Processes for preparing phenethylamine compounds

Abstract

The present disclosure provides cost-effective, efficient, and scalable processes for preparing phenethylamine compounds.

Description

BACKGROUND There are three, closely related subtypes of serotonin 5-HT2 receptors (5-HT2RS), 5-HT2A, 5-HT2B, and 5-HT2C, and they are primary targets of classic serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and 2,5-dimethoxy-4-bromoamphetamine (DOB). Classic serotonergic psychedelics and entactogens have been actively investigated by the research and medical community to alleviate a multitude of central nervous system (CNS) disorders (Reiff, C. M., et al., 2020, Am J Psychiatry 177, 391-410), such as: (i) post-traumatic stress disorder (PTSD) (Jerome, L., et al., 2020, Psychopharmacology (Berl) 237, 2485- 2497), (ii) major depressive disorder (MDD), (iii) treatment-resistant depression (TRD) (Goldberg, S. B., et al., 2020, Psychiatry Res 284, 112749), (iv) obsessive-compulsive disorder (OCD) (Moreno, F. A., et al., 2006, J Clin Psychiatry 67, 1735-1740), (v) social anxiety disorder (ClinicalTrials.gov, number NCT02008396), (vi) substance use disorders, including but not limited to alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, (vii) anorexia nervosa, (viii) bulimia nervosa (ClinicalTrials.gov, numbers NCT04454684 and NCT04052568), (ix) Alzheimer’s disease (ClinicalTrials.gov, number NCT04123314), and (x) cluster headache and migraine (Nichols, D. E., 2016, Psychedelics, Pharmacol Rev 68, 264-355; Johnson, M. W., et al., 2019, Pharmacol Ther 197, 83-102; Sewell, R. A., et al., 2006, Neurology 66, 1920-1922; ClinicalTrials.gov, number NCT04218539). These drugs have also been investigated to alleviate conditions of the autonomic nervous system (ANS), including pulmonary disorders (e.g., asthma and chronic obstructive pulmonary disorder (COPD) and cardiovascular disorders (e.g., atherosclerosis), among others (Nichols, D. E., et al., 2017, Clin Pharmacol Ther 101, 209-219; Flanagan, T. W., et al., 2019, Life Sci 236, 116790; Flanagan, T. W., et al., 2019, Sci Rep 9, 13444; Sexton, J. D., et al., 2019, Front Psychiatry 10, 896). Potent and selective phenethylamines that act as serotonin 5-HT2 receptors agonists are described in International Application No. PCT / EP2021 / 072896 (WO 2022 / 038170), the entire content of which is hereby incorporated by reference in its entirety. The need for new targeted therapies (e.g., small molecule agonists) to treat CNS and ANS disorders such as those described herein brings with it a requirement for efficient synthetic processes to prepare those agonists. The phenethylamine agonists described in International Application No. PCT / EP2021 / 072896 require a more cost-effective, efficient, and scalable preparation process. Specifically, a preparation process is needed that avoids the use of precious metal (e.g., palladium) coupling reactions. The processes disclosed herein meet this need by providing a concise synthetic route to prepare phenethylamine compounds for an efficient and industrially scalable process. SUMMARY The present disclosure provides, inter alia, a process for preparing a compound of Formula I: OR2 (I) wherein the variables are defined herein. This process is an efficient and cost-effective method for preparing compounds that act as serotonin 5-HT2 receptor agonists. As such, the present disclosure provides a scalable process for preparing compounds that can be used in the treatment of diseases associated with an 5-HT2 receptor, such as post-traumatic stress disorder (PTSD), major depressive disorder (MDD), treatment-resistant depression (TRD), obsessive-compulsive disorder (OCD), social anxiety disorder, substance use disorders, including but not limited to alcohol use disorder, opioid use disorder, amphetamine use disorder, nicotine use disorder, and cocaine use disorder, anorexia nervosa, bulimia nervosa, Alzheimer’s disease, pain, and cluster headache and migraine, and others such as those associated with reduced neuroplasticity and / or neuroinflammation. DETAILED DESCRIPTION Provided herein is a process for preparing a compound of Formula I: OR2 (I) wherein the variables are defined herein. In some embodiments, the process follows the subsequent scheme: Definitions As used in this specification and the appended claims, the singular forms “a,” “an” and 5 “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a solvent” includes a combination of two or more such solvents, reference to “a base” includes one or more bases, or mixtures of bases, and the like. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive and covers both “or” and “and.” 10          The term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include Cm, Ci-6 and the like. The term “alkyl” refers to a straight- or branched-chain alkyl group having the indicated number of carbon atoms in the chain. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, and isohexyl.. 15 The term C1-C3 alkyl as used herein refers to a straight- or branched-chain alkyl group having from 1 to 3 carbon atoms in the chain. The term Ci-Ce alkyl as used here refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain. As used herein, the term “aryl” means an aromatic carbocyclic system containing 1, 2 or 3 rings, wherein such rings may be fused, wherein fused is defined above. If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term “aryl” includes, but is not limited to, phenyl, naphthyl, indanyl, and 1,2,3,4-tetrahydronaphthalenyl. In some embodiments, aryl groups have 6 carbon atoms. In an embodiment, the aryl group has six to ten carbon atoms. In another embodiment, the aryl group is phenyl. The term “cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term “Cn-m cycloalkyl” refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C3-7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused ( / .e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Preparation of compounds involves the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety. Adjustments to the protecting groups and formation and cleavage methods described herein may be adjusted as necessary in light of the various substituents. As used herein, “protecting group” refers to a molecular framework that is introduced onto a specific functional group in a poly-functional molecule to block its reactivity under reaction conditions needed to make modifications elsewhere in the molecule. In some embodiments, the protecting group is benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), phthalimide, dichlorophthalimide, tetrachlorophthalimide, 4-nitrophthalimide, 2,3-diphenylmaleimide, succinimide, 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl)ethoxycarbonyl (Tsc), t-butoxycarbonyl (Boc), 1-adamantyloxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcBoc), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N’,N’-dimethylhydrazinyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP). In some embodiments, the protecting group is methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), allyl, t-butyldimethylsilyl (TBDMS), or pivoyl (Piv). When a protecting group such as one of those listed above is introduced onto a nitrogen functional group of the molecule, it may be referred to as a “nitrogen protecting group.” In some embodiments, the protecting group (or nitrogen protecting group) is phthalimide. As used herein, the phrase “protecting group reagent” refers to a reactant that installs a protecting group on another reactant in a process. Protecting group reagents include reactants that protect a free nitrogen atom or free oxygen atom. Examples of protecting group reagents include but are not limited to phthalic anhydride, dichlorophthalic anhydride, tetrachlorophthalic anhydride, 4-nitrophthalic anhydride, 2,3-diphenylmaleic anhydride, succinic anhydride, MOMCI, MEMCI, Boc2O, TrtCI, SEMCI, BnCI, PivCI, TBDPSCI, TIPSCI, TMSCI, and BzCI. Mono- or bisesters (e.g., mono-methyl or bis-methyl esters) of any of the anhydrides may also be used as the protecting group reagent. As used herein, the phrase “alkylating reagent” refers to chemical species that alkylates a reactant. A “trifluoromethylating reagent” is an alkylating agent that donates a -CF3 moiety to the reactant. As used herein, the phrase “oxidizing reagent” refers to a substance in a redox chemical reaction that gains or accepts an electron from a reducing agent. An oxidizing reagent is a chemical species that undergoes a chemical reaction in which it gains one or more electrons. As used herein, the phrase “reducing reagent” refers to a chemical species that donates an electron to an electron recipient in a redox reaction. Substitution with heavier isotopes such as deuterium, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. (A. Kerekes et.al. J. Med. Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015, 58, 308-312). The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The present disclosure also includes salt forms of the compounds described herein. Examples of salts (or salt forms) include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety. The acid used to form the salt (or salt form) may be a monoacid, a diacid, a triacid, a tetraacid, or may contain a higher number of acid groups. The acid groups may be, e.g., a carboxylic acid, a sulfonic acid, a phosphonic acid, or other acidic moieties containing at least one replaceable hydrogen atom. Examples of acids which may be used to form the salts (or salt forms) disclosed herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, phenylacetic acid, acylated amino acids, alginic acid, ascorbic acid, L-aspartic acid, sulfonic acids (e.g., benzenesulfonic acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid, ethanedisulfonic acid, etc.), benzoic acids (e.g., benzoic acid, 4-acetamidobenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-amino-salicylic acid, gentisic acid, etc.), boric acid, (+)-camphoric acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, formic acid, fumaric acid, galactaric acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (-)-D-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, (+)-D-malic acid, hydroxymaleic acid, malonic acid, (±)-DL-mandelic acid, isethionic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, succinic acid, sulfuric acid, sulfamic acid, tannic acid, tartaric acids (e.g., DL-tartaric acid, (+)-L-tartaric acid, (-)-D-tartaric acid), thiocyanic acid, propionic acid, valeric acid, and fatty acids (including fatty mono- and diacids, e.g., adipic (hexandioic) acid, lauric (dodecanoic) acid, linoleic acid, myristic (tetradecanoic) acid, capric (decanoic) acid, stearic (octadecanoic) acid, oleic acid, caprylic (octanoic) acid, palmitic (hexadecenoic) acid, sebacic acid, undecylenic acid, caproic acid, etc.). The compounds of the disclosure may, accordingly, be used or synthesized as free bases, solvates, hydrates, salts, or as combination salt-solvates or salt-hydrates. The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. In some embodiments, reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas. As used herein, “solvent” or “organic solvent” refers to any solvent that contains one or more carbon-hydrogen bonds. Example nonlimiting organic solvents include hexane, heptane, tetrahydrofuran, dichloromethane, methanol, ethanol, isopropanol, ethyl acetate, propylene glycol methyl ether, / V, / V-dimethylformamide, / V, / V-dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, and the like. As used herein, “protic solvent” refers to any solvent that contains a labile hydrogen atom. Typically, the labile hydrogen atom is bound to an oxygen (as in a hydroxyl group), a nitrogen (as in an amino group), or a sulfur (as in a thiol group). Suitable protic solvents can include, byway of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, propylene glycol methyl ether, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. As used herein, “aprotic solvent” refers to any solvent that does not contain a labile hydrogen atom. Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), / V, / V-dimethylformamide (DMF), / V, / V-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), / V-methylpyrrolidinone (NMP), formamide, / V-methylacetamide, / V-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, / V, / V-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide. The reactions of the processes described herein can be carried out at appropriate temperatures that can be readily determined by the skilled artisan. Reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures). The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan. In some embodiments, preparation of compounds can involve the addition of acids or bases to effect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts. Example acids can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid. As used herein, the term “base” refers to any species that contains a filled orbital containing an electron pair which is not involved in bonding. Example bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, pyridine, imidazole, triethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), sodium ethoxide, potassium ethoxide, and the like. Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include sodium, lithium, and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides. Upon carrying out preparation of compounds according to the processes described herein, isolation and purification operations such as concentration, filtration, extraction, solidphase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired products. Processes for preparing the compound of Formula I The present disclosure provides, inter alia, processes for preparing a compound of Formula I, which is useful for the treatment of CNS disorders. Thus, in an aspect, provided herein is a process for preparing a compound of Formula I: OR2 F3c AJ R1 ✓k T OR3 (I) or a pharmaceutically acceptable salt thereof; wherein X is S, S(O), or S(O)2; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; comprising the steps of f) reacting a compound of Formula VII: ?r2 ^pg) OR3 (VII) wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; with a trifluoromethylating reagent to form a compound of Formula VIII: ?r2 f3cs^y^ r1 OR3 (VIII) wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII with an oxidizing reagent to form a compound of Formula VIII*: ?r2 fQ) F3CsyJJ r1 OR3 (VIII*) wherein PG is a nitrogen protecting group; Y is S(O) or S(O)2; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII or VIII* under deprotecting conditions to form the compound of Formula I. In an embodiment, the process further comprises the step of e) treating a compound of Formula VI: OR3 (VI) wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; with a reducing reagent to form the compound of Formula VII. In another embodiment, the process further comprises the step of d) reacting a compound of Formula V: (V) wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; with chlorosulfonic acid to form the compound of Formula VI. In yet another embodiment, the process further comprises the step of c) reacting a compound of Formula IV: OR2 (IV) wherein R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; with a protecting group reagent to form the compound of Formula V. In still another embodiment, the process further comprises the step of b) treating a compound of Formula III: OR2 (HI) wherein R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; with a reducing reagent to form the compound of Formula IV. In another embodiment, the process further comprises the step of a) reacting a compound of Formula II: OR2 O (II) wherein R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R1-NO2, wherein R1 in Formula Ila is C1-7 alkyl optionally substituted with deuterium; to form the compound of Formula III. In another embodiment, the process further comprises the step of reacting a compound that is 2,5-dihydroxybenzaldehyde: OH O with R2X and R3X; wherein R2 and R3 are each independently C1-6 alkyl optionally substituted with deuterium; and each X is independently a leaving group such as halo (e.g., I, Br, Cl), a sulfonate (e.g., triflate, tosylate, mesylate, etc.), dinitrogen (-N2+), and the like; to form a compound of Formula II. In an embodiment, the process comprises preparing a compound of Formula I: OR2 F3c AJ R1 ✓k T OR3 (I) or a pharmaceutically acceptable salt thereof; wherein X is S, S(O), or S(O)2; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; comprising the steps of a) reacting a compound of Formula II: OR2 O (II) wherein R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R1-NO2, wherein R1 in Formula Ila is C1-7 alkyl optionally substituted with deuterium; to form a compound of Formula III: OR2 Ol R1 OR3 (HI) wherein R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; b) treating the compound of Formula III with a reducing reagent to form a compound of Formula (IV) wherein R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; c) reacting the compound of Formula IV with a protecting group reagent to form a compound of Formula V: ?r2 q OR3 (V) wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; d) reacting the compound of Formula V with chlorosulfonic acid to form a compound of Formula wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; e) treating the compound of Formula VI with a reducing reagent to form a compound of Formula VII: wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; f) reacting the compound of Formula VII with a trifluoromethylating reagent to form a compound of Formula VIII: (VIII) wherein PG is a nitrogen protecting group; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII with an oxidizing reagent to form a compound of Formula VIII*: (VIII*) wherein PG is a nitrogen protecting group; Y is S(O) or S(O)2; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII or VIII* under deprotecting conditions to form the compound of Formula I. In another embodiment of the processes, the process further comprises reacting the compound of Formula I with an alkylating reagent to form a compound of Formula IX: or a pharmaceutically acceptable salt thereof; wherein X is S, S(O), or S(O)2; R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium; R2 is C1-6 alkyl optionally substituted with deuterium; and R3 is C1-6 alkyl optionally substituted with deuterium; and R4 is C1-6 alkyl optionally substituted with C3-6 cycloalkyl or aryl. In an embodiment, the alkylating reagent for preparing the compound of Formula IX is selected from the group consisting of benzyl halide (e.g., benzyl bromide, benzyliodide, etc.), benzaldehyde, cyclopropylmethylhalide (e.g., cyclopropylmethyl bromide, cyclopropylmethyl chloride, etc.), cyclopropanecarboxaldehyde, aldehydes such as formaldehyde and acetaldehyde, and alkyl halide (e.g., methyl iodide, methyl bromide, ethyl bromide, and the like). In yet another embodiment, the compound of Formula Ila is nitromethane or nitroethane. In still another embodiment, the compound of Formula Ila is nitromethane. In another embodiment, the compound of Formula Ila is nitroethane. In an embodiment, the reacting of the compound of Formula II with the compound of Formula Ila in step a) involves using an organic amine in the presence of an acid. In another embodiment, the organic amine is selected from the group consisting of ammonium acetate, n-butylamine, and ethylenediaminetetraacetic acid (EDTA). In yet another embodiment, the organic amine is n-butylamine. In still another embodiment, the acid is hydrochloric acid or acetic acid. In an embodiment, the acid is acetic acid. In another embodiment, step a) is run at reflux temperature. In another embodiment, the reducing reagent in step b) is selected from the group consisting of LiAIFU, LiBH4, NaBH4, H2 Pd / C, PPha, sodium amalgam, sodium hydride, Na(OAc)3BH, NaBHsCN, and BH3-THF. In still another embodiment, the reducing reagent in step b) is LiAIFU. In an embodiment, the treating the compound of Formula III with the reducing reagent in step b) involves dissolving the reactants in an organic solvent. In another embodiment, the organic solvent is an aprotic solvent. In yet another embodiment, the solvent is a polar solvent. In still another embodiment, the solvent is selected from the group consisting of tetrahydrofuran (THF), acetonitrile, water, and toluene. In an embodiment, the solvent is THF. In an embodiment, the protecting group reagent in step c) is phthalic anhydride or succinic anhydride. In another embodiment, the protecting group reagent in step c) is phthalic anhydride. In yet another embodiment, the protecting group reagent in step c) is succinic anhydride. In another embodiment, the protecting group reagent in step c) is benzyl bromide. In another embodiment, the protecting group reagent in step c) is acetyl chloride or acetic anhydride. In an embodiment, the reacting of the compound of Formula IV with the protecting group reagent in step c) involves dissolving the compound of Formula IV and the protecting group reagent in a solvent and refluxing. In another embodiment, the solvent is an aprotic solvent. In yet another embodiment, the solvent is a nonpolar solvent. In still another embodiment, the solvent is toluene. In another embodiment, the reflux temperature is between 120 °C to 130 °C. In an embodiment, the reacting of the compound of Formula V with chlorosulfonic acid in step d) involves diluting the reaction mixture with an organic solvent. In another embodiment, the organic solvent is dichloromethane. In yet another embodiment, the reacting of the compound of Formula V with chlorosulfonic acid in step d) involves using at least 2 equivalents of chlorosulfonic acid, at least 4 equivalents of chlorosulfonic acid, at least 6 equivalents of chlorosulfonic acid, at least 8 equivalents of chlorosulfonic acid. In another embodiment, the reducing reagent in step e) is selected from the group consisting of LiAIH4, NaBH4, H2 Pd / C, PPha, sodium amalgam, sodium hydride, NaBHsCN, and BH3-THF. In still another embodiment, the reducing reagent in step e) is PPha. In an embodiment, the treating of the compound of Formula VI with the reducing reagent in step e) involves dissolving the reactants in an organic solvent. In another embodiment, the organic solvent is an aprotic solvent. In yet another embodiment, the solvent is a polar solvent. In still another embodiment, the solvent is selected from the group consisting of toluene, THF, and ethyl acetate. In an embodiment, the solvent is toluene. In an embodiment, the trifluoromethylating reagent in step f) is a compound of Formula X: CF3 OTf oio (X). The compound of Formula X is also known as trifluoromethyl thianthrenium triflate or 5-(trifluoromethyl)-5H-thianthren-5-ium trifluoromethanesulfonate. Other trifluoromethylating reagents include but are not limited to, trifluoromethyl thianthrenium tetrafluoroborate, sodium trifluoromethanesulfinic acid (Langlois reagent), diaryl(trifluoromethyl) sulfonium salt (Ar2S+CF3SbFe"), 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate, 5-(trifluoromethyl)dibenzothiophenium tetrafluoroborate, hypervalent iodine(lll)-CF3 reagents orTogni reagents such as 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole, or other salts thereof where the recited trifluoromethanesulfonate (triflate) or tetrafluoroborate anion is replaced with another suitable anion. In an embodiment, the reacting of the compound of Formula VII with the trifluoromethylating reagent in step f) involves reacting the compound of Formula VII with the compound of Formula X (or other trifluoromethylating reagent such as trifluoromethyl thianthrenium tetrafluoroborate, sodium trifluoromethanesulfinic acid, etc.) in the presence of a base and a solvent. In another embodiment, the solvent is an aprotic solvent. In yet another embodiment, the solvent is a polar solvent. In still another embodiment, the solvent is selected from the group consisting of acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, and pyridine. In an embodiment, the solvent is dimethylformamide. In another embodiment, the solvent is acetonitrile. In yet another embodiment, the base is selected from triethylamine, pyridine, 4-dimethylaminopyridine, imidazole, and potassium persulfate. In still another embodiment, the base is triethylamine. In another embodiment, the oxidizing reagent in step g) is selected from the group consisting of mCPBA, potassium permanganate, pyridinium chlorochromate (PCC), ceric ammonium nitrate (CAN), hydrogen peroxide, potassium nitrate, pyridinium dichromate (PDC), Dess-Martin periodinane, diethyl azodicarboxylate (DEAD), 2,3-dichloro-5,6-Dicyanobenzoquinone (DDQ), diisopropyl azodicarboxylate (DIAD), NMO, osmium tetroxide, and TEMPO. In yet another embodiment, the oxidizing reagent in step g) is mCPBA. In another embodiment, the molar equivalence of the oxidizing reagent in step g) relative to the compound of Formula VIII is adjusted for monooxidation for sulfoxide formation (X or Y is S(O)) or bisoxidation for sulfone formation (X or Y is S(O)2). For example, monooxidation may be carried out through the use of about one molar equivalent (e.g., about 1.0 to about 1.5 molar equivalence) of oxidizing agent (e.g., mCPBA), whereas bisoxidation may be produced through the use of superstiochiometric (e.g., about 2.0+ molar equivalence) of oxidizing agent. In another embodiment, the deprotecting conditions in step h) comprise aqueous alkylamine such as methylamine, butylamine, etc. In another embodiment, the deprotecting conditions in step h) comprise methylamine. Other deprotecting conditions in step h) comprise the use of one or more of the following: hydrazine, arylhydrazine (e.g., phenylhydrazine), alkylhydrazine (e.g., methylhydrazine), strong bases such as sodium sulfide, a reducing reagent (e.g., sodium borohydride), enzyme reagents such as phthalyl amidase, polyamines (e.g., N,N- dimethyl-1,3-propanediamine, N-methyl-1,3-propanediamine, ethylenediamine, polymer bound ethylenediamine), hydroxylamine, hydrazine acetate, and the like. In an embodiment, the process comprises forming a pharmaceutically acceptable salt of the compound of Formula I. The salt formation step may involve contacting the compound of Formula I as a free base with an acid. In an embodiment, a stoichiometric (or superstoichiometric) quantity of the acid is contacted with the free base compound of Formula I. In an embodiment, a sub-stoichiometric (e.g., 0.5 molar equivalents) quantity of the acid is contacted with the free base compound of Formula I. The use of sub-stoichiometric quantities of the acid may be desirable when, for example, the acid contains at least two acidic protons (e.g., two or more carboxylic acid groups) and the target salt is a hemi-acid salt. The contacting may optionally be performed in a solubilizing solvent (i.e., a solvent that is capable of dissolving the salt form thus obtained), a non-limiting example of which is 1,4-dioxane. When a solubilizing solvent is used, the salt formation step may optionally involve removing the solubilizing solvent after salt formation is deemed complete, and optionally replacing with a non-solubilizing solvent (i.e., a solvent which is not capable of dissolving the salt form), a non-limiting example of which is ethyl acetate. The contacting may optionally be performed in a non-solubilizing solvent whereby the salt form is precipitated out of solution upon formation. The salt formation step may comprise isolating the salt form. Isolation of the salt may be performed by various well-known isolation techniques, such as filtration, decantation, and the like. In an embodiment, the isolating step is performed by filtration. In an embodiment, the salt is isolated in crystalline form. In an embodiment, the salt is isolated in amorphous form. After isolation, additional crystallization and / or recrystallization steps may also optionally be performed, if desired, for example to increase purity, crystallinity, etc. In an embodiment, the salt formation step is performed during workup of the deprotecting conditions from the step h). In an embodiment, the pharmaceutically acceptable salt of the compound of Formula I is a hydrochloride (HCI) salt. In yet another embodiment, X is S. In still another embodiment, X is S(O). In an embodiment, X is S(O)2. In another embodiment, Y is S(O). In yet another embodiment, Y is S(O)2. In another embodiment, R1 is H. In yet another embodiment, R1 is D. In still another embodiment, R1 is methyl. In an embodiment, R2 is methyl. In another embodiment, R2 is CD3. In yet another embodiment, R3 is methyl. In still another embodiment, R3 is CD3. In an embodiment, R2 is methyl and R3 is methyl. In another embodiment, R2 is CD3 and R3 is CD3. In yet another embodiment, R4 is methyl. In still another embodiment, R4 is ethyl. In an embodiment, R4 is -CH2-cyclopropyl. In another embodiment, R4 is -CH2-phenyl. In yet another embodiment, PG is phthalimide. In still another embodiment, PG is succinimide. In another aspect, provided herein is a process for preparing a compound of Formula I: OR2 F3c AJ R1 ✓k T OR3 (I) wherein X is S, S(O), or S(O)2; R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; comprising the steps of f) reacting a compound of Formula VII’: or2 Jl J R1 O HS J OR3 (VIP) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; with a compound of Formula X: CF3 OTf coo to form a compound of Formula VIII : (VIII’) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII’ with mCPBA to form a compound of Formula VIII*’: (VIII*’) wherein Y is S(O) or S(O)2; R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII’ or VIII*’ under deprotecting conditions to form the compound of Formula I. In another embodiment, the process further comprises the step of e) treating a compound of Formula VI’: (VI’) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; with triphenylphosphine to form the compound of Formula VII’. In yet another embodiment, the process further comprises the step of d) reacting a compound of Formula V’: (V’) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; with chlorosulfonic acid to form the compound of Formula VI’. In still another embodiment, the process further comprises the step of c) reacting a compound of Formula IV: OR2 (IV) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; with phthalic anhydride to form the compound of Formula V’. In an embodiment, the process further comprises the step of b) treating a compound of Formula III: OR2 NO2 R1 OR3 (HI) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; with lithium aluminum hydride to form the compound of Formula IV. In another embodiment, the process further comprises the step of a) reacting a compound of Formula II: OR2 O OR3 (II) wherein R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R1-NO2, wherein R1 is C1-4 alkyl optionally substituted with deuterium; to form the compound of Formula III. In another embodiment, the process further comprises the step of reacting a compound that is 2,5-dihydroxybenzaldehyde: with R2X and R3X; wherein R2 and R3 are each independently C1-6 alkyl optionally substituted with deuterium; and each X is independently halo; to form a compound of Formula II. In an embodiment, the process comprises preparing a compound of Formula I: (I) or a pharmaceutically acceptable salt thereof; wherein X is S, S(O), or S(O)2; R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; comprising the steps of a) reacting a compound of Formula II: OR2 O (II) wherein R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; with a compound of Formula Ila: R1-NO2, wherein R1 is C1-4 alkyl optionally substituted with deuterium; to form a compound of Formula III: wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; b) treating the compound of Formula III with lithium aluminum hydride to form a compound of Formula IV: OR2 (IV) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; c) reacting the compound of Formula IV with phthalic anhydride to form a compound of Formula (V’) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; d) reacting the compound of Formula V’ with chlorosulfonic acid to form a compound of Formula VI’: °r2             / / A J R1 O ciOzS y OR3 (vr) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; e) treating the compound of Formula VI’ with triphenylphosphine to form a compound of Formula VII’: or2             / / Jl J R1 0 HS J OR3 (VIP) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; f) reacting the compound of Formula VII’ with a compound of Formula X: CF3 OTf a:u (X) to form a compound of Formula VIII’: or2             / / JlJ R1 0 F3CS^r OR3 (VHP) wherein R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; g) optionally treating the compound of Formula VIII’ with an oxidizing reagent to form a compound of Formula VIII*’: wherein Y is S(O) or S(O)2; R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; and h) treating the compound of Formula VIII’ or VIII*’ with aqueous methylamine to form the compound of Formula I. In another embodiment, the process further comprises reacting the compound of Formula I with an alkylating reagent to form a compound of Formula IX: OR3 (IX) or a pharmaceutically acceptable salt thereof; wherein X is S, S(O), or S(O)2; R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium; R2 is C1-3 alkyl optionally substituted with deuterium; and R3 is C1-3 alkyl optionally substituted with deuterium; and R4 is C1-3 alkyl, C1-3 alkyl-(C3-6 cycloalkyl), or C1-3 alkyl-(phenyl). In yet another embodiment of the processes, the compound of Formula I is selected from the group consisting of OMe ^NH2 ocd3 ^NH2 F3cs^ OMe f3cs^ ocd3 ji OMe v yNH2 ocd3 ,nh2 f3cs^ Y OMe I f3cs^ ocd3 OMe ^NH2 ocd3 ^NH2 F3CX / 3 xs / / w 0 0 [I J OMe F3C\ J 0 0 H J OCD3 OMe ^NH2 OCD3 ^NH2 F3C. J J -g / L f3c. J 3 s 11 0 OMe 0 OCD3 5          or a pharmaceutically acceptable salt thereof. In still another embodiment, the compound of Formula IX is selected from the group or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is isolated in high yield. In some embodiments, the compound of Formula I is isolated in at least about 85% yield. In some embodiments, the compound of Formula I is isolated in at least about 90% yield. In some embodiments, the compound of Formula I is isolated with high purity. In some embodiments, the compound of Formula I is isolated with at least about 90% purity. In some embodiments, the compound of Formula I is isolated with at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% purity. In some embodiments, the compound of Formula I is isolated with at least about 95% purity. In some embodiments, the compound of Formula I is isolated with at least about 99% purity. In some embodiments, the compound of Formula IX is isolated in high yield. In some embodiments, the compound of Formula IX is isolated in at least about 85% yield. In some embodiments, the compound of Formula IX is isolated in at least about 90% yield. In some embodiments, the compound of Formula IX is isolated with high purity. In some embodiments, the compound of Formula IX is isolated with at least about 90% purity. In some embodiments, the compound of Formula IX is isolated with at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% purity. In some embodiments, the compound of Formula IX is isolated with at least about 95% purity. In some embodiments, the compound of Formula IX is isolated with at least about 99% purity. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. The reactions of the processes described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. In some embodiments, reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas. Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, a,a,a-trifluorotoluene, 1,2-dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, 1,2-dichlorobenzene, chlorobenzene, fluorobenzene, mixtures thereof and the like. Suitable ether solvents include: dimethoxymethane, tetra hydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, mixtures thereof and the like. Suitable protic solvents can include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), 1,3- dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPLI), 1,3-dimethyl-2-imidazolidinone (DMI), N methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide. Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene. Supercritical carbon dioxide and ionic liquids can also be used as solvents. The reactions of the processes described herein can be carried out at appropriate temperatures that can be readily determined by the skilled artisan. Reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures). The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan. In some embodiments, preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts. Example acids can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include formic acid, acetic acid, propionic acid, butanoic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, tartaric acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid. Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides. Upon carrying out preparation of compounds according to the processes described herein, the usual isolation and purification operations such as concentration, filtration, 5 extraction, solid-phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired products. EXAMPLES The compounds and processes disclosed herein are further illustrated by the following 10 examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, which are within the skill of the art. Alternative syntheses and biological activity for the compounds described herein are disclosed in PCT / EP2021 / 072896, the content of which is incorporated by reference in its 15 entirety. Example 1: Experimental Protocols Scheme 1 In the route of Scheme 1, chlorosulfonation of dimethoxybenzene (lnt-1*) was explored with chlorosulfonic acid under different conditions. In most of the conditions, the desired product formation was observed but maximum conversion was obtained using DCM as a solvent. Reaction conditions were further optimized in relation to solvent volumes and scaled up to gram scale. In the next step, various reducing agents were screened to form thiol intermediate 3*, e.g., Zn / Acid, Staudinger reduction (PPha) and metal hydrides, where Zn / HCI resulted in best conversions. Later, the isolated lnt-3* was found to be unstable and prone to oxidation to give a disulfide by-product. To overcome this problem, triphenylphosphine was added in the reaction during isolation (as a stabilizing agent). In the next step, trifluoromethylation of lnt-3* was attempted using different trifluoromethylating agents. All the reagents tried gave < 10% desired product. None of the reagents resulted in >10% desired product formation. Therefore, this process is not suitable for process scale. Scheme 2 CH3NO2, nBuNH2 O Va-c R' ^R AcOH, 115 °C, 5h Step-a CISO3H DCM Step-d 0 Vllla-c R' 1 N, f3cs 0 no2 O III CIO3S O Vla-c R' i N R PPh3, toluene N-deprotection HCI salt formation Step-h Step-b Step-e nh2hci Formula I F3CS 0 LiAIH4, THF 55-65 °C, 18 h nh2 N-protection IV HS Vlla-c R' % Step-c ?F3 6Tf TEA, ACN Step-f a: R / R‘ = phthalimide b: R = CBz R' = H c: R- Ac R' = H In the route of Scheme 2, synthesis of I nt-l 11 was attempted using different bases. Reactions using ammonium acetate, sodium hydroxide, and different organic amines resulted in desired product formation. Of the organic amines, the best conversion was obtained by using n-butylamine in acetic acid. Crude material obtained was sufficiently pure to be used in the next step without any further treatment. In Step-b, various reducing reagents were screened, e.g., Ni / Pd / Rh hydrogenations, metal hydride reagents, such as LiAIFL, NaBH4, UBH4, and NiCl2 / NaBH4. Reduction using lithium aluminum hydride gave maximum conversion to Int-IV. The crude material was subjected to the next step without any purification. In the subsequent step, N-protecting groups were explored in view of their compatibility with downstream chemistry. For this, N-Acetylation, N-Cbz protection, and N-phthalimide protection were considered as a priority screening to understand the complete route feasibility: a) N-Cbz protection was successful on small scale, but this intermediate did not result in desired thiol scaffold when subjected to optimized reduction conditions (described in route-1). b) N-phthalimide protection resulted in good conversion and isolated as solid material. This intermediate worked well in downstream chemistry (discussed below). c) N-acetyl protection also resulted in desired product on small scale. Later, this intermediate was subjected to the trifluoromethylation step, which gave the desired product but in lower yields. Also, the material obtained was gummy mass, which requires column purification. Further, deprotection trials also resulted in lower yields. As discussed above, N-phthalimide protection resulted in maximum conversion and was easier to isolate as a solid compound, thus it was optimized and scaled-up to gram scale. Later, phthalimido-protected intermediate-Va was subjected to chlorosulfonation conditions (step d) followed by triphenylphosphine mediated reduction (step e) using the earlier optimized process (Scheme 1). The crude material Vila was purified through column chromatography to remove triphenylphosphine related byproducts. This key scaffold was subjected to extensive screening using different trifluoromethylating agents detailed below. Of all the screened conditions, a thianthrene trifloromethanesulfonate derivative in acetonitrile using triethylamine gave best conversion (40-50%). Later, Intermediate-Villa was subjected to N-deprotection conditions using methylamine. The desired product that formed was converted to its hydrochloride salt. For purification, the crude material was slurried in ethyl acetate to get desired specifications of compound 1 as its HCI salt. Scheme 3 summarizes the optimal reaction conditions that results from the optimization studies described in Example 3. 5 Example 2. Optimization Studies for Scheme 1 Step-1: Synthesis of 2,5-dimethoxybenzenesulfonyl chloride (lnt-2*): Summary of Feasibility and optimization Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 1.0 0.9 Procedure: 1* (1.0 eq), HSO3CI (1.0 eq) stirred at rt for 16 hr. The progress of the reaction was monitored by TLC. Workup: Quenched the reaction mass (RM) in ice-cold water and extracted in DCM(2X10V) and concentrated under Crude LCMS showed no lnt-2* formation. Multiple peaks observed, 10% unreacted SM observed. vacuum below 50 °C till no solvent distills out to get crude. 2. 1.0 Not Isolated Procedure: 1* (1.0 eq), HSO3CI (1.0 eq) in Pyridine (10 V) stirred at 0°C to rt 1h. The progress of the reaction was monitored by TLC. No conversion of SM observed. 3. 1.0 Not Isolated Procedure: 1* (1.0 eq), HSO3CI (1.0 eq) in TEA (2.5 eq) stirred at 0°C to rt 1h. The progress of the reaction was monitored by TLC. LCMS showed no lnt-2* formation. 67% unconverted SM observed 4. 1.0 1.0 (58.4%) Procedure: 1* (1.0 eq), HSO3CI (8.0 eq) in DCM (0.9 V) stirred at 0°C to rt 1h. The progress of the reaction was monitored by TLC. Work-up: Quenched the reaction mass in ice-cold water and extracted in DCM(2X10V) and concentrated under vacuum below 50 °C till no solvent distills out to get crude lnt-2*. Crude LCMS showed 97.68% I nt-2*, confirmed by NMR. 5. 10.0 10.2 (59%) Procedure: 1* (1.0 eq), HSO3CI (8.0 eq) in DCM (0.9 V) stirred at 0°C to rt 1h. The progress of the reaction was monitored by TLC. Work-up: As per Entry-4. lnt-2* formation confirmed by NMR. 6. 25.0 12.5 (29.2%) Procedure: 1* (1.0 eq), HSO3CI (8.0 eq) in DCM (0.9 V) stirred at 0°C to rt 1h. The progress of the reaction was monitored by TLC. Work-up: Quenched the reaction mass in ice-cold water and extracted in DCM (2X10V) and concentrated under vacuum below 50 °C till no solvent distills out to get crude lnt-2* I nt-2* was confirmed, but the yield was less. 7. 10.0 10.3 (60.2%) Procedure: 1* (1.0 eq), HSO3CI (8.0 eq) in DCM (3 V) stirred at 0°C to rt 1h. The progress of the reaction was monitored by TLC. Work-up: Diluted the reaction mass with DCM (12 V) and quenched in ice-cold water (15 V) and extracted in DCM (10 V). Washed the combined organic layer with brine solution (5 V) and concentrated under vacuum below 40 °C till no solvent distills out to get crude lnt-2*. The consistency in the yield of lnt-2* was achieved by diluting the RM with DCM during quenching. 8. 10.0 11.5 (67.1%) Procedure: 1* (1.0 eq), HSO3CI (8.0 eq in DCM) in DCM (20+20 V) stirred at 0 °C to rt 1h. The progress of the reaction was monitored by TLC. The yield of lnt-2* was improved by diluting the RM and Work-up: Diluted the reaction mass with DCM (15V) and quenched in ice-cold water (15 V) and extracted in DCM (10 V). Washed the combined organic layer with brine solution (5 V) and concentrated under vacuum below 40 °C till no solvent distills out to get crude lnt-2*. chlorosulfonic acid with DCM. 9. 50.0 60.0 (70%) Procedure: 1* (1.0 eq), HSO3CI (8.0 eq in DCM) in DCM (20+20 V) stirred at 0 °C to rt 1h. The progress of the reaction was monitored by TLC. Work-up: Diluted the reaction mass with DCM (15 V) and quenched in ice-cold water (15 V) and extracted in DCM (10 V). Washed the combined organic layer with brine solution (5 V) and concentrated under vacuum below 40 °C till no solvent distills out to get crude lnt-2*. The Consistency in the yield of lnt-2* as achieved by diluting the RM and chlorosulfonic acid. Scale up was successful. 10. 100.0 110.0 (64.2%) Procedure: 1* (1.0 eq), HSO3CI (8.0 eq in DCM) in DCM (20+20 V) stirred at 0°C to rt 1h. The progress of the reaction was monitored by TLC. Work-up: Diluted the reaction mass with DCM (15 V) and quenched in ice-cold water (15 V) and extracted in DCM (10 V). Washed the combined organic layer with brine solution (5 V) and concentrated under vacuum below 40 °C till no solvent distills out to get crude lnt-2*. lnt-2* was scaled up successfully on 100 gram scale. Entry-9 was considered for scale-up batches. Step-2: Synthesis of 2,5-dimethoxybenzenethiol (lnt-3*): 5 Summary of Feasibility and Optimization Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 0.5 0.2 (Crude) Procedure: lnt-2* (1.0 eq), 30% Aq. H2SO4 (8.0 eq) Heated to 100 °C and added Zinc (5 eq.) in lots and stirred at 100 °C for 3-4 TLC shown absence of SM and formation of Two h. The progress of the reaction was monitored by TLC. Workup: Cooled the reaction mass to RT, Filtered and washed with MTBE (5 V) The filtrate was extracted in MTBE (2X10V) and concentrated the MTBE layer under vacuum below 50 °C till no solvent distills out to get crude lnt-3*. Major spots. Purification by silica gel column chromatography is in process. 2. 0.5 F-1: 0.08 F-2: 0.12 Procedure: lnt-2* (1.0 eq), 30% Aq. H2SO4 (8.0 eq) Heated to 100 °C and added Zinc (5 eq.) in lots and stirred at 100 °C for 3-4 h. The progress of the reaction was monitored by TLC. Workup: As per the entry No. 1 Purification: Purified the crude by silica gel column chromatography to get pure Int-3* two fractions isolated. Fraction-1 matches lnt-3*, confirmed by NMR and LCMS. Fraction-2 matches di-sulfide impurity, confirmed by NMR and LCMS. 3. 1.0 0.6 (Crude) Procedure: lnt-2* (1.0 eq), 30% Aq. HCI (8.0 eq) Heated to 100 °C and added Zinc (5 eq.) in lots and stirred at 100 °C for 3-4 h. The progress of the reaction was monitored by TLC. Workup: As per the entry No. 1 lnt-3* along with disulfide was observed. 4. 1.0 0.6 (Crude) Procedure: lnt-2* (1.0 eq) Acetic Acid (10 V) Heated to 100 °C and added Zinc (5 eq.) in lots and stirred at 100 °C for 3-4 h. The progress of the reaction was monitored by TLC. Workup: As per the entry No. 1 lnt-3* Along with disulfide was observed 5. 0.5 0.08 Procedure: lnt-2* (1.0 eq) in Toluene-THF (1:1, 30 V), Triphenyl Phosphine (4 eq.), Heated to 90 °C and stirred at 90 °C for 78 h. The progress of the reaction was monitored by TLC. Workup: Cooled the reaction mass to RT, added water (10 V) and separated the layers. Extracted Aq. Layer with Ethyl Acetate (10 V), Combined the Organic layers dried over sodium sulfate and concentrated the Organic layer under vacuum below 50 °C till no solvent distills out to get crude lnt-3*. Purification: Purified the crude by silica gel column chromatography using 0-20% Ethyl Acetate Hexanes as eluent. The Pure fractions were combined and concentrated under vacuum below 50 °C till no solvent distills out to get Pure lnt-3*. lnt-3* isolated with disulfide was observed. In NMR lnt-3* observed with some impurities. 6. 2.0 1.3 (90.3%) Procedure: lnt-2* (1.0 eq) in Toluene-THF (1:1, 30 V), Triphenyl Phosphine (4 eq), Heated to 90°C and stirred at 90 °C for 7-8 h. The progress of the reaction was monitored by TLC. Workup: As per Entry No.5 Purification: As per Entry No. 5 lnt-3* isolated with Triphenyl phosphine. Purity 70%. And remains stable with TPP. 7. 0.5 0.12 (33.3%) Procedure: lnt-2* (1.0 eq) in THF (5 V), added LiAIH4 (5.0 eq) under nitrogen 0-5°C and stirred at 20-25°C for 18 h. The progress of the reaction was monitored by TLC. Workup: Quenched the reaction mass with hydrated sodium sulfate and filtered the solids, washed the bed with Ethyl acetate (5 V) and concentrated under vacuum below 40 °C till no solvent distills out to get crude lnt-3*. I nt-3* was confirmed by spectral data. 74% of lnt-3* observed in crude. 8. 2.0 0.8 (Crude) Procedure: lnt-2* (1.0 eq) in THF (5 V), added LiAIH4 (5.0 eq) under nitrogen 0-5°C and stirred at 20-25 °C for 18 h. The progress of the reaction was monitored by TLC. Workup: As per Entry No.7 Before work up on TLC lnt-3* spot was observed but after isolation it was converted into the spot corresponding with disulfide derivative along with impurities. 9. 10.0 7.0 (with TPP) Procedure: lnt-2* (1.0 eq) in Toluene-THF (1:1, 30 V), Triphenyl Phosphine (10 eq.), Heated to 90 °C and stirred at 90 °C for 48 h. The progress of the reaction was monitored by TLC. Workup: As per Entry No.5 Purification: As per Entry No. 5 I nt-3* was confirmed by spectral data. Triphenyl phosphine stabilizes lnt-3*. 9. 10.0 3.5 g (48.6%) Procedure: lnt-2* (1.0 eq), 30% Aq. HCI (8.0 eq) Heated to 100 °C and added Zinc (5 eq.) in lots and stirred at 100°C for 1-2 h. The progress of the reaction was monitored by TLC. Workup: The reaction mass was directly extracted with n-Hexane (2X10 V) and Added PPhs (1.0 g) in Organic layer and concentrated the organic layer under vacuum below 40-45 °C till no solvent distills out to get crude lnt-3*. I nt-3* was confirmed by spectral data and was stabilized by adding triphenylphosphine in to RM. The synthesis of lnt-3* was explored using different reducing reagents and reaction conditions like Zn / HCI, Zn / AcOH, triphenylphosphine, lithium aluminium hydride. In all conditions, lnt-3* was formed, but a dimer of lnt-3* was also observed. The Zn / HCI, triphenylphosphine reaction condition gave major lnt-3*, later scaled-up in multiple batches. Step-3: Synthesis of (2,5-dimethoxyphenyl) (trifluoromethyl) sulfane (lnt-4*): Summary of Feasibility and Optimization Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 0.1 0.06 (Crude) Procedure: lnt-3* (1.0 eq), DMSO (10 V), CF3SO2Na (2 eq), I2O5 (2 eq.) were stirred at 20-25 °C for 16 h. The progress of the reaction was monitored by TLC. Workup: Quenched the reaction mass with water (20 V) and extracted in Ethyl acetate (2X 10 V). Combined the organic layers and concentrated under vacuum below 40 °C till no solvent distills out to get crude lnt-4*. Major new formed peak not showing m / z corresponding to lnt-4* 2. 0.1 0.05 (Crude) Procedure: lnt-3* (1.0 eq), DMSO (10 V), CF3SO2Ag (2 eq), K2S2O8 (2 eq.), 1205(2 eq.) were stirred at 20-25°C for 16h. The progress of the reaction was monitored by TLC. Workup: As per entry No.1 LCMS shown the formation of new non polar peak, no m / z corresponding to that of lnt-4*. 3. 0.2 0.2 (crude) Procedure: Under argon lnt-3* (1.0 eq), DMSO (10 V), CF3SO2Ag (2 eq), I2O5 (2 eq.), stirred at 90-95 °C for 16 h. The progress of the reaction was monitored by TLC. Workup: As per Entry No.1 Non-polar peak formation was observed which was not consistent with lnt-4*. 4. 0.2 - Procedure: Under argon lnt-3* (1.0 eq), DMSO (10 V), CF3SO2Na (2 eq), K2S2O8 (2 Eq.), stirred at 90-95 °C for 16 h. The progress of the reaction was monitored by TLC. No desired product observed in LCMS. 5. 0.2 - Procedure: lnt-3* (1.0 eq), DMF (10 V), Int-B (2 eq), TEA (3 eq.), stirred at 90-40 °C for 16 h. The progress of the reaction was monitored by TLC No desired product observed in LCMS. The synthesis of lnt-4* was explored using different reagents and conditions, but none of the conditions resulted in desired product formation. 5 Example 3. Optimization Studies for Scheme 3 Step-a: Synthesis of (E)-1,4-dimethoxy-2-(2-nitrovinyl) benzene (lnt-2): CH3NO2, nBuNH2 AcOH, 115 °C, 5h Step-a Summary of Feasibility and Optimization Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 2.0 1.5g (59.7%) Procedure: Part A: SM-1 (1.0 eq), Nitromethane (1.0 eq), in MeOH (100 V) + NaOH (10.5M) was added at 0 °C stirred for 30 min at 0°C to rt. Part B: 40% HCI solution was stirred at 0 °C & Part A was added drop wised to it. stirred for 1 h at 50 °C. The progress of the reaction was monitored by TLC. Workup: Filtered the yellow solids and washed with water and dried at 50 °C to get lnt-2. lnt-2 was confirmed by spectral data. 2. 10.0 7.7 g (60%) Procedure: Part A: SM-1 (1.0 eq), Nitromethane (1.0 eq), in MeOH (100 V) + 10.5 M NaOH was added at 0 °C stirred for 30 min at 0 °C to rt. Part B: 40% HCI solution was stirred at 0 °C & Part A was added drop wised to it. stirred for 1 h at 50 °C. The progress of the reaction was monitored by TLC. Workup: As per entry No.1 lnt-2 was confirmed by spectral data. The reaction profile was consistent. 3. 5.0 3.2 (51.2%) Procedure: SM-1 (1.0 eq), ammonium acetate (0.2 eq), in Nitromethane (6.0 eq) was stirred & refluxed for 2.5 h at 100 °C. lnt-2 was confirmed by spectral data and Workup: Reaction mass was directly concentrated under reduced vacuum completely below 45 °C to afford dark orange colored crude. Purification : Crude was recrystallized with methanol (5 V) to get lnt-2 is consistent by using Ammonium acetate conditions. 4. 25.0 15.0 (60%) Procedure: SM-1 (1.0 eq), ammonium acetate (0.2 eq), in Nitromethane (6.0 eq) was stirred & refluxed for 2.5 h at 100 °C. Workup: As per entry No. 3 Purification: As per entry No. 3 lnt-2 was confirmed by spectral data, The profile was consistent on gram scale. 5. 30.0 22.0 (58.3%) Procedure: SM-1 (1.0 eq), ammonium acetate (0.2 eq), in Nitromethane (6.0 eq) was stirred & refluxed for 2.5 h at 100 °C. Workup: As per entry No. 3 Purification: As per entry No. 3 lnt-2 was scaled up with consistent profile on gram scale. 6. 0.5 0.5 (79.5%) Procedure: SM-1 (1.0 eq), n-Butylamine (1 V), Nitromethane (2.0 eq) was stirred in glacial acetic acid (5 V) & refluxed for 2 to 5 h at 110 °C. Workup: Reaction mass was directly concentrated under reduced pressure to afford dark orange colored crude. Purification: Crude was slurry washed by water (10 V) to get lnt-2. lnt-2 was confirmed using n-Butylamine / AcOH conditions, the yield was improved. 7. 0.5 - Procedure: SM-1 (1.0 eq), Nitromethane (1.7 eq) was stirred in acetic acid (3.6 V) stirred at rt for 16 h. SM remained unconverted after 16h using AcOH. 8. 10.0 9.5 (76.0%) Procedure: SM-1 (1.0 eq), ammonium acetate (0.2 eq) & Nitromethane (3.0 eq) was stirred in I PA (5 V) & refluxed for 2 to 5 h at 110 °C. Workup: Reaction mass was directly concentrated under reduced pressure to afford dark orange colored crude. Purification: Crude was recrystallized with I PA (5V)to get lnt-2. Yield of lnt-2 was improved by diluting the reaction mass with IPA (5 V). 9. 10.0 10.0 (80.0%) Procedure: SM-1 (1.0 eq), ammonium acetate (0.2 eq) & Nitromethane (3.0 eq) was stirred in THF (5 V) & refluxed for 2 to 5 h at 110 °C. Workup: Reaction mass was directly concentrated under reduced pressure to afford dark orange colored crude. Purification : Crude was slurried with Water (5 V) to get lnt-2. Yield of lnt-2 was improved by diluting the reaction mass with THF (5 V). The Int-2 obtained has the desired profile as well. 10. 10.0 10.0 (79.4%) Procedure: SM-1 (1.0eq), n- Butylamine (1 V), Nitromethane (2.0 eq) was stirred in glacial acetic acid (5 V) & refluxed for 2 to 5 h at 110 °C. Workup: Reaction mass was diluted with DCM (20 V) & sat. NaHCO3 (10 V), stirred for 10 min. The organic layer was collected and washed with water (20 V), brine (20 V). Then organic layer was collected & concentrated under vacuum below 45 °C to get dark orange colored crude. Yield of lnt-2 was improved by applying n-Butyl amine procedure. The lnt-2 obtained has the desired profile in crude itself as well. 11. 1.0 - Procedure: SM-1 (1.0 eq), EDTA (0.2 eq), Nitromethane (2.0 eq) was stirred in IPA (5 V) & refluxed for 2 to 16 h at 110 °C. LCMS data shown major SM-1 remain unconverted, no lnt-2 formation was observed. 12. 1.0 - Procedure: SM-1 (1.0 eq), NH4OAc (0.3 eq), Nitromethane (2.0 eq) was stirred in MeOH (5 V) & refluxed for 2 to 16 h at 60 °C. SM-1 along-with impurities observed. 13. 1.0 - Procedure: SM-1 (1 .Oeq), NH4OAc (0.3 eq), Nitromethane (2.0 eq) was stirred in EtOH (5 V) & refluxed for 2 to 16 h at 80°C SM-1 along-with impurities observed. 14. 10.0 10.4 (80.2%) Procedure: SM-1 (1.0 eq), n-Butylamine (1 V), Nitromethane (2.0 eq) was stirred in glacial acetic acid (5 V) & refluxed for 2 to 5 h at 110°C Yield of lnt-2 was consistent using n-Butyl amine procedure. The lnt-2 obtained has the desired profile in crude. 15. 50 53 (84.5%) Procedure: SM-1 (1.0 eq), n-Butylamine (1 V), Nitromethane (2.0 eq) was stirred in glacial acetic acid (5 V) & refluxed for 2 to 5 h at 110 °C. Workup: Reaction mass was allowed to cool at room temperature, the yellow solid was precipitate out. The solid suspension was diluted with water (5 V) and filtered over Buchner funnel, solid was washed with sat. NaHCO3 (10 V x 3), water (4 X 10 V). Then yellow solid was dissolved in MDC (20 V) and dried over Na2SO4. The organic layer was concentrated under reduced pressure to afford crude of lnt-2. lnt-2 was confirmed by Spectral data. Scale-up on gram scale was successful. I nt-2 was confirmed and the process was optimized for gram scale synthesis summarized in the above table. The optimized condition using n-butyl amine and acetic acid was finalized. The same procedure was used for scale up. Step-b: Synthesis of (2-(2,5-dimethoxyphenyl) ethan-1-amine (lnt-3): Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 1.0 0.9 (Crude) Procedure: lnt-2 (1.0 eq), LAH (4.0 eq) in THF (10 V) stirred at 60°C for 4h. The progress of the reaction was monitored by TLC. Workup: Quenched the reaction mass with 1M NaOH and extracted with Ethyl acetate(2X10 V). Combined the ethyl acetate layers and acidified with 2N HCI and then separated the layers. Washed the Aq. Layer with Ethyl acetate(5 V). Then basified the Aq. layer using sodium carbonate and extracted with ethyl acetate (2X10 V). Combined the Ethyl acetate layers and concentrated under vacuum below 45 °C till no solvent distills to get the crude lnt-3. I nt-3 was confirmed by spectral data. Feasibility was completed. 2. 5.0 4.5 (Crude) Procedure: lnt-2 (1.0 eq), LAH (4.0 eq) in THF (10 V) stirred at 60 °C for 4 h. The progress of the reaction was monitored by TLC. Workup: As per entry No.1 I nt-3 was confirmed by spectral data. 3. 2.0 1.6 (Crude) Procedure: lnt-2 (1.0 eq), LAH (4.0 eq) in THF (10 V) stirred at 60 °C for 4 h. The progress of the reaction was monitored by TLC. Workup: As per entry No.1 I nt-3 was confirmed by spectral data. NMR shown some undesired impurities. 4. 15.0 12.7 (Crude) Procedure: lnt-2 (1.0 eq), LAH (4.0 eq) in THF (10 V) stirred at 60 °C for 4 h. The progress of the reaction was monitored by TLC. Workup: As per entry No.1 Crude lnt-3 was confirmed by spectral data and shown 72% purity. 5. 22.0 22.0 (Crude) Procedure: lnt-2 (1.0 eq), LAH (4.0 eq) in THF (10 V) stirred at 60°C 4 h. The progress of the reaction was monitored by TLC. Workup: Reaction mass was diluted with DCM (20 V) and quenched in sodium sulfate deca-hydrate (2 w / w of LAH) slowly at rt and stirred for 1 hr. then filtered over Buckner funnel, filtrate was collected and concentrated under vacuum below 45 °C till no solvent distills out to afford crude lnt-3. Crude lnt-3 was confirmed by spectral data, The quenching using sodium sulfate decahydrate was successful on gram scale. 6. 0.5 - Procedure: lnt-2 (1.0 eq), LAH (10 eq), THF (40 V) was stirred at 25°C and refluxed for 48 h at 80°C. LCMS showed Int-3 (54.49%) along with intermediate 37.4%. 7. 0.5 - Procedure: lnt-2 (1.0 eq), NaBH4 (6 eq), THF (40 V) was stirred at 0°C and refluxed for 48 h at 80 °C. LCMS not shown lnt-3 only intermediate 18.4%. 8. 0.5 - Procedure: lnt-2 (1.0 eq), NaCNBH3 (6 eq), THF (40 V) was stirred at 0°C and refluxed for 48 h at 80 °C. LCMS not shown lnt-3 only intermediate 27.2%. 9. 0.5 - Procedure: lnt-2 (1.0 eq), Na(OAc)3BH (3 eq), THF (40 V) was stirred at 0°C and refluxed for 48 h at 80 °C. LCMS not shown lnt-3 formation. 10. 0.5 - Procedure: SM-1 (1.0 eq), LiBH4 (3 eq), THF (40 V) was stirred at 0 °C and refluxed for 48 h at 80 °C. LCMS not shown lnt-3 formation. 11. 0.5 - Procedure: lnt-2 (1.0 eq), NiCl2.H2O (0.4 eq), NaBH4 (8 eq), ACN :WATER (3:0.3) was stirred at 0 °C to rt for 16 h. lnt-3(46.2%) along with unreacted SM (19.4%) was observed. 12. 0.5 - Procedure: SM-1 (1.0 eq), NiCI2.H2O (1.0 eq), NaBH4 (10 eq), ACN: WATER (3:0.3) was stirred at 0°C to rt for 16 h lnt-3 (51.7%), and intermediate (9.5%) was observed 13. 0.5 - Procedure: lnt-2 (1.0 eq), NiCl2.H2O (1.0 eq), NaBH4 (10 eq), THF :WATER (3:0.3) was stirred at 0°C to rt for 16 h. 24% I nt- 3 formation was observed. 14. 0.5 - Procedure: lnt-2 (1.0 eq), Rhodium alumina (20% w / w), H2 gas (20-25 kg), 4M HCI in Dioxane (1 V) was stirred at 100°C to rt for 16 h. No lnt-3 formation. 15. 0.5 - Procedure: lnt-2 (1.0 eq), Raney Nickel (20%w / w), H2 gas (20-25kg), methanol (20 V) was stirred at 80 °C for 16 h. 2.5% lnt-3 formed, with more no of impurities. 16. 0.5 - Procedure: lnt-2 (1.0 eq), Pd-C (20% w / w), H2 gas (20-25kg), methanol (20 V) was stirred at 80 °C for 16 h. 12.5% lnt-3 formed, with more no of impurities. 17. 48.0 42.0 (Crude) Procedure: lnt-2 (1.0eq), LAH (10 eq), TOLUENE (40 V) was stirred at 0°C and refluxed for 16 h at 90 °C. Work up: Reaction mass was diluted with DCM (20 V) and quenched in sodium sulfate deca-hydrate (2.0 w / w of LAH) slowly at rt and stirred for 1 h then filtered over Buckner funnel, filtrate was collected and concentrated below 45 °C to get crude lnt-3. I nt-3 was confirmed by Spectral data. Scale-up was successful. 18. 10.0 8.6 (Crude) Procedure: SM-1 (1.0 eq), LAH (3.0 eq), THF (40 V) was stirred at 0 °C and refluxed for 16 hat 90 °C. Work up: Reaction mass was diluted with DCM (20 V) and quenched in sodium sulfate deca-hydrate (2 w / w of LAH) slowly at rt and stirred for 1 hr. then filtered over Buckner funnel, filtrate was collected and concentrated below 45 °C to get crude lnt-3. 3 eq. of LAH also resulted in complete conversion of lnt-2 to lnt-3. So the quenching quantity of LAH was reduced and was good for scale up prospective. Conclusion: In the step-b for the reduction of Int-2 different reagents were used to get the complete conversion. Lithium aluminium hydride gave the maximum conversions. Initially 6 to 10 eq. of LAH were used, however, the reaction was optimized with 3 equivalents of LAH. The 5 process was scaled-up in multiple batches. Step-c: Synthesis of 2-(2,5-dimethoxyphenethyl) isoindoline-1,3-dione (lnt-4a): Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 0.6 0.3 (29.1%) Procedure: lnt-3 (1.0 eq) in toluene (40 V) and added Phthalic anhydride (1.5 e q.) and stirred at 120 °C to 130 °C. for 16 h. I nt-4a was confirmed by spectral data. The progress of the reaction was monitored by TLC and LCMS. Workup: Added sat sodium bicarbonate (10 V) to the RM and separated the layers. Concentrated the DCM layer under vacuum below 50 °C till no solvent distills to get the Crude lnt-4a. Purification: Purified the crude by silica gel column chromatography using 0-5% Ethyl acetate:Hexanes as eluent. The Pure fractions were combined and concentrated under vacuum below 50 °C till no solvent distills out to get pure lnt-4a. 2. 2.0 1.1 (32.3%) Procedure: I nt-3 (1.0 eq) in toluene (40 V) was added phthalic anhydride (1.5 eq) and stirred at 120 °C to 130 °C. for 16h. The progress of the reaction was monitored by TLC and LCMS. Workup: As per entry No.1 Purification: As per entry No.1 Desired conversion was achieved in 16 h and lnt-4a was confirmed by spectral data. 3. 4.0 2.5 (36.7%) Procedure: I nt-3 (1.0 eq) in toluene (40 V) and added Phthalic anhydride (1.5 eq.) and stirred at 120 °C to 130 °C. for 16h. The progress of the reaction was monitored by TLC and LCMS. Workup: As per entry No.1 Purification: As per entry No.1 Desired conversion was achieved in 16h and lnt-4a was confirmed by spectral data. 4. 12.7 10.0 (45.8%) Procedure: I nt-3 (1.0 eq) in toluene (40 V) and added phthalic anhydride (1.5 eq.) and stirred at 120 °C to 130 °C. for 16 hr. The progress of the reaction was monitored by TLC and LCMS. Workup: As per entry No.1 Purification: As per entry No.1 I nt-4a was confirmed by spectral data and the profile was consistent. 5. 20.0 12.0 (34.9% Procedure: I nt-3 (1.0 eq) in toluene (40 V) and added Phthalic anhydride (1.5 eq.) and stirred at 120 °C to 130 °C. for 16 h. The progress of the reaction was monitored by TLC and LCMS. Workup: As per entry No.1 Purification: As per entry No.1 I nt-4a was confirmed by spectral data and the profile was consistent on gram scale. 6. 4.5 3.3 (44.3% ) Procedure: lnt-3 (1.0 eq) in toluene (40 V) and added Phthalic anhydride (1.5 eq) and stirred at 120 °C to 130 °C. for 16 h. The progress of the reaction was monitored by TLC and LCMS. Workup: Added sat sodium bicarbonate (10 V) to the RM and separated the layers. I nt-4a was confirmed by Spectral data. The purification of Int-4a using EtOH was successful. Concentrated the DCM layer under vacuum below 50 °C till no solvent distills to get the Crude lnt-4a. Purification: The crude was slurry washed by EtOH (5 V), & filtered over Buchner funnel to get lnt-4a. 7. 42.0 42.0 (58.9%) Procedure: lnt-3 (1.0 eq) in toluene (40 V) and added Phthalic anhydride (1.5 eq) and stirred at 120 °C to 130 °C. for 16 h. The progress of the reaction was monitored by TLC and LCMS. Workup: Added sat sodium bicarbonate (10 V) to the RM and separated the layers. Concentrated the DCM layer under vacuum below 50 °C till no solvent distills to get the Crude lnt-4a. Purification: The crude was slurry washed by IPA (5 V), & filtered over Buchner funnel to get lnt-4a. I nt-4a was confirmed by Spectral data. The purification of Int-4a using IPA was successful. The N-phthalimide protection works well on trial scale. Initially, the intermediate was purified by silica gel column purification, but a later crystallization method in isopropanol was developed. The optimized conditions were used in scale up batches. Step-d: Synthesis of 4-(2-(1,3-dioxoisoindolin-2-yl) ethyl)-2,5-dimethoxybenzenesulfonyl chloride (lnt-5a): 10 Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 0.2 0.16 (60.7% Crude) Procedure: lnt.4a (1.0eq) in DCM (20 V) added CISO3H (8 eq.) in DCM (20 V) and stirred at 0°C to 5 °C. The progress of the reaction was monitored by TLC. Workup: Diluted the reaction mass with DCM (10 V) and quenched the reaction lnt-5a was confirmed by spectral data. mass in Ice water. Dried the DCM layer over sodium sulfate and concentrated under vacuum below 50 °C till no solvent distills out to get Crude lnt-5a. 2. 2.8 2.5 (69.4% Crude) Procedure: lnt-4a (1.0eq) in DCM (20V) added CISO3H (8 eq.) in DCM (20V) and stirred at 0 °C to 5 °C. The progress of the reaction was monitored by TLC. Workup: The reaction mass was quenched in Ice water to afford white solid precipitation, filtered over Buchner funnel and dried under reduced pressure to get Crude lnt-5a. Int-5a was confirmed by spectral data. 3. 1.0 0.8 (60.7% Crude) Procedure: lnt-4a (1.0 eq) in DCM (20 V) added CISO3H (8 eq.) in DCM (20 V) and stirred at 0 °C to 5 °C. The progress of the reaction was monitored by TLC. Workup: As per entry No. 2 Int-5a was confirmed by spectral data. 4. 5.0 4.5 (68.3% Crude) Procedure: lnt-4a (1.0 eq) in DCM (20 V) added CISO3H (8 eq.) in DCM (20 V) and stirred at 0 °C to 5 °C. The progress of the reaction was monitored by TLC. Workup: The reaction mass was quenched in Ice water and stirred for 15-20 min vigorously. Then the aqueous layer was extracted with DCM (2X 40 V), organic layer was dried over sodium sulfate and concentrated to afford yellow solid Crude lnt-5a. Int-5a was confirmed by spectral data. The extraction of lnt-5a in DCM was helpful to extract the I nt from aqueous layer. 5. 12.0 11.5 (73.2% Crude) Procedure: lnt-4a (1.0 eq) in DCM (20 V) added CISO3H (8 eq.) in DCM (20 V) and stirred at 0 °C to 5 °C. The progress of the reaction was monitored by TLC. Workup: As per Entry No.5 Synthesis of lnt-5a on gram scale was successful and Int-5a was confirmed by spectral data. 6. 42.0 46.0 (83.2%) Procedure: lnt-4a (1.0 eq) in DCM (20 V) added CISO3H (8 eq.) in DCM (20 V) and stirred at 0 °C to 5 °C. The progress of the reaction was monitored by TLC. Workup: Diluted the reaction mass with DCM (10 V) and quenched the reaction mass in ice water. Dried the DCM layer over sodium sulfate and concentrated under vacuum below 50 °C till no solvent distills out to get Crude lnt-5a. Int-5a was confirmed by Spectral data. Scale-up was successful. The chlorosulfonation of lnt-4a was performed using the conditions optimized in Scheme 1. The conversion of starting material was completed in 2-3 h. Different reaction parameters were optimized for gram scale synthesis shown in the table above. The optimized procedure using 8 eq. chlorosulfonic acid was used for scale up batches. Step-e: Synthesis of 2-(4-mercapto-2,5-dimethoxyphenethyl) isoindoline-1,3-dione (lnt-6a): Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 0.2 0.09 (58.8%) Procedure: lnt-5a (1.0 eq) in Toluene: THF (1:1, 10 V), PPhs (6.0 eq) was added, stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. Work-up: Added water(10 V) in to the reaction mass and extracted with ethyl acetate (2X10 V). Combined the organic layers and concentrated under vacuum below 50 °C till no solvent distills out to get Crude lnt-6a. Purification: Purified the crude by silica gel column chromatography using 0-5% Ethyl Acetate Hexanes as eluent. The Pure fractions were combined and concentrated under vacuum below 50 °C till no solvent distills out to get Pure lnt-6a. lnt-6a was confirmed by spectral data. Feasibility completed. 2. 1.0 0.5 (59.8%) Procedure: lnt-5a (1.0 eq) in Toluene: THF (1:1,10V), PPhs (6.0 eq) was added, stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. Work-up: As per Entry No.1 Purification: As per Entry No.1 Int-6a was confirmed by spectral data. 3. 6.0 2.1 (62.6%) Procedure: lnt-5a (1.0 eq) in Toluene: THF (1:1,10V), PPhs (6.0 eq) was added, stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. Work-up: As per Entry No.1 Purification: As per Entry No.1 Int-6a was confirmed by spectral data and the profile was consistent. 6. 11.5 6.2 (66.5%) Procedure: lnt-5a (1.0 eq) in Toluene: THF (1:1,10V), PPhs (6.0 eq) was added, stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. Work-up: As per Entry No.1 Purification: As per Entry No.1 Int-6a was confirmed by spectral data and the profile and yield was consistent. 5. 66.0 25.0 (66.9%) Procedure: lnt-5a (1.0 eq) in Toluene: THF (1:1, 10 V), PPhs (6.0 eq) was added, stirred at 100 °C for 16 h. The progress of the reaction was monitored by TLC. Work-up: Added water (10 V) in to the reaction mass and extracted with ethyl acetate (2X10 V). Combined the organic layers and concentrated under vacuum below 50 °C till no solvent distills out to get Crude lnt-6a Purification: The crude was purified by column chromatography in EtOAc-Hexane to get lnt-6a. Int-6a was confirmed by Spectral data. Scale-up was successful. The purification required column chromatography. In the synthesis of lnt-6a, various reagents for the reduction of lnt-5a were used. The conversion was more facile using triphenylphosphine in toluene conditions. The purification required column chromatography. Attempts were made for removal of excess triphenylphosphine 5 and the triphenylphosphine oxide that formed, but limited purge of both was achieved. Having a scope of optimization, the reaction conditions were optimized to achieve the gram scale synthesis of lnt-6a. Step-f: Synthesis of 2-(2,5-dimethoxy-4-((trifluoromethyl)thio) phenethyl) isoindoline-1,3 10 dione(lnt-7a): Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 0.05 - Procedure: lnt-6a (1.0 eq.), CF3SO2Ag (3 eq.), I2O5 (2 eq.), DMSO (20 V), stirred at 90-100 °C for 12-16 h. The progress of the reaction was monitored by TLC. LCMS data showed no formation of lnt-7a. 2. 0.05 - Procedure: lnt-6a (1.0 eq.), CF3SO2Ag (3 eq.) K2S2O8 (2 eq.), DMSO (20 V), stirred at 90-100 °C for 12-16 h. The progress of the reaction was monitored by TLC. LCMS data showed no formation of lnt-7a. 3. 0.05 - Procedure: lnt-6a (1.0 eq.), CF3SO2Na (3 eq.) I2O5 (2 eq.), DMSO (20 V), stirred at 90-100 °C for 12-16 h. The progress of the reaction was monitored by TLC. LCMS and Mass data showed no formation of lnt-7a. 4. 0.05 0.035 (58.3%) Procedure: lnt-6a (1.0 eq.), CF3SO2Na (3 eq.), K2S2O8 (2 eq.), DMSO (20 V), stirred at 90-100°C for 12-16 h. The progress of the reaction was monitored by TLC. Workup: Added water(10 V) and extracted with Ethyl acetate(2X10 V). Combined the Ethyl acetate layers and concentrated under vacuum below 50 °C till no solvent distills out to Crude lnt-7a. Formation of lnt-7a was confirmed by 1H NMR, Mass and LCMS analysis. 19F NMR analysis shown the formation of lnt-7a. Feasibility completed. 5. 0.5 0.16 (26.7%) Procedure: lnt-6a (1.0 eq.), CF3SO2Na (3 eq.), K2S2O8 (2 eq.), DMSO (20 V), stirred at 90-100 °C for 12-16 h. The progress of the reaction was monitored by TLC. Workup: Added water (10 V) and extracted with Ethyl acetate (2X10 V). Combined the Ethyl acetate layers and concentrated under vacuum below 50 °C till no solvent distills out to Crude lnt-7a. Int-7a was confirmed by 1H NMR, Mass and LCMS analysis. 19F NMR analysis confirmed lnt-7a. 6. 0.1 - Procedure: lnt-6a (1.0 eq.), CF3SO2Na (3 eq.), K2S2O8 (2 eq.), AgNOs (0.3 eq.), DMSO (20 V), stirred at 90-100 °C for 2024h. The progress of the reaction was monitored by TLC and LCMS LCMS analysis data showed 39% lnt-7a formation. 7. 0.1 - Procedure: lnt-6a (1.0 eq.), CF3SO2Na (3 eq.), K2S2O8 (2 eq.), AgNOs (0.3 eq.), ACN (20 V), stirred at 90-100 °C for 2024h. The progress of the reaction was monitored by TLC and LCMS LCMS analysis data showed 45% lnt-7a formation. 8. 0.1 - Procedure: lnt-6a (1.0 eq.), CF3SO2Na (4 eq.), K2S2O8 (2 eq.), DM SO (20 V), stirred at 90-100 °C for 20-24 h. The progress of the reaction was monitored by TLC and LCMS. LCMS analysis data showed 67.4% lnt-7a formation. 9. 0.1 - Procedure: lnt-6a (1.0 eq.), Reagent-X (4 eq.), TEA (4 eq.), DMF (20 V), stirred at 90-100°C for 20-24h. The progress of the reaction was monitored by TLC and LCMS. LCMS analysis data showed 35.22% lnt-7a formation. 10. 0.1 0.06 (50.1%) Procedure: lnt-6a (1.0 eq.), Reagent-X (1 eq.), TEA (2 eq.), DMF (20 V), stirred at 90-100°C for 20-24h. The progress of the reaction was monitored by TLC. Workup: Added water(10V) and compound was extracted with Ethyl acetate(2X10V). Combined ethyl acetate layers concentrated to obtain crude Int-7a. Purification: Crude was purified by silica gel column chromatography using Ethyl acetate hexanes (2-20%) as eluent. The pure fractions were combined and concentrated under vacuum below 50 °C to get Pure lnt-7a Int-7a was fully characterized by 1H NMR, LCMS, HPLC. The synthesis using Reagent-X as trifluromethylating agent was successful. 11. 1.0 0.52 (43.4%) Procedure: lnt-6a (1.0 eq.), Reagent-X (1 eq.), TEA (2 eq.), DMF (20 V), stirred at 90-100°C for 20-24h. The progress of the reaction was monitored by TLC. Workup: Added water(10 V) and compound was extracted with Ethyl acetate(2X10V). Combined ethyl acetate layers concentrated to obtain crude Int-7a. Purification: Crude was purified by silica gel column chromatography using Ethyl acetate hexanes (2-20%) as eluent. The pure fractions were combined and concentrated under vacuum below 50 °C to get Pure lnt-7a Int-7a was fully characterized by 1H NMR, LCMS, HPLC and 19F NMR. 12. 0.1 0.06 (50.1%) Procedure: lnt-6a (1.0 eq.), CF3SO2Na (4 eq.), K2S2O8 (2 eq.), ACN: DMSO (1:1 V), stirred at 90-100°C for 20-24h. The progress of the reaction was monitored by TLC. Workup: As per Entry No.11 Purification: As per Entry No.11 Int-7a was formed and characterized by Spectral data. 13. 0.1 0.04 (33.3%) Procedure: lnt-6a (1.0 eq.), Reagent-X (1 eq.), TEA (1 eq.), DMF (20 V), stirred at 20-25°C for 2h. The progress of the reaction was monitored by TLC Workup: As per Entry No.11 Purification: As per Entry No.11 Int-7a was formed and characterized by Spectral data. 14. 2.5 1.5 (50.1% Procedure: lnt-6a (1.0 eq.), Reagent-X (1 eq.), TEA (1 eq.), DMF (20 V), stirred at 20-25°C for 2h. The progress of the reaction was monitored by TLC Workup: As per Entry No.11 Purification: As per Entry No.11 Int-7a was formed and characterized by Spectral data. 15. 0.5 0.35 (58.5%) Procedure: lnt-6a (1.0 eq.), Reagent-X (1 eq.), TEA (1.5 eq.), ACN (20 V), stirred at 25-30°C for 18h. The progress of the reaction was monitored by TLC. Workup: Added water(10V) and compound was extracted with Ethyl acetate(2X10V). Combined ethyl acetate layers concentrated to obtain crude Int-7a. Purification: As per Entry No.11. Int-7a was formed and characterized by Spectral data. Reaction using acetonitrile as solvent gave better yield. 16. 10.0 4.5 (37.5 %) Procedure: lnt-6a (1.0 eq.), Reagent-X (1 eq.), TEA (1.5 eq.), ACN (20 V), stirred at 25-30°C for 18h. The progress of the reaction was monitored by TLC. Workup: Added water (10V) and compound was extracted with Ethyl acetate(2X10V). Combined ethyl acetate layers concentrated to obtain crude lnt-7. Purification: Purified the crude by silica gel column chromatography to get the pure lnt-7a. Int-7a was formed and characterized by Spectral data. The key step for the success of this route is the synthesis of lnt-7a. Different trifluoromethylating reagents were explored out of which sodium trifluoromethanesulfinate (Langlois reagent) and thianthrene triflate (Reagent-X) were successful. Int-7a was confirmed, 5 and the process was optimized for gram scale synthesis. Step-h: Synthesis of 2-(2,5-dimethoxy-4-((trifluoromethyl)thio)phenyl)ethan-1-amine hydrochloride (Compound 1): Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 0.03 0004 Procedure: lnt-7a (1.0 eq.), Hydrazine Hydrate (2 eq.), ethanol (20 V), stirred at 40°C for 2-4h. The progress of the reaction was monitored by TLC. Workup: Concentrated the RM under vacuum below 45 °C to get the residue. Added water(10V) and extracted with Ethyl acetate (2X10V). Combined the Ethyl acetate layers and concentrated under vacuum below 45 °C till no solvent distills out to get Crude Compound 1 (free Base) Compound 1 was confirmed by LCMS data. 2. 0.15 0.08 (64.2%) Procedure: lnt-7a (1.0 eq.), Hydrazine Hydrate (2 eq.), Ethanol (20 V), stirred at 40°C for 2-4 h. The progress of the reaction was monitored by TLC. Workup: Concentrated the RM under vacuum below 45 °C to get the residue. Added water(10V) and extracted with Ethyl acetate (2X10V). Combined the Ethyl acetate layers and concentrated under vacuum below 45 °C till no solvent distills out to get Crude Compound 1 (Free base). Purification: The crude reaction mass was dissolved in ethyl acetate (5V) and Added HCI in 1,4 Dioxane (2V) into it. Stirred at 2025°C for 1h. Filtered the product. Dried under vacuum below 45 °C to get the Compound 1 (HCI salt) NMR data confirmed the Compound 1. LCMS shown the m / z of Free Base, the Compound 1 was confirmed by 19F NMR also. Feasibility was completed. 3. 0.1 0.04 (51.6%) Procedure: lnt-7a (1.0 eq.), methyl amine 40% aq. (10 V), stirred at 25-30 °C for 10-12 h. The progress of the reaction was monitored by TLC. Spectral data confirmed the Compound 1. The deprotection using Workup: Concentrated the RM under vacuum below 45 °C to get Crude Compound 1 (Free base). Purification: The crude Compound 1 (free base) was dissolved in ethyl acetate (5V) and Added HCI in 1,4 Dioxane(2V) into it. Stirred at 20-25°C for 1h. Filtered the product. Dried under vacuum below 45 °C to get the Compound 1 (HCI salt) aq. Methyl amine was successful. 4. 0.05 - Procedure: lnt-7a (1.0 eq.), methyl amine 40% aq. (5V), stirred at 25-30 °C for 10-12 h. The progress of the reaction was monitored by TLC. Int-7a was converted completely by LCMS using 5V Aq. Methyl amine. 5. 0.05 - Procedure: lnt-7a (1.0 eq.), methyl amine 40% aq. (5V), Toluene (5V) stirred at 25-30 °C for 10-12 h. The progress of the reaction was monitored by TLC 48% unconverted lnt-7a By LCMS data 6. 0.05 - Procedure: lnt-7a (1.0 eq.), NaOH (1M, 4 eq.), stirred at 25-30 °C for 10-12 h. The progress of the reaction was monitored by TLC 90% unconverted lnt-7a By LCMS data. 7. 1.0 0.55 (58.2%) Procedure: lnt-7a (1.0 eq.), methyl amine 40% aq. (10 V), stirred at 25-30 °C for 10-12 h. The progress of the reaction was monitored by TLC. Workup: Concentrated the RM under vacuum below 45 °C to get Crude Compound 1 (Free base). Purification: The crude reaction mass was dissolved in ethyl acetate(5V) and Added HCI in 1,4 Dioxane(2V) into it. Stirred at 2025°C for 1 h. Filtered the product. Dried under vacuum below 45 °C to get the Compound 1 (HCI salt). Int-7a was converted completely by LCMS using 5V Aq. Methylamine and Compound 1 was confirmed by spectral data. Compound 1 was confirmed, and the process was optimized for gram scale synthesis. The deprotection reaction was optimized with different reagents amongst which methylamine was used considering the safety aspects. The hydrochloride salt was prepared using 1,4 5 dioxane HCI and then the salt was finally slurried from ethyl acetate. The optimized process was applied for the gram scale synthesis and the desired quality of Compound 1 was successfully achieved. Step-1: Synthesis of 5-(trifluoromethyl)-5H-thianthren-5-ium trifluoromethanesulfonate (Reagent- X): tf2o, dcm 35 °C Step-1 CF3 TfO Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. 5.0 6.9 (Crude) Procedure: Charged SM-A in DCM (15V) and then triflic anhydride (1.2 eq.) and stirred at 35°C for 24 h. The progress of the reaction was monitored by TLC. Work up : Concentrated the organic layer under vacuum below 40-45°C till no solvent distills out to get Crude Reagent-X. Reagent-X was confirmed by spectral data. The crude was used further as such in next steps. Feasibility completed. 2. 17.0 18 (Crude) Procedure: SM-A (1.0 eq.), triflic anhydride (1 eq.), DCM (10 V) were stirred at 25-30°C for 20-24h. Workup: Reaction mixture was added in NaHCOs solution and compound extracted in DCM (2X10V). Combined DCM layers concentrated to obtain crude lnt-2, which was washed with MTBE (3X2V) and dried the solid under vacuum at 30°C to get the Reagent-X. Reagent-X was confirmed by spectral data. 3. 50.0 55 (54.8%) Procedure: SM-A (1.0 eq.), triflic anhydride (1 eq), DCM (10 V), stirred at 25-30°C for 20-24h. Workup: As per entry no.2 Reagent-X was confirmed by spectral data. Scale up was successful. 4. 40.0 42.0 (52.2%) Procedure: SM-A (1.0 eq.), triflic anhydride (1 eq), DCM (10 V), stirred at 25-30°C for 20-24h. Workup: As per entry no.2 Reagent-X was confirmed by spectral data. Scale up was successful on gram scale. The synthesis of Reagent-X is reported in J. Am. Chern. Soc., 2021, 143(20),7623. The process reagent synthesis is very operation friendly, robust and scalable. The synthesis was accomplished and optimized in scale perspective. The reagent resulted into the clean facile synthesis of lnt-7a. Scheme 2 with different protecting groups: Step-c to e: N-CBz strategy: 5 Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. Step-c 5.0 g 4.0 (45.9%) Procedure: lnt-3 (1.0eq) in DCM (20V) and K2CO3 (3.0 eq) added Benzyl chloroform ate (1.5 Eq.) and stirred at 50°C. for 16 h. The progress of the reaction was monitored by TLC and LCMS. Workup: Added sat sodium bicarbonate (10V) to the RM and separated the layers. Concentrated the DCM layer under vacuum below 50°C till no solvent distills to get the Crude lnt-4B. Purification: The crude was purified by flash chromatography in EtOAc hexane to afford lnt-4B lnt-4B was confirmed by Spectral data. The yield and purity was consistent on gram scale. 2. Step-d 0.45 g 0.38 Procedure: lnt-4B (1.0eq) in DCM (20V) and CISO3H (8.0 eq) along with DCM (20V) was added and stirred at 0°C to rt. The progress of the reaction was monitored by TLC. LCMS showed the presence of m / z of lnt-5B (M-Cbz). 3. Step-e 0.5 g - Procedure: Int-5B (1.0 eq) in Toluene: THF (1:1, 10V), PPh3 (6.0 eq) was added, stirred at 100°C for 16 h. The progress of the reaction was monitored by TLC. No desired product formation observed. lnt-5B was confirmed by LCMS analysis, but the subsequent step-e did not result in desired product formation. Polar spots observed seem to indicate Cbz-protection may not be stable under reaction conditions. 5 Step-c to h: N-acylation strategy: Summary of Feasibility Experiments: No. Input (g) Output (g) Experimental Details Remarks 1. Step-c 5.0 g 3.7 (60.6%) Procedure: lnt-3 (1.0 eq) in DCM (20 V) and DMAP (1.0 eq) added acetic anhydride (1.5 eq.) and stirred at rt. for 16 hr. The progress of the reaction was monitored by TLC and LCMS. Workup: Added sat sodium bicarbonate (10 V) to the RM and separated the layers. Concentrated the DCM layer under vacuum below 50°C till no solvent distills to get the Crude lnt-4C. Purification: The crude was purified by flash column chromatography in EtOAc-Hexane to afford lnt-4C. lnt-4C was confirmed by spectral data. 2. Step-d 3.7 g 3.9 (73.1%) Procedure: lnt-4C (1.0 eq) in DCM (20V) and CISO3H (8.0 eq) along with DCM (20v) was added and stirred at 0°C to rt. The progress of the reaction was monitored by TLC. Workup: Diluted the reaction mass with DCM (10 V) and quenched the reaction mass in Ice water. Dried the DCM layer over sodium sulfate and concentrated under vacuum below 50 °C till no solvent distills out to get Crude lnt-5C Int-5C was confirmed by Spectral data and consistent on gram scale. 3. Step-e 3.9 1.5g (48.4%) Procedure: lnt-5C (1.0 eq), Glacial Acetic acid (20 V) Heated to 100°C and added Zinc (20 eq) in portions and stirred at 100°C for 1 h. The progress of the reaction was monitored till 16 h & checked by TLC. Workup: Cooled the reaction mass to RT, Filtered and washed with DCM (5V) The filtrate was extracted in DCM(2X10V) and concentrated the DCM layer under vacuum below 50 °C till no solvent distills out to get crude lnt-6C. Int-6C was confirmed by Spectral data. The gram scale synthesis accomplished. Loss of product in aq. Layer. 4. Step-f 1.1 0.5 (35.9%) Procedure: lnt-6C (1.0 eq.), Reagent-X (1 eq.), TEA (1.5 eq.), DMF (20 V), stirred at 2530°C for 18h. The progress of the reaction was monitored by TLC. Workup: Added water (10V) and compound was extracted with Ethyl acetate (2X10V). Combined ethyl acetate layers concentrated to obtain crude lnt-7C. Purification: Purified the crude by silica gel column chromatography to get the pure Int-7C. Int-7C was confirmed by LCMS data. The procedure in consistent on gram scale. 5. Step-h 0.5 Not Isolated Procedure: lnt-7C (1.0 eq.), HCI in Dioxane (10 V), stirred at 90-100 °C for 10-12 h. The progress of the reaction was monitored by TLC. LCMS shows the desired m / z but no major spot observed on TLC. Isolation not attempted. N-acylation strategy was demonstrated until the pentultimate step, but all intermediates obtained were sticky material and hard to isolate. The process required significant optimization before scale-up. Example 4: Optimized Protocol Step-a: Synthesis of (E)-1,4-dimethoxy-2-(2-nitrovinyl) benzene (lnt-2): CH3NO2, nBuNH2 AcOH, 115 °C, 5h Step-a Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio 2,5-Dimethoxy benzaldehyde (lnt-1) 400.0 g 166.20 2.4067 1.0 Nitromethane 293.8 g 61.00 4.8134 2.0 n-Butylamine 400.0 ml - - 1.0V Acetic Acid 2000.0 ml - - 5V Sodium bicarbonate 900 g - - 2.25 w / w Sodium Sulfate 400 g - - 1w / w DM Water 30000 ml - - 75 V Procedure: To a stirred solution of lnt-1 (1.0 eq) in acetic acid (5 V), nitromethane (2.0 eq), and n-5 butylamine (1 V) was stirred for 5-10 min. Then the reaction mass was stirred at 110 °C for 4-5 h. The progress of the reaction was monitored by TLC and HPLC. Workup: Reaction mass was allowed to cool at room temperature, and the yellow solid was crystallized. The slurry was diluted with water (5 V) and filtered over Buchner funnel, solid was washed with 10 sat. NaHCOs (10 V x 3) and water (10 V x 4 times). The solid was dried under vacuum at 50-55 °C to afford crude of lnt-2. Purification: The crude was used as such for next steps without any further purification. Result: Wt. of Crude Yield (%) Purity, (%) HPLC 430 g 85.4 99.26 15 1HNMR: 400 MHz, 8 ppm : 8.19 (m, 2H), 7.42(m, 1H), 7.11(m,1H), 3.87(s,3H), 3.75(s, 3H). Step-b: Synthesis of (2-(2,5-dimethoxyphenyl) ethan-1-amine (lnt-3): Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio lnt-2 240.0 g 209.20 1.1472 1.0 LiAIH4(2M in THF) 1720.0 ml 37.95 3.4416 3.0 THF 9600.0 ml - - 40v DCM 4800.0 ml - - 20v Sodium sulfate decahydrate 2400.0 g - - 10 w / w Procedure: To the solution of lnt-2 (1.0 eq) in THF (40 V) was added to the solution of LAH in THF (2M, 3 eq.) under nitrogen at 0-15 °C. The temperature of the reaction mass was then raised to 55-65 °C and the mass was stirred at 55-65 °C for 16-18 h. The progress of the reaction was monitored by TLC and HPLC. Workup: Reaction mass was diluted with DCM (20V) and quenched in sodium sulfate decahydrate (10 w / w of LAH) slowly at rt and stirred for 1 hr. The reaction mixture was filtered over Buckner funnel, and the filtrate was collected and concentrated under vacuum below 45 °C to afford crude lnt-3. Purification: The crude was used for next steps without any further purification. Result: Wt. of Crude Yield (%), Crude Purity, (%) HPLC 205 g 98.5 83.6 1HNMR: 400 MHz, 6 ppm : 6.86(m, 1H), 6.72(m, 2H), 3.71(s, 3H), 3.65(s, 3H), 2.71(t, J=7.2Hz, 13.6 Hz, 2H), 2.60 (t, J=7.2Hz, 14.0Hz, 2H). Step-c: Synthesis of 2-(2,5-dimethoxyphenethyl) isoindoline-1,3-dione (lnt-4a): Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio lnt-3 205.0 g 181.24 1.1310 1.0 Phthalic Anhydride 251.3 g 148.10 1.6966 1.5 Toluene 8200.0 ml - - 40v Sodium Bicarbonate 150.0 g - - 0.73w / w IPA 1230.0 ml - - 6v Procedure: To a stirred solution of lnt-3 (1.0 eq) in toluene (40 V), phthalic anhydride (1.5 eq) was added. The reaction mass was stirred at 120-130 °C for 16-18 h. The progress of the reaction was 5 monitored by TLC. Workup: Saturated sodium bicarbonate (10V) was added to the reaction mixture and the layers were separated. The DCM layer was concentrated under vacuum below 50°C to get the crude lnt-4a. Purification: 10 The crude lnt-4a was slurried in IPA (5V), filtered, and the filtered solid was washed with IPA(1V). The product was dried to get pure lnt-4a. Result: Wt. of Pure Yield (%) Purity, (%) 208.0 g 62.5 over two steps 98.3 1HNMR: 400 MHz, 8 ppm : 7.82(m, 4H), 6.78-6.76 (m, 1H), 6.70-6.65(m, 2H), 3.81 (t, J=Q.8 Hz, 2H), 3.58(s, 3H), 3.51 (s, 3H), 2.87(t, J=6.4 Hz, 2H). Step-d: Synthesis of 4-(2-( 1,3-dioxoisoindolin-2-yl)ethyl)-2,5-dimethoxybenzenesulfonyl chloride (lnt-5a): Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio lnt-4a 208.0 g 311.3 0.6681 1.0 Chlorosulfonic Acid 622.7 g 116.5 5.3453 8.0 DCM 8200 ml - - 40.0 V Sodium Sulfate 416.0 g - - 2.0 w / w Procedure: To a stirred solution of lnt-4a (1.0 eq) in DCM (20 V) was added the solution of chlorosulfonic acid (8 eq) in DCM (20 V) at 0-5 °C. The reaction mass was stirred at 0-5 °C for 4-6 h. The progress of the reaction was monitored by TLC. Workup: The reaction mass was diluted with DCM (10 V) and the reaction mass was quenched in ice water. The DCM layer was dried over sodium sulfate and concentrated under vacuum below 50 °C to get crude lnt-5a. Purification: The crude was used for next steps without any further purification. Result: Wt. of Crude Yield (%), Crude Purity, (%) 215.0 78.5 93.8 1HNMR: 400 MHz, 6 ppm : 7.84-7.79(m, 4H), 7.16(s, 1H), 6.71(s, 1H), 3.82(t, J = 6.8Hz, 2H), 3.56(s, 3H), 3.49(s, 3H), 2.90(t, J =6.4 Hz, 2H). Step-e: Synthesis of 2-(4-mercapto-2,5-dimethoxyphenethyl) isoindoline-1,3-dione (lnt-6a): Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio lnt-5a 46.0 g 4098 0.1122 1.0 Triphenylphosphine 176.6 g 262.3 0.6732 6.0 Toluene 230.0 ml - - 5.0 V Tetrahydrofuran 230.0 ml - - 5.0 V Hexanes 9200 ml - - 200.0 V Ethyl Acetate 2300.0 ml - - 50.0V DM Water 160 ml - - 10.0 V Silica Gel 100-200 mesh 1380 g - - 30.0 w / w Procedure: To a stirred solution of lnt-5a (1.0 eq) in toluene-THF (1:1, 10 V), triphenyl phosphine (6.0 eq) was added. The reaction mass was heated to 100 °C and stirred at 100 °C for 16 h. The 5 progress of the reaction was monitored by TLC and HPLC Workup: Water(10V) was added to the reaction mass and then the reaction mass was extracted with ethyl acetate (2X10V). The organic layers were combined and concentrated under vacuum below 45 °C to get crude lnt-6a. 10 Purification: The crude was purified by column chromatography with EtOAc-Hexane (2-10%) as eluent. The pure fractions were combined and concentrated under vacuum below 45 °C to get the pure Int-6a. Result: Wt. of Pure Yield (%), Pure Purity,(%) 25.0 g 64.9 95.1 15 1HNMR: 400 MHz, 6 ppm : 7.82(m, 4H), 6.87(m, 1H), 6.71(m, 1H), 4.72(s, 1H-SH), 3.80(t, J =5.2 Hz, 2H), 3.60(s, 3H), 3.50(s, 3H), 2.85(t, J =5.6 Hz, 2H). Step-f: Synthesis of 2-(2,5-dimethoxy-4-((trifluoromethyl)thio) phenethyl)isoindoline-1,3-dione(lnt-7a): Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio lnt-6a 80.0 g 343.4 0.2329 1.0 Reagent-X 145.7 g 445.2 0.2329 1.0 Triethyl amine 35.3 g 101.1 0.3493 1.5 Acetonitrile 1600.0 ml - - 20.0 V Hexanes 16000.0 ml - - 200.0 V Ethyl Acetate 4000.0 ml - - 50.0 V Water 800.0 ml - - 10.0 V 5 Procedure: To a stirred solution of lnt-6a (1.0 eq) in acetonitrile (20V), triethyl amine (1.5 eq) and Reagent-X (1.0 eq) were added. The reaction mass was stirred at 25-30 °C for 18 h. The progress of the reaction was monitored by TLC and HPLC. Workup: 10 Water (10 V) was added and the compound was extracted with ethyl acetate (2X10V). Combined ethyl acetate layers were concentrated to obtain crude lnt-7a. Purification: The crude was purified by column chromatography with EtOAc-Hexane (2-12%) as eluent. The pure fractions were combined and concentrated under vacuum below 45 °C to get the pure Int-15   7a. Result: Wt. of Pure Yield (%), Pure Purity, (%) 41.5g 43.3 98.0 1HNMR: 400 MHz, 8 ppm : 7.82(m, 4H), 7.07(m, 1H), 7.00(m, 1H), 3.85(t, J= 6.8Hz„ 2H), 3.67(s, 3H), 3.58(s,3H), 2.96(t, J= 6.4Hz). 19FHNMR: MHz, 8 ppm : -41.81(s) Step-h: Synthesis of 2-(2,5-dimethoxy-4-((trifluoromethyl)thio)phenyl)ethan- 1-amine hydrochloride (Compound 1): o. / =\ CH3NH2, 2M HCI in dioxane, EtOAc A^^nh2hci J Y f3csx 0 Step-h f3cs^y °\ 7a Compound 1 Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio lnt-7a 41 g 411.4 1.0719 1.0 Methyl Amine 410 ml - - 10 V DCM 1640.0 ml - - 40 V HCI in 1,4 Dioxane (4M) 1640.0 ml - - 40 V Ethyl Acetate 1230.0 ml - - 30.0 V Procedure: To a stirred solution of lnt-7a (1.0 eq) methylamine (10V) was added. The reaction mass was stirred at 25-30 °C for 10-12 h. The progress of the reaction was monitored by TLC. Workup: The reaction mass was extracted in DCM (2X20V). The combined DCM layer was concentrated under vacuum below 45 °C. Then HCI in 1,4 Dioxane (10V) was added and the reaction mass stirred for 12h. The reaction mass was concentrated under vacuum below 45 °C. Ethyl acetate (15V) was added to the residue and stirred for 2.0 h. The product was filtered and washed with ethyl acetate (3X 5 V) to get off white solid of Int-6 (HCI salt). Then the solid was dried under vacuum below 45 °C to get Compound 1 (HCI Salt). Purification: The crude exhibited the required quality. Result: Wt. of Final Yield (%) Purity, (%) 24.5 g 77.4 99.79 1HNMR: 400 MHz, 6 ppm : 8.29(bs, 2H-NH2), 7.18(s, 1H), 7.149s, 1H), 3.83(s, 3H), 3.81(s, 1H), 3.0(m, 2H), 2.95(m, 2H). 19FHNMR: MHz, 6 ppm : -41.58(s) Step-1: Synthesis of 5-(trifluoromethyl)-5H-thianthren-5-ium trifluoromethanesulfonate (Reagent- X): Raw Material Table: Chemicals Quantity Mol. Wt. Moles Mole ratio Thianthrene (Int-A) 100.0 g 216.3 0.4623 1.0 Triflic Anhydride 130.4 g 282.1 0.4623 1.0 DCM 4000.0 ml - - 40.0 V MTBE 800.0 ml - - 8.0 V Sodium bicarbonate 75.0 g - - 0.75 w / w DM Water 1000.0 ml - - 10.0 V Procedure: To a stirred solution of Int-A (1.0 eq) in DCM (20V), triflic anhydride (1.0 eq) was added at 25-35 °C. The reaction mass was stirred at 25-35 °C for 20-24 h. The progress of the reaction was monitored by TLC. Workup: Reaction mixture was added in NaHCOs solution (10V) and the compound extracted in DCM (2X10V). Combined DCM layers were concentrated to obtain crude Reagent-X, which was washed with MTBE (4X2V) and the solid was dried under vacuum at 50 °C to get crude Reagent-X. Purification: The crude was used for next steps without any further purification. Result: Wt. of Crude Yield (%), Crude Purity, (%) 116.0 57.7 99.76 1HNMR: 400 MHz, 6 ppm : 8.62-8.59 (m, 2H), 8.16-8.13(m, 2H), 8.06-8.02(m, 2H), 7.89-7.859(m, 2H). To summarize, various routes and strategies were thoroughly explored for the synthesis of Compound 1. In this approach of Scheme 1 the chlorosulfonation of dimethylbenzene was quite smooth and the process was established on gram scale. For the reduction step, a variety of reducing reagents were tested but only triphenyl phosphine and Zn / HCI conditions gave the desired conversion to thiol intermediate. The thiol had less stability and converted to its disulfide analogue upon standing even at low temperatures. The stability of the thiol intermediate was achieved by adding a small amount of triphenylphosphine in the reaction mass or isolated intermediate. For the subsequent conversion of thiol to trifluoromethoxy ether analogue, a variety of different reagents were tested, but the desired conversion was not achieved. As a result, this approach was not further developed. For the process of Scheme 2, different Henry reaction conditions were used and the experimental procedure was optimized using n-butyl amine and acetic acid. The crude obtained gave >98% purity by HPLC and was used as such in the next step. In the next step, various conditions using different reducing reagents were investigated. Of the tested reducing reagents, lithium aluminum hydride conditions gave best results. The reaction and workup conditions were optimized to give crude material, which was sufficiently pure to be used for next step. In the next step, for the protection of the free amine, phthalimido protection was explored then subsequently optimized. Efforts were also taken to optimize workup to achieve the compound in a pure state. The phthalimido-protected intermediate was subjected to chlorosulfonation using chlorosulfonic acid. The reaction and isolation conditions were optimized for gram scale synthesis. The crude was used in the next step without further purification. The chlorosulfonic intermediate was then subjected to different reduction conditions to get the thiol intermediate, out of which triphenylphosphine gave best results. The intermediates were purified by column, which can be eliminated by using triphenylphosphine removing agents. The thiol intermediate was further converted to a thiotrifluoromethoxy ether intermediate for which various reagents and conditions were tried. Best conversions were achieved by using sodium trifluoromethanesulfinate (Langlois reagent) and thianthrene triflate reagents for which reaction conditions were further optimized to achieve the best yields. Initially, the intermediate was purified by column chromatography, which was later eliminated by crystallization. Finally, the trifluoromethoxy ether intermediate was subjected to deprotection for which reaction conditions were optimized. The process for isolation was also achieved after many trials. Deprotection using methylamine was executed considering safety and efficiency aspects. The hydrochloride salt was prepared using HCI in 1,4 dioxane by slurring the crude HCI salt in ethyl acetate to get final Compound 1 (HCI salt). Different protecting groups were also explored for amine protection, out of which acetyl protection was successful on small scale, however, the yield was lower than the phthalimide protection strategy. In conclusion, the process described herein was successful in generating multigram scale (10-15 g) of final compound, without the usage of expensive palladium catalysis. The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference {e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

1. A process for preparing a compound of Formula I: OR2(I)or a pharmaceutically acceptable salt thereof; whereinX is S, S(O), or S(O)2;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;comprising the steps off) reacting a compound of Formula VII:?r2OR3(VII)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;with a trifluoromethylating reagent to form a compound of Formula VIII:?r2 (OF3CS^pl R1OR3(VIII)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;g) optionally treating the compound of Formula VIII with an oxidizing reagent to form a compound of Formula VIII*:whereinPG is a nitrogen protecting group;Y is S(O) or S(O)2;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium; andh) treating the compound of Formula VIII or VIII* under deprotecting conditions to form the compound of Formula I.

2. The process of claim 1, wherein the process further comprises the step of e) treating a compound of Formula VI:(VI)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted withdeuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;with a reducing reagent to form the compound of Formula VII.

3. The process of claim 2, wherein the process further comprises the step ofd) reacting a compound of Formula V:(V)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium; with chlorosulfonic acid to form the compound of Formula VI.

4. The process of claim 3, wherein the process further comprises the step of c) reacting a compound of Formula IV:OR2(IV)whereinR1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;with a protecting group reagent to form the compound of Formula V.

5. The process of claim 4, wherein the process further comprises the step ofb) treating a compound of Formula III:OR2NO2R1OR3(HI)whereinR1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;with a reducing reagent to form the compound of Formula IV.

6. The process of claim 5, wherein the process further comprises the step of a) reacting a compound of Formula II:OR2 OOR3(II)whereinR2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;with a compound of Formula Ila: R1-NO2, wherein R1 is C1-7 alkyl optionally substituted with deuterium;to form the compound of Formula III.

7. The process of any one of claims 1-6, wherein the process comprises preparing a compound of Formula I:OR2(I)or a pharmaceutically acceptable salt thereof; whereinX is S, S(O), or S(O)2;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;comprising the steps ofa) reacting a compound of Formula II:OR2 O(II)whereinR2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;with a compound of Formula Ila: R1-NO2, wherein R1 is C1-7 alkyl optionally substituted with deuterium;to form a compound of Formula III:OR2(III)whereinR1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;b) treating the compound of Formula III with a reducing reagent to form a compound of Formula(IV)whereinR1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;c) reacting the compound of Formula IV with a protecting group reagent to form a compound of Formula V:?r2 fp?)r1OR3(V)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;d) reacting the compound of Formula V with chlorosulfonic acid to form a compound of FormulaVI:OR2 ^Pg)jT Zr ricio2sOR3(VI)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;e) treating the compound of Formula VI with a reducing reagent to form a compound of Formula VII:(VII)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;f) reacting the compound of Formula VII with a trifluoromethylating reagent to form a compound of Formula VIII:(VIII)whereinPG is a nitrogen protecting group;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium;g) optionally treating the compound of Formula VIII with an oxidizing reagent to form a compound of Formula VIII*:(VIII*)whereinPG is a nitrogen protecting group;Y is S(O) or S(O)2;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is C1-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium; andh) treating the compound of Formula VIII or VIII* under deprotecting conditions to form the compound of Formula I.

8. The process of any one of claims 1-7, wherein the process further comprises reacting the compound of Formula I with an alkylating reagent to form a compound of Formula IX:(IX)or a pharmaceutically acceptable salt thereof;whereinX is S, S(O), or S(O)2;R1 is selected from the group consisting of H, D, and C1-6 alkyl optionally substituted with deuterium;R2 is Ci-6 alkyl optionally substituted with deuterium; andR3 is C1-6 alkyl optionally substituted with deuterium; andR4 is C1-6 alkyl optionally substituted with C3-6 cycloalkyl or aryl.

9. The process of any one of claims 6-8, wherein the compound of Formula Ila is nitromethane or nitroethane.

10. The process of any one of claims 5-9, wherein the reducing reagent in step b) is LiAIFU.

11. The process of any one of claims 4-10, wherein the protecting group reagent in step c) isphthalic anhydride or succinic anhydride.

12. The process of any one of claims 2-11, wherein the reducing reagent in step e) is PPha.

13. The process of any one of claims 1-12, wherein the trifluoromethylating reagent in step f)is a compound of Formula X:CF3 OTf cco(X).

14. The process of any one of claims 1-13, wherein the oxidizing reagent in step g) is mCPBA.

15. The process of any one of claims 1-14, wherein the deprotecting conditions in step h) comprise aqueous methylamine.

16. The process of any one of claims 1-15, wherein X is S.

17. The process of any one of claims 1-15, wherein X is S(O).

18. The process of any one of claims 1-15, wherein X is S(O)2.

19. The process of any one of claims 1-18, wherein R1 is H.

20. The process of any one of claims 1-18, wherein R1 is D.

21. The process of any one of claims 1-18, wherein R1 is methyl.

22. The process of any one of claims 1-21, wherein R2 is methyl.

23. The process of any one of claims 1-21, wherein R2 is CD3.

24. The process of any one of claims 1-23, wherein R3 is methyl.

25. The process of any one of claims 1-23, wherein R3 is CD3.

26. The process of any one of claims 1-18, wherein R2 is methyl and R3 is methyl.

27. The process of any one of claims 1-18, wherein R2 is CD3 and R3 is CD3.

28. The compound of any one of claims 8-27, wherein R4 is methyl.

29. The compound of any one of claims 8-27, wherein R4 is ethyl.

30. The compound of any one of claims 8-27, wherein R4 is -CH2-cyclopropyl.

31. The compound of any one of claims 8-27, wherein R4 is -CH2-phenyl.

32. The process of any one of claims 1-7 and 9-31, wherein PG is phthalimide.

33. The process of any one of claims 1-7 and 9-31, wherein PG is succinimide.

34. A process for preparing a compound of Formula I:OR2(I)whereinX is S, S(O), or S(O)2;R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;comprising the steps off) reacting a compound of Formula VII’:or2          / A J R1 OHS VOR3(VIP)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;with a compound of Formula X:CF3 OTf oio (X)to form a compound of Formula VIII’:OR2 1¼ / / f3cs^y^ r1 °OR3(VHP)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;g) optionally treating the compound of Formula VIII’ with mCPBA to form a compound of Formula VIII*’:(VIII*’)whereinY is S(O) or S(O)2;R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium; andh) treating the compound of Formula VIII’ or VIII*’ under deprotecting conditions to form the compound of Formula I.

35. The process of claim 34, wherein the process further comprises the step of e) treating a compound of Formula VI’:(VI’)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;with triphenylphosphine to form the compound of Formula VII’.

36. The process of claim 35, wherein the process further comprises the step of d) reacting a compound of Formula V’:(V’)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;with chlorosulfonic acid to form the compound of Formula VI’.

37. The process of claim 36, wherein the process further comprises the step of c) reacting a compound of Formula IV:(IV)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;with phthalic anhydride to form the compound of Formula V’.

38. The process of claim 37, wherein the process further comprises the step of b) treating a compound of Formula III:OR2(HI)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;with lithium aluminum hydride to form the compound of Formula IV.

39. The process of claim 38, wherein the process further comprises the step ofa) reacting a compound of Formula II:OR2 O(II)whereinR2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;with a compound of Formula Ila: R1-NO2, wherein R1 is C1-4 alkyl optionally substituted with deuterium;to form the compound of Formula III.

40. The process of any one of claims 34-39, wherein the process comprises preparing a compound of Formula I:OR2(I)or a pharmaceutically acceptable salt thereof;whereinX is S, S(O), or S(O)2;R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium; comprising the steps ofa) reacting a compound of Formula II:OR2 O(II)whereinR2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;with a compound of Formula Ila: R1-NO2, wherein R1 is C1-4 alkyl optionally substituted with deuterium;to form a compound of Formula III:whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;b) treating the compound of Formula III with lithium aluminum hydride to form a compound of Formula IV:OR2NH2OR3(IV)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;c) reacting the compound of Formula IV with phthalic anhydride to form a compound of FormulaV’:(V’)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;d) reacting the compound of Formula V’ with chlorosulfonic acid to form a compound of FormulaVI’:(VI’)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;e) treating the compound of Formula VI’ with triphenylphosphine to form a compound of Formula VII’:(VIP)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;f) reacting the compound of Formula VII’ with a compound of Formula X:CF3 OTf(X)to form a compound of Formula VIII’:(VHP)whereinR1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium;g) optionally treating the compound of Formula VIII’ with an oxidizing reagent to form a compound of Formula VIII*’:(VIII*’)whereinY is S(O) or S(O)2;R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium; andh) treating the compound of Formula VIII’ or VIII*’ with aqueous methylamine to form the compound of Formula I.

41. The process of any one of claims 34-40, wherein the process further comprises reacting the compound of Formula I with an alkylating reagent to form a compound of Formula IX:(IX)or a pharmaceutically acceptable salt thereof;whereinX is S, S(O), or S(O)2;R1 is selected from the group consisting of H, D, and C1-3 alkyl optionally substituted with deuterium;R2 is C1-3 alkyl optionally substituted with deuterium; andR3 is C1-3 alkyl optionally substituted with deuterium; andR4 is C1-3 alkyl, C1-3 alkyl-(C3-6 cycloalkyl), or C1-3 alkyl-(phenyl).

42. The process of any one of claims 1-41, wherein the compound of Formula I is selected from the group consisting ofOMe ^NH2 OCD3 [| ^NH2 F3cs^ OMe li j F3CS^^ ocd3F3CS^ OMe z OMe ^nh2 OMe ^nh2 F3C. / 3 xs o o U J OMe OMe ^nh2 F3C. J 3 s II 0 I J OMef3cs^ ocd3 ocd3 ^nh2 ocd3 ^NH2 F3C\ J 3 XS ' / w o o i j ocd3 ocd3 ^NH2 F3C^ / 3 s II 0 ocd3or a pharmaceutically acceptable salt thereof.

43. The process of any one of claims 8-33 and 41, wherein the compound of Formula IX is selected from the group consisting off3cs OMe jfy OMe H OMe H   A If II f3cs^ xxx OMe OMe u f3csx JI J OMe OMe H t ll II II f3cs^ OMef3cj ocd3 Xj ocd3 H ocd3 H A i f3cs^ 1 J ocd3 ocd3 H h 'jT f3cs- JI J ocd3 ocd3 H [f II f3cs^ ocd35          or a pharmaceutically acceptable salt thereof.