – 7.90 (m, 2H), 7.83 – 7.75 (m, 2H), 7.44 – 7.35 (m, 2H), 7.32 – 7.20 (m, 1H);19F NMR (376 MHz, CDCl3) δ -58.03, - 135.81 – -136.13 (m), -137.20 (ddd, J = 20.2, 11.7, 8.4 Hz).

[0088] Example 1t (synthesis of compound X18): N N I A three neck round bottom flask, ogen inlet, and temperature probe was charged with 3-fluoro-4-iodobenzonitrile (4 g, 16 mmol) in EtOH (24.7 mL) and the reaction was cooled to 0-5 °C in an ice bath. Acetyl chloride (23.0 mL, 324 mmol) was then added slowly over 2 h and the reaction was warmed to 15 °C and stirred overnight. After 19 h,the reaction was sampled and conversion of starting material appeared complete by NMR spectroscopy. The reaction was sparged with nitrogen into a base trap and concentrated to give an off-white solid that was dried overnight and used in the next step without further purification.

[0089] A three neck round bottom flask equipped with a magnetic stir bar, nitrogen inlet, and temperature probe was charged with ethyl 3-fluoro-4-iodobenzimidate hydrochloride (5.34 g, 16.2 mmol) in pyridine (24.7 mL) and the reaction was cooled to 0-5 °C in an ice bath to give a suspension. (4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (4.07 g, 17.8 mmol) was then added and stirred. After 2 h, triethyl orthoformate (4.05 mL, 24.3 mmol) was added in one portion, and the reaction mixture was heated to 100 °C. After 1 h, the reaction was cooled to 10 °C and poured into water (100 mL) to give a grey suspension. The suspension was stirred for 15 min in an ice bath and the solids were collected by filtration and washed with additional water (35 mL). The solids were dried in a vacuum oven overnight to give a brown solid as the desired product, 3-(3-fluoro-4-iodophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (6.80 g, 14.1 mmol, 87% yield):1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 7.92 – 7.66 (m, 5H), 7.40 (d, J = 8.3 Hz, 2H);19F NMR (471 MHz, CDCl3) δ -58.02, -93.35; LCMS / UPLC-MS (ESIMS) m / z 450.0 ([M+H]+).

[0090] Example 1u (synthesis of compound X18): To a 100 mL glass reactor equipped with a mechanical stirrer, temperature probe, and nitrogen inlet was charged with 3- fluoro-4-iodobenzonitrile (4.50 g, 13.7 mmol), sodium acetate (2.24 g, 27.3 mmol) and ethanol (35.0 mL, 0.391 M). To the solution was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (3.12 g, 13.7 mmol) and the reaction was stirred 25 °C for 2 h at which point full conversion was observed by UPLC / HPLC analysis. Upon complete conversion, triethyl orthoformate (3.60 mL, 21.6 mmol) was added, and the reaction mixture was heated to 75 °C overnight. Full conversion was observed by HPLC analysis, and the reaction was cooled to room temperature and poured into water (150 mL). The mixture was cooled in an ice bath and stirred for 0.5 h to induce precipitation of solids. Solids were collected by filtration, washed with water (100 mL) and dried in a vacuum oven at 40 °C overnight to give 3-(3-fluoro-4-iodophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (5.10 g, 11.3 mmol, 83% yield) as a reddish-brown solid:1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 7.89 (dd, J = 8.9, 1.8 Hz, 1H), 7.86 (dd, J = 8.2, 6.4 Hz, 1H), 7.82 – 7.77 (m, 2H), 7.74 (dd, J = 8.2, 1.8 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H);19F NMR (471 MHz, CDCl3) δ -58.01, -93.36.

[0091] Synthesis of compounds of Formula Two.

[0092] Example 2a (synthesis of compound 2.1.1) via reduction with sodium sulfite: H N NH2l A three neck round bottom flask equiand temperature probe was charged with 4-(trifluoromethoxy)aniline (1.00 g, 1 equiv, 5.65 mmol), water (5.00 mL), and HCl (1.93 g, 1.66 mL, 32% Wt, 3 equiv, 16.9 mmol). The reaction was cooled to 0 °C before a solution of sodium nitrite (409 mg, 1.05 equiv, 5.93 mmol) in water (5.00 mL) was added dropwise, maintaining the temperature below 5 °C. The reaction mixture was stirred for 1 h at 0 °C and then was added dropwise to a solution of sodium sulfite (1.99 g, 2.8 equiv, 15.8 mmol) in water (10.0 mL) at 25 °C to generate a yellow / orange suspension that was stirred for 30 minutes. The flask was equipped with a reflux condenser, hydrochloric acid (11.0 mL, 32%) was added, and the59eactionn was stirred at 100 °C for 1.5 h. The reaction was cooled to 0 °C to generate an off- white suspension. The solids were collected by filtration, washed with 30 mL of toluene, and dried in a 50 °C vacuum oven for 18 hours to yield the desired product as an off-white solid (1.14 g, 88% yield).1H NMR (500 MHz, D2O) δ 7.37 (d, J = 8.6 Hz, 1H), 7.15 – 7.07 (m, 1H);19F NMR (471 MHz, D2O) δ -58.25.

[0093] Example 2b (synthesis of compound 2.1.1) via reduction with sodium sulfite in flow: An approximately 6 wt% aqueous solution of 4-(trifluoromethoxy)aniline is preparedwith 3 equiv of HCl, and a separate aqueous solution of ~10 wt% NaNO2is prepared. The 4- (trifluoromethoxy)aniline solution is pumped at a flow rate of 5-10 mL / min into mixing unit. The NaNO2solution is pumped at a flow rate of 0.8-1.8 mL / min, also into the mixing unit, which is at a temperature between 0 and 20 °C. The two solutions then move to a continuous reactor with a residence time between 5-10 min. The mixture exits the reactor and moves to a second continuous reactor which is at 0-60 °C, where it mixes with a ~20 wt% Na2SO3solution pumped at a flow rate of 2.1-4.3 mL / min. The residence time of the second reactor ranges from 3.5-7.3 min. The reaction mixture is pumped into a 1 L jacketed reactor with aq. HCl at 60 °C, with excess Na2SO3in the presence of aq. HCl. The reaction is stirred for 1 hour and then 100 mL of toluene are added, and the reaction heated to 90 °C. The aqueous layer is decanted and cooled to 0 °C, and upon cooling the HCl salt of 2.1.1 precipitates as an off-white solid that is collected by filtration. Analytical data matched that from above.

[0094] Example 2c (synthesis of compound 2.1.1) via reduction with vitamin C: A three neck round bottom flask equipped with a stir bar, temperature probe, and nitrogen inlet was charged with 4-(trifluoromethoxy)aniline (5 g, 28 mmol), water (25 mL) and acetonitrile (25 mL). The mixture was cooled to 0 °C and 32% hydrochloric acid (24.1 mL, 254 mmol) was added. This slurry was stirred at 0 °C and then a solution of sodium nitrite (2.142 g, 31.1 mmol) in water (5 mL) was added dropwise to the reaction mixture while the temperature was not allowed to exceed 4 °C. After addition was complete, the reaction was stirred at 0 °C for 1 h. After 1 h, the reaction mixture was sparged with N2to remove any NOx. A solution of ascorbic acid (5.22 g, 29.6 mmol) in water (20 mL) was added dropwise at 0 °C with sweeping N2and a thick slurry formed that was stirred for 30 min. The off-white solids were collected by filtration, rinsed with 25 mL water, and dried in a vacuum oven overnight. After drying, 500 mg of the dried solids were added to a vial and dissolved in 0.75 mL water and 2.25 mL of 32% hydrochloric acid and stirred at 70 °C for 4 h.5 mL of water and 2.5 mL toluene were added, and the mixture was cooled to 0 °C and solids formed That were collected by filtration. The solidswere washed with toluene and dried in a 50 °C vacuum oven overnight to yield the desired product as an off-white solid (295 mg, 94% yield): Analytical data matched that from above.

[0095] Example 2d (synthesis of compound 2.1.1) via Ullmann coupling with aryl bromide and hydrazine: A vial equipped with a nitrogen inlet and stir bar was charged with copper(I) iodide (19 mg, 0.10 mmol), N1,N2-bis(2,6-dimethylphenyl)oxalamide (BMPO, 29.6 mg, 0.100 mmol), N,N,N-trimethylhexadecan-1-aminium bromide (CTAB, 72.9 mg, 0.20 mmol), 1-bromo-4-(trifluoromethoxy)benzene (0.74 mL, 5.0 mmol), potassium phosphate (212 mg, 1.00 mmol) and water (1.0 mL). The mixture was stirred at 80 °C for 20 min. Then potassium phosphate (212 mg, 1.00 mmol) was added, and the mixture was cooled to room temperature over 5 min. Hydrazine monohydrate (0.61 mL, 12 mmol) was added, and nitrogen was bubbled through the reaction mixture for 10 min, after which the vial was heated to 80 °C and stirred for 21 h. The reaction was cooled to room temperature and analyzed by NMR spectroscopy, showing 1:1 ratio of SM and product. The reaction mixture was then diluted with DCM (15 mL) to give a biphasic mixture that was filtered over a plug of Celite®(20 mL frit, ~1 inch Celite®plug). The filtrate was collected and washed with brine (15 mL) and then acidified with 37% HCl (0.5 mL) to give a yellow-orange suspension that was stirred for 5 minutes and then filtered and dried to give the desired product, (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride as an off-white solid (392 mg, 1.72 mmol, 34.3% yield): analytical data matched that from above.

[0096] Synthesis of compounds of Formula Three.

[0097] Example 3a (synthesis of compound 3.1.1.1): NH22 HCl To a vial equipped with a magnetic stir bag t was added 4-amino-3- fluorobenzonitrile (5 g, 37 mmol) in ethanol (56.1 mL, 0.655 M), which was placed in an icebath and stirred at 0 °C. Acetyl chloride (52.2 mL, 735 mmol) was added dropwise over 2.5 h via addition funnel, and the mixture was warmed to room temperature and stirred for 18 hours. The thick solution was diluted with a 1:1 mixture of EtOAc / hexanes (50 mL), the solids were collected by filtration, and dried in a vacuum oven to produce the desired product as a white solid, ethyl 4-amino-3-fluorobenzimidate dihydrochloride (7.19 g, 32.9 mmol, 90% yield):1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 10.55 (s, 1H), 7.86 (dd, J = 12.8, 2.2 Hz, 1H), 7.73 (dd, J = 8.7, 2.2 Hz, 1H), 6.86 (t, J = 8.8 Hz, 1H), 4.52 (q, J = 7.0 Hz, 2H), 2.53 (s, 1H), 1.45 (t, J = 7.0 Hz, 3H);19F NMR (376 MHz, DMSO-d6) δ -134.75.

[0098] Example 3b (synthesis of compound 3.1.1.2): NPhth HCl HN F OEt A 40 mL vial equipped with a stir bar was charged with 4-(1,3-dioxoisoindolin-2-yl)-3- fluorobenzonitrile (2.0 g, 7.5 mmol) and anhydrous HCl in ethanol (8.2 M HCl solution, 15 mL), and stirred at 35 °C for 19 h. The resulting white suspension was sampled by19F NMR spectroscopy to confirm complete conversion had occurred. The reaction was cooled to room temperature and the solids were collected by filtration and washed with anhydrous EtOH and dried in a 50 °C vacuum oven to yield ethyl 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride as a white solid (2.38 g, 6.76 mmol, 91% yield):1H NMR (400 MHz, CDCl3) δ 8.61 – 8.50 (m, 1H), 8.32 – 8.22 (m, 1H), 8.06 – 7.93 (m, 2H), 7.90 – 7.80 (m, 2H), 7.71 – 7.58 (m, 1H), 5.00 (q, J = 7.0 Hz, 2H), 1.66 (t, J = 7.0 Hz, 3H;19F NMR (376 MHz, CDCl3) δ - 113.35.

[0099] Example 3c (synthesis of compound 3.1.1.3): NO2To a vial equipped with a magnetic stir bar and nitrogen inlet was added 3-fluoro-4- nitrobenzonitrile (1.0 g, 6.0 mmol) in ethanol (9.2 mL, 0.65 M), which was placed in an ice bath and stirred at 0 °C. Acetyl chloride (8.56 mL, 120 mmol) was added dropwise over 1.5 h via syringe pump and the nitrogen sweep was turned off. The reaction mixture was stirred overnight and warmed to room temperature overnight. After stirring for 15 h the yellow solution was concentrated under reduced pressure to yield the desired product as a yellow solid, ethyl 3- fluoro-4-nitrobenzimidate hydrochloride (1.56 g, 5.77 mmol, 96% yield):1H NMR (400 MHz, CDCl3) δ 13.17 (s, 1H), 8.56 – 8.49 (m, 1H), 8.34 (dd, J = 10.6, 2.0 Hz, 1H), 8.23 (dd, J = 8.7, 7.1 Hz, 1H), 5.01 (q, J = 7.0 Hz, 2H), 1.68 (t, J = 7.0 Hz, 3H);19F NMR (376 MHz, CDCl3) δ - 114.03.

[0100] Example 3d (synthesis of compound 3.1.1.4): H N CCl3To a 100 mL glass reactor equippr, temperature probe, and nitrogen inlet was charged with 2,2,2-trichloro-N-(4-cyano-2-fluorophenyl)acetamide (5.00 g, 17.8 mmol) in EtOH (35.0 mL, 0.509 M ) and the reaction was cooled to 5 °C. Acetyl chloride (27.8 g, 355 mmol) was then added slowly over 2 h and the reaction was warmed to 25 °C and stirred overnight. After 16 h, conversion appeared complete by HPLC analysis so the reaction mixture was concentrated under reduced pressure to yield the desired product ethyl 3-fluoro-4-(2,2,2- trichloroacetamido)benzimidate hydrochloride as an off-white solid:1H NMR (500 MHz, CDCl3) δ 8.82 (d, J = 4.0 Hz, 1H), 8.59 (t, J = 8.2 Hz, 1H), 8.46 – 8.37 (m, 1H), 8.32 (d, J = 8.8 Hz, 1H), 4.96 (q, J = 7.0 Hz, 2H), 1.65 (t, J = 7.0 Hz, 3H);19F NMR (471 MHz, CDCl3) δ - 127.66.

[0101] Example 3e (synthesis of compound 3.1.1.6):H N OEt To a 100 mL glass reactor equippe er, temperature probe, and nitrogeninlet was charged with (4-cyano-2-fluorophenyl)carbamate (4.12 g, 19.8 mmol) in ethanol (30.0 mL, 0.660 M), and the reaction was cooled to 5 °C. Acetyl chloride (28.1 mL, 396 mmol) was then added slowly over 2 h and the reaction was warmed to 25 °C and stirred overnight. After 16 h, conversion appeared complete by UPLC analysis, so the reaction mixture was concentrated under reduced pressure. Residual solid was then washed with excess ethanol and dried in a vacuum oven at 40 °C overnight to yield the desired product as a colorless solid, ethyl 4- ((ethoxycarbonyl)amino)-3-fluorobenzimidate hydrochloride (2.84 g, 49% yield):1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.17 – 8.08 (m, 2H), 7.99 (dt, J = 8.7, 2.6 Hz, 1H), 4.62 (qd, J = 7.0, 1.9 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H);19F NMR (471 MHz, DMSO-d6) δ -123.70.

[0102] Example 3f (synthesis of compound 3.1.1.7): Br F To a 100 mL glass reactor equippedirrer, temperature probe, and nitrogen inlet was charged with 3-fluoro-4-bromobenzonitrile (4.00 g, 20.0 mmol) in EtOH (35.0 mL, 0.571 M) and the reaction was cooled to 5 °C. Acetyl chloride (31.4 g, 400 mmol) was then added slowly over 2 h and the reaction was warmed to 25 °C and stirred overnight. After 16 h, conversion appeared complete by UPLC analysis, so the reaction mixture was concentrated under reduced pressure to yield the desired product ethyl 4-bromo-3-fluorobenzimidate hydrochloride as an off-white solid (4.63 g, 82% yield):1H NMR (500 MHz, DMSO-d6) δ 8.16 – 8.08 (m, 1H), 8.03 (dd, J = 8.5, 7.1 Hz, 1H), 7.85 (dt, J = 8.5, 2.2 Hz, 1H), 4.58 (tt, J = 8.7, 4.3 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H);19F NMR (471 MHz, DMSO-d6) δ -106.08.

[0103] Example 3g (synthesis of compound 3.1.1.8): F HCl HN F A three neck round bottom flask equi , temperature probe, nitrogen inlet, andoutlet attached to a base scrubber was charged with 3,4-difluorobenzonitrile (2.5 g, 18 mmol) and ethanol (27.4 mL, 0.66 M). The reaction mixture was cooled in an ice bath to 0-5 °C. The nitrogen inlet was removed, and acetyl chloride (25.6 mL, 359 mmol) was added dropwise over 2 h via syringe pump. The mixture was slowly warmed to room temperature. After stirring for 16 h, the solution was analyzed by NMR spectroscopy and showed full conversion. The reaction mixture was transferred to a round bottom flask, sparged with nitrogen into a base trap, concentrated under reduced pressure, and dried in a vacuum oven to produce the desired product as an off-white solid, ethyl 3,4-difluorobenzimidate hydrochloride (3.95 g, 17.82 mmol, 99% yield):1H NMR (400 MHz, CDCl3) δ 12.80 (s, 1H), 12.11 (s, 1H), 8.44 (d, J = 9.0 Hz, 1H), 8.22 (t, J = 8.9 Hz, 1H), 7.39 (q, J = 8.6 Hz, 1H), 4.95 (q, J = 6.9 Hz, 2H), 1.63 (t, J = 6.7 Hz, 4H);19F NMR (376 MHz, CDCl3) δ -124.03 (d, J = 20.9 Hz), -133.43 (d, J = 22.2 Hz).

[0104] Example 3h (synthesis of compound 3.1.1.9): I F To a 100 mL glass reactor equipped wirrer, temperature probe, and nitrogen inlet was charged with 3-fluoro-4-iodobenzonitrile (2.00 g, 16.2 mmol) in EtOH (35.0 mL, 0.463 M) and the reaction was cooled to 5 °C. Acetyl chloride (25.4 g, 324 mmol) was then added slowly over 2 h and the reaction was warmed to 25 °C and stirred overnight. After 16 h, conversion appeared complete by UPLC analysis so the reaction mixture was concentrated under reduced pressure to yield the desired product ethyl 3-fluoro-4-iodobenzimidate hydrochloride asan off-white solid (4.84 g, 91% yield):1H NMR (500 MHz, DMSO-d6) δ 8.16 (dd, J = 8.3, 6.4 Hz, 1H), 8.03 – 7.87 (m, 1H), 7.66 (dd, J = 8.3, 2.1 Hz, 1H), 4.56 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H);19F NMR (471 MHz, DMSO-d6) δ -93.24.

[0105] Example 3i (synthesis of compound 3.1.1.10): NPhth HCl HNA reactor equipped with a reflux condenser, base scrubber, overhead stirrer and temperature probe was charged with 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzonitrile (3 g, 11.3 mmol) and n-butanol (26 mL, 284 mmol). The reaction mixture was cooled to 5 °C and acetyl chloride (16 mL, 225.4 mmol) was added slowly using an addition funnel over 20 to 30 minutes. The mixture was then warmed to 35 °C and stirred overnight. Heptanes (46 mL, 31.5 g, 27.9 equiv) was added to the reaction mixture and the resulting suspension was filtered and washed with heptanes to afford the desired product, butyl 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (3.92 g, 87% yield, 95% purity) as an off-white solid: LCMS / UPLC-MS (ESIMS) m / z 341.2 ([M+H]+).

[0106] Example 3j (synthesis of compound 3.1.1.11): NPhthA reactor equipped with a reflux condenser, base scrubber, overhead stirrer and temperature probe was charged with 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzonitrile (3.03 g, 11.4 mmol) and n-propanol (17.2 g, 287 mmol). The reaction mixture was cooled to 5 °C and acetyl chloride (17.9 g, 228 mmol) was added slowly using an addition funnel over approximately 20 minutes. The mixture was then warmed to 35 °C and stirred overnight After cooling to room temperature,heptanes (25.9 g) was added to the reaction mixture. The resulting suspension was filtered, washed with heptanes (26.3 g) and dried to afford the desired product, propyl 4-(1,3- dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (3.3 g, 9.15 mmol, 80% yield) as a white solid:1H NMR (500 MHz, DMSO) δ 12.04 (s, 1H), 8.26 (dd, J = 10.5, 2.0 Hz, 1H), 8.12 (dd, J = 8.5, 2.0 Hz, 1H), 8.07 – 7.95 (m, 4H), 7.86 (t, J = 7.8 Hz, 1H), 4.56 (t, J = 6.4 Hz, 2H), 1.95 – 1.86 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H);13C NMR (126 MHz, DMSO) δ 169.37, 166.15, 158.24, 156.23, 135.72, 131.93, 131.65, 129.39, 129.33, 126.14, 125.49, 125.39, 124.45, 117.81, 117.62, 75.07, 21.50, 10.52;19F NMR (471 MHz, DMSO) δ -116.92; LCMS / UPLC-MS (ESIMS) m / z 327.1 ([M+H]+).

[0107] Synthesis of compounds of Formula 3.2.

[0108] Example 3.2a (synthesis of 3.2.1.1): NH2A round bottom flask equipped with ature probe, nitrogen inlet, and reflux condenser was charged with 3,4-difluorobenzonitrile (1.0 g, 7.2 mmol), tetramethylammonium chloride (79 mg, 0.72 mmol), potassium 1,3-dioxoisoindolin-2-ide (1.47 g, 7.90 mmol), water (13 µL, 0.72 mmol) and DMF (7.19 mL, 1 M). The reaction was placed in a heating block and heated to an internal temperature of 100-110 °C and monitored for conversion of starting material. After 160 h, no starting material was observed and water (0.26 mL, 14 mmol) was added. After observing low conversion at 185 h, 25 h after adding water, additional water (1.3 mL, 72 mmol) was added. After 280 h, high conversion of aniline was observed and the reaction was cooled to room temperature and diluted with water (20 mL). The suspension was stirred for 5 min and then filtered to give a brown solid and white filtrate. Both layers were combined into a separatory funnel along with DCM (50 mL) and additional water (10 mL). The organic layer was collected, dried over sodium sulfate, filtered and concentrated to give a light brown / off-white solid as crude, 4-amino-3-fluorobenzonitrile (873 mg, 5.32 mmol, 74% yield, 83% purity):1H NMR (500 MHz, CDCl3) δ 7.27 – 7.24 (m, 2H), 6.76 (t, J = 8.6 Hz, 1H), 4.23 (br, 2H);19F NMR (471 MHz, CDCl3) δ -133.93; GCMS (EIMS) m / z 136.2.

[0109] Example 3.2b (synthesis of 3.2.1.2): NPhth NC FTo a jacketed reactor equipped with an stirrer, nitrogen inlet, and temperature probewas added 4-amino-3-fluorobenzonitrile (5.81 g, 50.0 mmol) in acetic acid (50.0 mL, 1.0 M), which was heated to 90 °C. Phthalic anhydride (7.41 g, 50.0 mmol) was then added and stirred overnight. After stirring overnight, the thick solution was cooled to room temperature and poured into water (100 mL) and allowed to sit for 5 min. A white solid formed which was collected by filtration and dried in a vacuum oven overnight to produce the desired product as a white solid, 4-(1,3-dioxoisoindolin-2-yl-)3-fluorobenzonitrile (11.2 g, 42.2 mmol, 84% yield):1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 5.5, 3.1 Hz, 2H), 7.85 (dd, J = 5.5, 3.0 Hz, 2H), 7.74 – 7.45 (m, 3H);19F NMR (376 MHz, CDCl3) δ -113.51.

[0110] Example 3.2c (synthesis of 3.2.1.2): A round bottom flask equipped with a stir bar, reflux condenser, temperature probe and nitrogen inlet was charged with 3,4- difluorobenzonitrile (3.48 g, 25.0 mmol) and potassium 1,3-dioxoisoindolin-2-ide (5.79 g, 31.3 mmol). Anhydrous DMF (25 mL) was then added, and the reaction was heated to 130 °C. After 8 h, the reaction was sampled and analyzed, showing high conversion by HPLC. The reaction was cooled to 40 °C and a thick suspension was present. The mixture was poured into water (35 mL) and stirred for 5 min. The mixture was then filtered through a frit and washed with water (20 mL) to afford the desired product, 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzonitrile (6.13 g, 21.2 mmol, 85% yield), as an off white solid after drying in 92% purity. Analytical data matched that from above.

[0111] Example 3.2d (synthesis of 3.2.1.4)H N CCl3A round bottom flask equipped with nd nitrogen inlet was charged with 4-amino-3-fluorobenzonitrile (2.00 g, 14.7 mmol) and DCM (49.0 mL) and the reaction was cooled to 0 °C in an ice bath. Triethylamine (3.07 mL, 22.04 mmol) and 2,2,2-trichloroacetyl chloride (2.05 mL, 18.4 mmol) were then added sequentially and the reaction was stirred for 3.5 hours in the ice bath. The reaction mixture was then warmed to room temperature and stirred. After stirring at room temperature for several days, the reaction was transferred to a separatory funnel with water (25 mL) and a saturated solution of sodium bicarbonate (25 mL). The organic layer was collected, and the aqueous layer was extracted with DCM (20 mL x2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a reddish-brown oil. The crude mixture was purified by silica gel chromatography (0-50% EtOAc / hexanes) to yield the desired product as a yellow solid after drying under reduced pressure, 2,2,2-trichloro-N- (4-cyano-2-fluorophenyl)acetamide (3.65 g, 12.97 mmol, 88% yield):1H NMR (400 MHz, CDCl3) δ 8.76 (br, 1H), 8.49 (t, J = 8.1 Hz, 1H), 7.57 (dt, J = 8.6, 1.5 Hz, 1H), 7.49 (dd, J = 10.3, 1.8 Hz, 1H);19F NMR (376 MHz, CDCl3) δ -127.75. GCMS (EIMS) m / z 279.9.

[0112] Example 3.2e (synthesis of 3.2.1.6): H N O A round bottom flask equipped witg d nitrogen inlet was charged with 4- amino-3-fluorobenzonitrile (5.63 g, 41.4 mmol) and pyridine (89.0 mL, 0.465 M) and the reaction was cooled to 0 °C in an ice bath. Ethyl chloroformate (10.0 mL, 103 mmol) was then added slowly. After stirring for 18 h, the reaction mixture was poured into DI water (180 mL) and allowed to stir in an ice bath for 0.5 h. The solution was then filtered, and the filtrate was collected and washed with DI water (2 X 100 mL). The wet solid was dried in a vacuum oven at 40 ℃ over two days to yield ethyl (4-cyano-2-fluorophenyl)carbamate (7.96 g, 38.2 mmol, 92%yield) as an off-white solid:1H NMR (400 MHz, CDCl3) δ 8.32 (t, J = 8.3 Hz, 1H), 7.46 (dt, J = 8.7, 1.6 Hz, 1H), 7.37 (dd, J = 10.6, 1.9 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H);19F NMR (471 MHz, CDCl3) δ -130.34. Example 3.2f (synthesis of 3.2.1.6): A reactor charged with 3,4-difluorobenzonitrile (2.00 g, 14.4 mmol), sodium cyanate (1.40 g, 21.6 mmol), ethanol (1.68 mL, 28.8 mmol), and DMF (40 mL) was stirred overnight at 140 °C for 18 hrs. The mixture was cooled to rt and added to water (200 mL) at 0 ℃. The resulting suspension was stirred for 30 mins, filtered and dried in a vacuum oven overnight at 40 ℃ to afford ethyl (4-cyano-2-fluorophenyl)carbamate (1.42 g, 6.82 mmol, 82% purity, 38% yield) as an off-white solid: Analytical data matched that from above.

[0113] Synthesis of compounds of Formula Four.

[0114] Example 4a (synthesis of 4.1.1.1): H NH N N H2A vial equipped with a magnecharged with (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (261 mg, 1.14 mmol) in pyridine (4.57 mL, 0.25 M) and cooled in an ice bath to 0 °C. Ethyl 4-amino-3-fluorobenzimidate hydrochloride (250 mg, 1.14 mmol) was then added portion wise over 1 min. The mixture was warmed to room temperature and stirred for 16 h. After 16 h, the dark purple solution was transferred to a separatory funnel with DCM (20 mL) and water (20 mL). The organic layer was collected, and the aqueous layer was back-extracted with DCM (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude mixture which was purified by column chromatography (0-100% EtOAc / hexanes) to yield the desired product, 4-amino-3- fluoro-N’-(4-(trifluoromethoxy)phenyl)benzimidohydrazide (100 mg, 0.31 mmol, 27% yield):1HNMR (500 MHz, CDCl3) δ 7.49 (dd, J = 12.2, 2.0 Hz, 1H), 7.34 (dd, J = 8.2, 2.0 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 7.08 – 6.99 (m, 2H), 6.78 (t, J = 8.6 Hz, 1H), 5.91 (s, 1H), 4.73 (s, 2H), 3.93 (s, 2H);19F NMR (471 MHz, CDCl3) δ -58.34, -134.97 (dd, J = 12.2, 8.9 Hz).

[0115] Example 4b (synthesis of 4.1.1.2): NHTo a flask was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (7.21 g, 31.5 mmol), sodium acetate (2.35 g, 28.7 mmol) and ethanol (60 mL). The mixture was stirred for 0.5 h at room temperature and then ethyl 4-(1,3-dioxoisoindolin-2-yl)-3-fluorobenzimidate hydrochloride (10.0 g, 28.7 mmol) was added, followed by sodium acetate (2.35 g, 28.7 mmol). The mixture was stirred for 2 h and then ethanol (20 mL) was added. The mixture was filtered, washed with ethanol (20 mL) and concentrated. The solid was the purified via column chromatography using a gradient of ethyl acetate in hexanes (0-100%). Fractions containing desired product were combined, concentrated and dried in a vacuum oven overnight at 42 °C to yield 4-(1,3-dioxoisoindolin-2-yl)- 3-fluoro-N'-(4-(trifluoromethoxy)phenyl)benzimidohydrazide (4.21 g, 8.18 mmol, 89% purity, 29% yield) as a brown solid containing ~11 wt% ethyl acetate:1H NMR (400 MHz, CDCl3) δ 8.02 – 7.93 (m, 2H), 7.86 – 7.78 (m, 2H), 7.70 (dt, J = 10.8, 1.9 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.44 – 7.35 (m, 1H), 7.11 (d, J = 8.9 Hz, 2H), 7.07 (s, 2H), 4.70 (s, 2H);19F NMR (376 MHz, CDCl3) δ -58.31, -117.31; LCMS / UPLC-MS (ESIMS) m / z 459.2 ([M+H]+).

[0116] Example 4c (synthesis of 4.1.1.3):H NH N N O2A vial equipped with a magnetic stir bar and nitrogen inlet was charged with 3- fluoronitrobenzimidate hydrochloride (500 mg, 2.01 mmol) in pyridine (4.02 mL, 0.5 M) and cooled in an ice bath at 0 °C. (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (552 mg, 2.41 mmol) was added and stirred for 5 min before the reaction mass was warmed to room temperature and stirred for 15 h. After 15 h, the red solution was transferred to a separatory funnel with DCM (20 mL) and water (20 mL). The organic layer was collected, and the aqueous layer was back-extracted with DCM (20 mL x 2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a crude mixture which was purified by column chromatography (0-100% EtOAc / hexanes), yielding the desired product as a dark green solid, 3- fluoro-4-nitro-N’-(4-(trifluoromethoxy)phenyl)benzimidohydrazine (516 mg, 1.44 mmol, 72% yield):1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 8.6, 7.5 Hz, 1H), 7.73 (dd, J = 11.9, 1.9 Hz, 1H), 7.66 (ddd, J = 8.7, 1.9, 0.9 Hz, 1H), 7.20 – 7.08 (m, 4H), 6.39 (s, 1H), 4.55 (s, 2H);19F NMR (376 MHz, CDCl3) δ -58.32, -116.03.

[0117] Synthesis of compounds of Formula Y.

[0118] Example Ya (synthesis of compound Y.1): Cl F3A 5 L reactor was fit with a nitrogen inlet, vacuum port, condenser with collection flask, overhead stir rod, thermocouple, and pump feed tube. The reactor was charged with m-toluidine (433.3 g, 1 equiv) and n-heptane (1,621 g). The reactor was sparged with nitrogen for 20 min andbrought to an internal temperature of 55 °C. A separate vessel was charged with Boc2O (882.6 g, 1 equiv) and n-heptane (214 g). The solution of Boc2O was pumped into the reactor over a period of 180 min. After the addition of Boc2O was complete, the bottle and pump line were rinsed with n-heptane (41 g). After an additional 30 min, the temperature was set to 80 °C. Once the temperature had stabilized, the pressure in the reactor was reduced under vacuum to begin removing solvent via a series of distillation operations. After the bulk solvent was removed, n- heptane (825 g) was added to the reactor and a subsequent distillation operation was conducted to remove t-BuOH. After distillation, the reactor was rapidly cooled to an internal temperature of 35 °C, and the solution was diluted to an approximate concentration of 25 w / w% product in n- heptane (1,327 g of additional n-heptane were added). The internal temperature was then adjusted to 2 °C. When the internal temperature reached ~30 °C, the crystallization was seeded (2.5 g product). After the temperature was held at 2 °C for 6 h, the reactor was drained into a vacuum filter. The filtrate was used to rinse the reactor. The wet filter cake was dried under static vacuum and the collected solid was transferred to drying dishes. The solid was dried in a vacuum oven at 50 °C for 48 h. This afforded tert-butyl m-tolylcarbamate (725 g of material less the 2.5 g seed weight = 722 g, 86%):1H NMR (500 MHz, CDCl3) δ 7.25 (d, J = 2.7 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 7.09 (dd, J = 8.0, 2.2 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.49 (s, 1H), 2.31 (s, 3H), 1.51 (s, 9H);13C NMR (126 MHz, CDCl3) δ 152.85, 138.90, 138.30, 128.78, 123.84, 119.18, 115.64, 80.40, 28.38, 21.53; LRMS (ESI-quad): [M+H-tBu] calculated for C8H10NO2+, 152.1; found, 152.0.

[0119] A 1 L reactor was equipped with nitrogen inlet, mechanical stirrer, thermocouple, and septa, and sealed under a positive pressure of nitrogen. The vessel was charged with sec-butyl lithium (260 mL, 1.4 M in cyclohexane, 364 mmol, 2.5 equiv). Mechanical stirring was set to 300 rpm. The vessel was cooled to an internal temperature of –28 °C. A solution of the substrate was prepared by charging a 250 mL flask with tert-butyl m- tolylcarbamate (30 g, 144.6 mmol), which was then dissolved into THF (15 mL, 184.5 mmol, 1.275 equiv) and tetramethylethylenediamine (TMEDA, 22 mL 144.6 mmol, 1.0 equiv). The solution of substrate was added dropwise to the reactor over 30 min. The internal temperaturewas maintained below –20 °C over the course of the addition. After an additional 60 min, DMF (23 mL, 289 mmol, 2 equiv) was added dropwise over 15 min. The internal temperature was maintained below –20 °C over the course of the addition. The reaction was quenched with 150 mL of water and the phases were separated. The organic layer was washed with another 100 mL of water and the phases were separated. The organic phase was distilled under vacuum to remove cyclohexane. Isopropyl alcohol was added and the mixture was distilled to remove residual cyclohexane and afford a solution of tert-butyl (2-formyl-5-methylphenyl)carbamate (~140 mmol) in 150 mL of IPA.

[0120] A 250 mL cylindrical jacketed reactor containing ~140 mmol of tert-butyl (2-formyl- 5-methylphenyl)carbamate in 150 mL of IPA was cooled to ~10 °C. To the reaction was added 2.8 g of solid NaBH4(0.5 equiv). The reaction mass was then heated to an external set temp to 20 °C. After monitoring by HPLC, the reaction was quenched with 24 mL AcOH (2.5 equiv) and 50 mL water. The reaction mass was stirred for 5 min and then 80 mL of toluene were added. To the reaction mass was added more water (20 mL) and the layers were separated. The organic layer was distilled and 60 mL of toluene were added to afford a solution of tert-butyl (2- (hydroxymethyl)-5-methylphenyl)carbamate (~140 mmol) in 150 mL of toluene.

[0121] A 250 mL jacketed reactor containing tert-butyl (2-(hydroxymethyl)-5- methylphenyl)carbamate (~140 mmol) in toluene (150 mL) was agitated. 120 mL of 45 wt% KOH solution (10 equiv) was added. The reaction was heated at 95 °C overnight. After stirring overnight, the reaction mass was cooled to 75 °C and then slowly cooled to -8 °C. The solids were collected via vacuum filtration and washed with toluene (100-125 mL) to produce (2- amino-4-methylphenyl)methanol as an off-white solid (11.4 g, 57% yield over three steps) upon drying overnight in a vacuum oven:1H NMR (500 MHz, DMSO-d6) δ 6.90 (d, J = 7.5 Hz, 1H), 6.43 (d, J = 1.7 Hz, 1H), 6.32 (dd, J = 7.5, 1.7 Hz, 1H), 4.91 (d, J = 4.6 Hz, 1H), 4.81 (s, 2H), 4.33 (d, J = 4.1 Hz, 2H), 2.14 (s, 3H);13C NMR (126 MHz, DMSO-d6) δ 146.77, 137.06, 128.37, 123.13, 117.09, 115.68, 61.55, 21.42. LRMS (ESI-quad); [M-OH] calculated for C8H10N+, 120.1; found, 120.0.

[0122] Methanesulfonic acid (11.8 mL, 182 mmol, 5 equiv) was added to (2-amino-4- methylphenyl)methanol (5.00 g, 36.4 mmol, 1 equiv) in trifluoroethanol (65 mL) at 40 °C. The reaction was stirred at 40 °C for 24 hours to afford the methanesulfonic acid salt of 5-methyl-2- ((2,2,2-trifluoroethoxy)methyl)aniline.

[0123] The reaction mixture was then cooled to RT and transferred to a 500 mL flask and concentrated on a rotary evaporator. Isopropyl acetate (109 mL) was added, and the reaction mixture was cooled in an ice bath. Chloroacetyl chloride (4.09 mL, 51.0 mmol, 1.4 equiv) was then added dropwise followed by the dropwise addition of aq.2 N sodium hydroxide (120 mL, 241 mmol, 6.6 equiv). The reaction was allowed to stir in the ice bath for ~15 minutes while checking HPLC. The layers were separated. The organic layer was washed with saturated NaHCO3(100 mL). The reaction mixture was concentrated to ~50 wt% solution and heptane was added to make ~1:4 w / w iPrOAc / heptane solution at ~5 wt%. The mixture was seeded at RT, cooled to 0 °C for 2 hours and filtered. The wet cake was washed with heptane to afford the desired product Y.1 as an off-white solid (8.7 g, 81% yield) upon drying:1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.94 (s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 4.70 (s, 2H), 4.20 (s, 2H), 3.84 (q, J = 8.6 Hz, 2H), 2.38 (s, 3H);19F NMR (376 MHz, CDCl3) δ -73.57.

[0124] Synthesis of compounds of Formula Z.

[0125] Example Za (synthesis of compound Z1): N F N 3CON F3A round bottom fla, , reflux condenser was charged with 2-chloro-N-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)acetamide (1.5 g, 5.1 mmol, 1 equiv), KSCN (0.69 g, 7.1 mmol, 1.4 equiv), K2CO3(35 mg, 0.25 mmol, 0.05equiv), and EtOAc (7.5 mL, 5 V). The reaction mixture was heated at 60 °C for 19 h. The reaction mixture was washed with water (10 mL) and 10% NaCl (10 mL). Solvent exchange from EtOAc to MeCN provided 2-imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one as a 35.9 wt% solution in MeCN (96% yield). The MeCN solution of 2-imino-3-(5-methyl-2-((2,2,2-trifluoroethoxy)methyl)phenyl)thiazolidin- 4-one was used directly in the final coupling step.

[0126] A flask equipped with a nitrogen inlet and mechanical stirrer was charged with 2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (677 mg, 1 equiv, 2.00 mmol), di(1H-1,2,4-triazol-1-yl)methanone (383 mg, 90% Wt, 1.05 equiv, 2.10 mmol) and acetonitrile (12.0 mL) and stirred at 29-30 °C overnight.2-Imino-3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)thiazolidin-4-one (1.95 g, 35.9% Wt, 1.1 equiv, 2.20 mmol) in MeCN was added to the reaction mixture, then heated at 40 °C overnight. After the reaction was complete as judged by HPLC analysis, the reaction mixture was cooled to RT, then 15 mL of water was added. The suspension was stirred overnight at rt. After filtration, the cake was washed with 15 mL of MeCN–water (1:2), water (10 mL) and MeOH (3 mL). The cake was dried in an oven at 50 °C under vacuum to afford the product (Z)-1-(2-fluoro-4-(1-(4- (trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-3-(3-(5-methyl-2-((2,2,2- trifluoroethoxy)methyl)phenyl)-4-oxothiazolidin-2-ylidene)urea (1.27 g, 1.86 mmol, 93.0% yield):1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.47 (t, J = 8.4 Hz, 1H), 7.96 (dd, J = 8.6, 1.8 Hz, 1H), 7.88 (dd, J = 12.0, 1.9 Hz, 1H), 7.86 – 7.73 (m, 2H), 7.49 (d, J = 3.1 Hz, 1H), 7.45 – 7.29 (m, 4H), 7.04 (d, J = 1.8 Hz, 1H), 4.62 (d, J = 12.4 Hz, 1H), 4.50 (d, J = 12.4 Hz, 1H), 3.95 (d, J = 2.7 Hz, 2H), 3.83 – 3.59 (m, 2H), 2.44 (s, 3H);19F NMR (376 MHz, CDCl3) δ 58.02, - 73.78, -131.31.

Claims

CLAIMS:

1. A process for the preparation of a compound of Formula X: N N N R2comprising the steps of: 1a. reacting a compound of Formula 2.1 or salt thereof: H N NH2)no ua . 1b. with a compound of Formula 3.1 or a salt thereof: NH R )nFormula 3.1 in the presence of a formate source, a solvent, and optionally a base; wherein: R is -(C1-C4)alkyl; R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F;R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and A is H, F or Cl.

2. The process according to claim 1, wherein the solvent is a polar, protic solvent or a non polar, aprotic solvent.

3. The process according to any of the claims 1-2, wherein: the formate source is selected from the group consisting of formic acid, formate esters, amidine and orthoesters; the polar, protic solvent is selected from the group consisting of methanol, ethanol, isopropanol, propanol, and butanol; and the base is sodium acetate, potassium acetate or lithium acetate.

4. The process according to any of the claims 1-3, wherein the compound of Formula 2.1 is a compound of Formula 2.1.1 or 2.1.2: H H N FNHN 2FNH2n2.1.1 2.1.

2.

5. The process according to any of the claims 1-3, wherein the compound of Formula 31 is a compound of Formula 3.1.1:NH OR )nwherein R2is selected from theg of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and R is –(C1-C4)alkyl.

6. The process according to claim 1, wherein the compound of Formula X is a compound of Formula Xa or Xb N N N 2 R2Xb wherein R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I.

7. The process according to any of the claims 1-6, wherein the compound of Formula 2.1 is prepared by: a. converting an aniline of Formula 2a to a diazonium salt of Formula 2.2:NH id, nitrite, solvent N A 2 ac2whereinb. reducing the diazonium salt of Formula 2.2 to a hydrazine of Formula 2.1: A H N2reductant N NH2A)nweren1s seecte rom te group consstng of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and - OCH2F.

8. The process according to claim 1, wherein the compound of Formula 3.1 is prepared by: converting a compound of Formula 3.2 to a compound of Formula 3.1: R2(HA) ROH, acidnR2Awherein R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; R is –(C1-C4)alkyl; A is H, F or Cl; andA is the counterion of an inorganic acid.

9. The process according to any of the claims 1-8, for the preparation of a compound of Formula Xa: N N N R2comprising the steps oa. reacting a compound of Formula 2.1.1: H N F NH F2A)nb. with a compound of Formula. . NH R2wherein R is sel2 ected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and R is a –(C1-C4)alkyl; in a polar, protic solvent in the presence of an optional base selected from the group consisting of sodium acetate, potassium acetate, and lithium acetate.

10. The process according to claim 9, wherein the compound of Formula Xa is selected from the group consisting of: N N N ; 3;N N N NHCOEt R2wherein R1is selected from the group consisting of F, -(C1-C4)alkyl, aryl, heteroaryl, cycloalkyl, -(C1-C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F; R2is selected from the group consisting of NH2, NPhth, NO2, NHCCl3, NHCO2Me, NHCO2Et, Br, F and I; and A is selected from the group consisting of -F, -Cl, -CF3, -(C1-C4) alkyl, -(C1- C4)alkoxy, -CHF2, -CH2F, -CF3, -OCF3, -OCF2H, and -OCH2F.

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