Processes related to formation of fungicidal ARYL amidines

Abstract

This disclosure relates to a compound, 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid ( S2 ), and processes to make and use a compound of S2. This disclosure relates to a compound, 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoyl chloride ( S6c ) or an acceptable salt thereof, and processes to make and use a compound of S6c. Additionally, processes related to the formation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate ( S1 ), an acceptable salt, solvate, or hydrate thereof are provided.

Description

PROCESSES RELATED TO FORMATION OF FUNGICIDAL ARYL AMIDINESCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No.63 / 718,609 filed November 9, 2024, which is expressly incorporated by reference herein.BACKGROUND

[0002] The fungicidal aryl amidine compound, 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI), an acceptable salt, solvate, or hydrate thereof, has been disclosed in application PCT / US2024 / 027678.SUMMARY

[0003] A compound, 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2), having the following formula is provided.S2

[0004] A compound, 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoyl chloride (S6c) or an acceptable salt thereof, having the following formula is provided.

[0005] Processes to make and use a compound of S2 are provided. Processes to make and use a compound of S6c or an acceptable salt thereof are provided. Additionally, processes relatedto the formation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable salt, solvate, or hydrate thereof are provided. The compound S2 may be useful in the process to prepare 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable salt, solvate, or hydrate thereof. The compound S6c or an acceptable salt thereof may be useful in the process to prepare 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI), an acceptable salt, solvate, or hydrate thereof.DETAILED DESCRIPTION

[0006] A compound, 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (also known as S2), having the following formula is provided.S2

[0007] Additionally, processes to make and use a compound of S2 are provided.

[0008] In another embodiment, a compound, having the following formula, wherein R is C2- C4, is provided.

[0009] A compound, 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoyl chloride (S6c) or an acceptable salt thereof, having the following formula is provided. An example of an acceptable salt is the hydrochloride salt, 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoyl chloride hydrochloride (S6c- HC1)

[0010] The compound S2 may be useful in the process to prepare 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable salt, solvate, or hydrate thereof. The compound S6c or an acceptable salt thereof may be useful in the process to prepare 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable salt, solvate, or hydrate thereof.

[0011] Also provided are processes related to the formation of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable salt, solvate, or hydrate thereof.

[0012] Definitions

[0013] It is understood that a substituent should comply with chemical bonding rules and steric compatibility constraints in relation to the particular compound to which it is attached. These definitions are only to be used for the purposes of this disclosure.

[0014] Throughout the disclosure, reference to the compound of SI or compounds of SI is read as also including acceptable salts, solvates, or hydrates thereof, unless otherwise indicated herein or clearly contradicted by context.

[0015] Throughout the disclosure, reference to the compound of or compounds of SI or S6 is read as also including all regioisomers, structural isomers, geometrical isomers, rotational isomers, tautomers, and stereoisomers, for example diastereomers, enantiomers, and mixtures thereof.

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

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

[0018] The term “ambient pressure” refers to pressures from about 80 kilopascals (kPa) to about 105 kPa.

[0019] The term “ambient temperature” or “room temperature” refers to temperatures ranging from about 20 °C to about 24 °C.

[0020] The term “catalyst” refers to any substance that increases the rate of a reaction without itself being consumed.

[0021] The term “telescope process” or “telescopic reaction” means a type of synthesis that subjects a reactant or reactants to successive chemical reactions in a sequential order in just one reactor or without isolation of intermediates.

[0022] An acid equivalent is dependent upon the number of protons an acid can deliver. For example, hydrochloric acid has one molar equivalent of acid, while oxalic acid has two.

[0023] Scheme One

[0024] In one embodiment, the reaction of Step A in Scheme One is the reaction of an amine with an activated carbonyl group.

[0025] In one embodiment, the activated carbonyl group is methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, / / -butyl chloroformate, di-tert-butyl decarbonate, and dimethyl carbonate.

[0026] The reaction of Step A in Scheme One is done in the presence of a base. Examples of bases are organic bases and inorganic bases. Examples of organic bases are pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 2-methylpyridine, 3-methylpyridine, N, N-diisopropylethylamine (“DIPEA”), A-methylimidazole (“NMI”), A-methylmorpholine (“NMM”), and triethylamine (“EtsN”). Examples of inorganic bases are potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), sodium carbonate (“Na2CO3”), and sodium bicarbonate (“NaHCOs”). In general, from about 1.0 moles to about 2 moles of base per mole of S3 may be used; preferably, from about 1.1 moles to about 1.5 moles of base per mole of S3 may be used. Mixtures of bases may also be used.

[0027] The reaction of Step A in Scheme One is conducted in the presence of a polar or a nonpolar solvent. Examples of solvents are ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), di chloromethane ("DCM”), and toluene (“PhCTfc”). Optionally, mixtures of solvents may be used.

[0028] The reaction of Step A in Scheme One may be conducted at temperatures from about -5 °C to about 35 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0029] The reaction of Step B in Scheme One is done in the presence of a Lewis acid, an acyl chloride, and a solvent, whereby S4 is acylated to afford 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (also known as S2 herein). Examples of Lewis acids are boron trifluoride (“BF3”), aluminum trichloride (“AICI3”), and iron trichloride (“FeCh”). In general, from about 1.5 moles to about 3 moles of Lewis acid per mole of S4 may be used; preferably, from about 1.9 moles to about 2.5 moles of Lewis acid per mole of S4 may be used.

[0030] The reaction of Step B in Scheme One is done in the presence of an acyl chloride. Examples of acyl chlorides are oxalyl dichloride, phosgene, diphosgene, and triphosgene. Ingeneral, from about 0.9 moles to about 1.5 moles of acyl chloride equivalent per mole of S4 may be used; preferably, from about 1.0 moles to about 1.3 moles of acyl chloride equivalent per mole of S4 may be used.

[0031] The reaction of Step B in Scheme One is conducted in the presence of a solvent. Examples of solvents are chlorobenzene (“PhCl”), di chlorobenzene, dichloromethane ("DCM”), trifluorotoluene, and toluene (“PhCHs”). Optionally, mixtures of solvents may be used.

[0032] The reaction of Step B in Scheme One may be conducted at temperatures from about -20 °C to about 20 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0033] Scheme TwoS2 S5

[0034] The reaction of Scheme Two is done in the presence of an aqueous base. Examples of aqueous bases are bases in aqueous solution (i.e., water), such as potassium hydroxide (“KOH”), potassium carbonate (“K2CO3”), potassium bicarbonate (“KHCO3”), sodium carbonate (“Na2CO3”), sodium hydroxide (“NaOH”), and sodium bicarbonate (“NaHCOs”). In general, from about 1.0 moles to about 10 moles of base per mole of S2 may be used; preferably, from about 1.5 moles to about 5 moles of base per mole of S2 may be used. Mixtures of bases may also be used.

[0035] The reaction of Scheme Two is done in the presence of a solvent. Examples of solvents include water, methanol, ethanol, propan-2-ol, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), l-methyl-2-pyrrolidin-2-one (“NMP”), dichloromethane ("DCM”), 1,2-di chloroethane ("DCE”), chloroform (“CHCI3”), acetonitrile (“ACN”), chlorobenzene (“PhCl”), toluene (“PhCHs”), and benzonitrile (“PhCN”). Optionally, mixtures of solvents may be used.

[0036] The reaction of Scheme Two may be conducted at temperatures from about 40 °C to about 100 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0037] Scheme ThreeS6b or salt thereof

[0038] The reaction of Steps Al, A2, and A3 in Scheme Three is done in the presence of a Vilsmeier reagent, also known herein as reagent V, which is prepared by reacting a formamide, R1R2NCHO, wherein Ri and R2 are independently C1-C2 alkyl and may or may not be the same, with an activating chloride. Examples of formamides include AA-dimethylformamide, N, N-diethylformamide, and -ethyl -A-m ethyl formamide. Examples of activating chlorides include oxalyl dichloride, phosgene, diphosgene, triphosgene, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, and thionyl chloride. In general, from about 1.2 moles to about 3 moles of reagent V per mole of S5 may be used; preferably, from about 1.5 moles to about 2.5 moles of reagent V per mole of S5 may be used.

[0039] The reaction of Steps Al, A2, and A3 in Scheme Three is conducted in the presence of a polar or a nonpolar solvent. Examples of solvents are ethyl acetate (“EtOAc”), tetrahydrofuran (“THF”), dichloromethane ("DCM”), and toluene (“PhCHs”). Optionally, mixtures of solvents may be used.

[0040] The reaction of Steps Al, A2, and A3 in Scheme Three may be conducted at ambient temperature and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0041] The products of the reaction of Steps Al, A2, and A3 in Scheme Three may be 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid (also known as S6a herein) or salt thereof (Step Al), an ester (S6b), wherein Ri is Ci-Cs alkyl, or salt thereof (Step A2), or SI or salt thereof (Step A3), depending upon how the reaction is terminated. The reaction of Steps Al, A2, and A3 in Scheme Three may be terminated by the addition of hydrolytic agents including water (Step Al), Ci-Cs alkyl alcohols (Step A2), such as methanol, ethanol, propan-1-ol, propan-2-ol, butan-l-ol, butan-2-ol, 2-methylpropan-l-ol, pentan- l-ol, 3-methylbutan-l-ol, 2-ethylhexan-l-ol, or 4-(difluoromethoxy)phenyl)methanol (Step A3).

[0042] The products of Steps Al, A2, and A3 in Scheme Three may be isolated as an acceptable salt or neutral form depending upon the addition of an appropriate acid or base.Examples include the addition of sodium or potassium bases, such as sodium or potassium hydroxide, sodium or potassium phosphate dibasic, sodium or potassium phosphate tribasic, sodium or potassium carbonate, or sodium or potassium bicarbonate to S6a or acceptable salt thereof (e.g., S5-HC1) to afford the corresponding carboxylate (S6a-Na and S6a-K); the addition of sodium or potassium bases, such as sodium or potassium hydroxide, sodium or potassium phosphate dibasic, sodium or potassium phosphate tribasic, sodium or potassium carbonate, or sodium or potassium bicarbonate to S6b-HCl to afford the neutral forms of S6b; and the addition of sodium or potassium bases, such as sodium or potassium hydroxide, sodium or potassium phosphate dibasic, sodium or potassium phosphate tribasic, sodium or potassium carbonate, or sodium or potassium bicarbonate to S1-HC1 to afford the neutral forms of SI.

[0043] As in Step B of Scheme Three, the ester, S6b, or acceptable salt thereof (e.g., S6b-HC1) may be converted to S6a or the corresponding carboxylate (S5-Na and S5-K)thereof, bytreatment with a base, such as sodium hydroxide, in the presence of a solvent, such as an alcohol, tetrahydrofuran (“THF”), acetonitrile (“ACN”), A'A-dimethylformamide (“DMF”), or toluene. In general, from about 1.0 moles to about 2.5 moles of base per mole of S6b may be used; preferably, from about 1.1 moles to about 2 moles of base per mole of S6b may be used. One skilled in the art would recognize that more equivalents of base may be necessary if a salt form of S6b is used. Mixtures of bases may also be used. Optionally, the process may be terminated by the addition of hydrochloric acid to provide S6a-HCl.

[0044] Alternatively, as in Step B of Scheme Three, the ester, S6b, or acceptable salt thereof may be converted to S6a or acceptable salt thereof, by treatment with an acid, such as hydrogen chloride delivered as a solution in organic solvent, water, or as a gas, in the presence of solvent, such as an alcohol, tetrahydrofuran (“THF”), toluene, or water. In general, from about 1 mole to about 25 moles of acid per mole of S6b may be used; preferably, from about 1 mole to about 10 moles of acid per mole of S6b may be used. In another aspect, aqueous solutions of various salts, including but not limited to sodium chloride, may be added to improve recovery of the S6a salts, such as S6a-HCl.

[0045] The reaction of Step B in Scheme Three may be conducted at temperatures from about ambient to about 100 °C, or from about 70 °C to about 100 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0046] Any neutral form of ester S6b may be converted to the hydrochloride or other acceptable salt thereof. In general, from about 1.0 moles to about 3 moles of hydrogen chloride or other acid per mole of S6b may be used; preferably, from about 1.2 moles to about 2.5 moles of hydrogen chloride per mole of S6b may be used. The neutral form of SI may be converted to the hydrochloride or other acceptable salt thereof. In general, from about 1.0 moles to about 3 moles of hydrogen chloride or other acid per mole of SI may be used; preferably, from about 1.2 moles to about 2.5 moles of hydrogen chloride per mole of SI may be used. This transformation may be conducted at temperatures from about -10 °C to about 35 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0047] Scheme Four

[0048] The reaction sequence of Scheme Four provides the preparation of l-(chloromethyl)-4-(difluoromethoxy)benzene (S10).

[0049] The reaction of Step A in Scheme Four, whereby 4-hydroxybenzaldehyde (S7) is transformed into 4-(difluoromethoxy)benzaldehyde (S8, not shown), may be conducted in the presence of abase, an alkylating agent, and a solvent. Examples of bases are sodium hydroxide (“NaOH”), potassium hydroxide (“KOH”), potassium carbonate (“K2CO3”), potassium phosphate (“K3PO4”), and sodium carbonate (“Na2CO3”). In general, from about 1.5 moles to about 10 moles of base per mole of S7 may be used; preferably, from about 2 moles to about 5 moles of base per mole of S7 may be used. Mixtures of bases may also be used.

[0050] The reaction of Step A in Scheme Four is conducted in the presence of an alkylating agent. Examples of alkylating agents include but are not limited to derivatives of ethyl bromodifluoroacetate, sodium chlorodifluoroacetate, fluoroform, diethyl (bromodifluoromethyl)phosphonate and chlorodifluoromethane (also known as Freon-22). In general, from about 1 mole to about 5 moles of alkylating agent per mole of S7 may be used; preferably, from about 1.2 moles to about 3 moles of base per mole of S7 may be used.

[0051] The reaction of Step A in Scheme Four is conducted in the presence of a solvent. Examples of solvents are toluene (“PhCHs”), N, A-di methyl form am ide (“DMF”), water, ethanol (“EtOH”), isopropanol (“z-PrOH”), / -butanol (“ / -BuOH”), / -amyl alcohol (“TAA”), tetrahydrofuran (“THF”), dichloromethane ("DCM”), and acetonitrile (“ACN”). Optionally, mixtures of solvents may be used and are preferred.

[0052] The reaction of Step A in Scheme Four may be conducted at temperatures from about -5 °C to about 65 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0053] The reaction of Step B in Scheme Four is conducted in the presence of a reducing agent and a solvent and affords 4-(difluoromethoxy)phenyl)methanol (S9, not shown). Examplesof reducing agents are sodium borohydride, lithium borohydride, and hydrogen gas in the presence of a transition metal catalyst such as nickel, palladium, platinum or rhodium. In general, from about 1 mole to about 5 moles of reducing agent equivalent per mole of 4-(difluoromethoxy)benzaldehyde (S8) may be used; preferably, from about 1.1 moles to about 4 moles of reducing agent equivalent per mole of S8 may be used. Alternatively, the aldehyde may be reduced via reaction with a surrogate aldehyde, such as formaldehyde.

[0054] The reaction of Step B in Scheme Four is conducted in the presence of a solvent. Examples of solvents are acetonitrile (“ACN”), isopropanol (“z-PrOH”), / -butanol (“ / -BuOH”), t-amyl alcohol (“TAA”), methanol (“MeOH”), ethanol (“EtOH”), aqueous sodium hydroxide, and tetrahydrofuran (“THF”). Optionally, mixtures of solvents may be used.

[0055] The reaction of Step B in Scheme Four may be conducted at temperatures from about -5 °C to about 35 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0056] Alternatively, Steps A and B may be done in reverse order.

[0057] The reaction of Step C in Scheme Four is conducted in the presence of a chlorinating agent and a solvent and affords l-(chloromethyl)-4-(difluoromethoxy)benzene (S10). Examples of chlorinating agents are phosgene, diphosgene, triphosgene, hydrogen chloride, thionyl chloride, phosphorus oxychloride, oxalyl dichloride, phosphorus trichloride, and phosphorus pentachloride. In general, from about 1 mole to about 3 moles of chlorinating agent equivalent per mole of 4-(difluoromethoxy)phenyl)methanol (S9) may be used; preferably, from about 1.0 moles to about 2 moles of chlorinating agent equivalent per mole of S9 may be used.

[0058] The reaction of Step C in Scheme Four is conducted in the presence of a solvent. Examples of solvents are toluene (“PhCHf’), di chloromethane ("DCM”), 1,2-di chloroethane ("DCE”), chloroform (“CHCh”), and chlorobenzene (“PhCl”). Optionally, mixtures of solvents may be used.

[0059] The reaction of Step C in Scheme Four may be conducted at temperatures from about -5 °C to about 35 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0060] In one aspect, purification of one or more of S8, S9 or S10 may be accomplished by melt crystallization. See, for example, melt crystallization processes described in Melt Crystallization: Fundamentals, Equipment and Applications, Ulrich, J., Glade, H., Eds.; Shaker: Aachen, 2003.S1 or salt thereof

[0062] The reaction of Scheme Five A is conducted in the presence of a base, a solvent, and optionally a phase-transfer catalyst. Examples of bases are organic bases and inorganic bases. Examples of bases are sodium methoxide (“NaOCFE”), sodium ethoxide (“NaOCEECEE”), N, N-diisopropylethylamine (“DIPEA”), triethylamine (“EtsN”), potassium carbonate (“K2CO3”), cesium carbonate (“CS2CO3”), sodium carbonate (“Na2CO3”), sodium hydroxide (“NaOH”), and sodium bicarbonate (“NaHCCE”) or mixtures thereof. The preferred base includes potassium carbonate. In general, from about 1.0 moles to about 5 moles of base per mole of S6a may be used; preferably, from about 1.5 moles to about 3 moles of base per mole of S6a may be used. One skilled in the art would recognize that more equivalents of base may be necessary if a salt form of S6b is used.

[0063] The reaction of Scheme Five A is conducted in the presence of a polar solvent.Examples of polar solvents are water, ethyl acetate (“EtOAc”), acetone, acetonitrile (“ACN”), methyl ethyl ketone (“MEK”), A, A-dimethylformamide (“DMF”), dimethyl sulfoxide (“DMSO”), isobutyl acetate (“z-BuOAc”), and tetrahydrofuran (“THF”). The preferred solvent includes ethyl acetate.

[0064] The reaction of Scheme Five A is conducted in the presence of an optional phasetransfer catalyst. Examples of phase-transfer catalysts are tetramethyl ammonium bromide (“TMAB”), tetraethylammonium bromide (“TEAB”), tetrapropylammonium bromide (“TP AB”), tetrabutylammonium bromide (“TBAB”), and benzyl triethylammonium chloride (“BTEAC”). Preferred phase-transfer catalysts include tetramethylammonium bromide (“TMAB”), tetraethylammonium bromide(“TEAB”), tetrapropylammonium bromide (“TP AB”), tetrabutylammonium bromide (“TBAB”), and benzyl triethylammonium chloride (“BTEAC”). The preferred phase-transfer catalyst includes benzyl tri ethyl ammonium chloride (“BTEAC”). In general, from about 0.01 mole to about 0.5 mole of phase-transfer catalyst per mole of S6a may be used; preferably, from about 0.05 mole to about 0.15 mole of phase-transfer catalyst per mole of S6a may be used.

[0065] The reaction of Scheme Five A may be conducted at temperatures from about 30 °C to about 70 °C, and ambient pressures from about 95 kilopascals (kPa) to about 105 kPa (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0066] Scheme Five BS1 or salt thereof

[0067] The reaction of Scheme Five B shows a process for the preparation of SI or an acceptable salt thereof via an activated carboxylic acid S6a-A or an acceptable salt thereof. An activated carboxylic acid S6a-A or an acceptable salt thereof, wherein A is an activating group,may be an acid halide, such as S6c, a mixed anhydride, or an acyl carbonate. Treatment of the activated carboxylic acid S6a-A or an acceptable salt thereof with S9 affords SI or an acceptable salt thereof.

[0068] In one preferred aspect, the activated carboxylic acid is an acid halide. The conversion of a carboxylic acid S6a or an acceptable salt thereof to an activated carboxylic acid S6a-A or an acceptable salt thereof shown in Scheme Five B is conducted in the presence of a carboxylic acid activator, an optional base, and a solvent. For an acid halide, such as S6c or an acceptable salt thereof wherein A is Cl, examples of a carboxylic acid activator are thionyl chloride, phosphorus pentachloride, and oxalyl dichloride. A preferred carboxylic acid activator is thionyl chloride. Examples of an optional base are triethylamine (“EtsN”), N, N-diisopropylethylamine (“DIPEA”), pyridine, sodium carbonate (“Na2CO3”), potassium carbonate (“K2CO3”), and sodium bicarbonate (“NaHCCh”). Preferred optional bases are sodium carbonate and potassium carbonate. In one preferred aspect, no base is used. Examples of solvents are toluene (“PhCHs”), ethyl acetate (“EtOAc”), dichloromethane (“DCM”), and tetrahydrofuran (“THF”). Preferred solvents are tetrahydrofuran and dichloromethane.

[0069] Scheme Five CS6b or salt thereof

[0070] The reaction of Scheme Five C shows a process for the preparation of S6b or an acceptable salt thereof via an activated carboxylic acid S6a-A or an acceptable salt thereof. Anactivated carboxylic acid S6a-A or an acceptable salt thereof, wherein A is an activating group, may be an acid halide, a mixed anhydride, or an acyl carbonate. Treatment of the activated carboxylic acid S6a-A or S6c or acceptable salts thereof with an alcohol such as R3OH, wherein R3 is Ci-Cs alkyl, affords S6b or an acceptable salt thereof.

[0071] In one preferred aspect, the activated carboxylic acid is an acid halide. The conversion of a carboxylic acid S6a or an acceptable salt thereof to an activated carboxylic acid S6a-A or an acceptable salt thereof is conducted in the presence of a carboxylic acid activator, an optional base, and a solvent. For an acid halide such as S6a-A (e g., S6c) or an acceptable salt thereof wherein A is Cl, examples of a carboxylic acid activator are thionyl chloride, phosphorus pentachloride, and oxalyl dichloride. A preferred carboxylic acid activator is thionyl chloride. Examples of an optional base are tri ethylamine (“EtsN”), N,N-diisopropylethylamine (“DIPEA”), pyridine, sodium carbonate (“NazCO. '), potassium carbonate (“K2CO3”), and sodium bicarbonate (“NaHCCh”). Preferred optional bases are sodium carbonate and potassium carbonate. In one preferred aspect, no base is used. Examples of solvents are toluene (“PhCHa”), ethyl acetate (“EtOAc”), dichloromethane (“DCM”), and tetrahydrofuran (“THF”). Preferred solvents are tetrahydrofuran and dichloromethane.

[0072] Scheme SixS1 or salt thereof

[0073] The reaction of Scheme Six is conducted in the presence of a catalyst and a solvent. Examples of Lewis acid catalysts are dibutyltin oxide, dibutyltin laurate, dibutyltin acetate, titanium isopropoxide, aluminum isopropoxide, and zirconium isopropoxide. Examples of basecatalysts are sodium methoxide (“NaOCHa”), potassium methoxide (“KOCH3”), sodium ethoxide (“NaOCH2CH3”), sodium pentoxide (“NaOCH2CH2CH2CH2CH3”), potassium tert-butoxide (“KOt-Bu”), potassium / <? / 7-amylate (“KO- / -Am”), sodium / c / 7-butoxide (“NaO / -Bu”), sodium hydroxide (“NaOH”), potassium hydroxide (“KOH”), and sodium hydride (“NaH”). Mixtures of catalysts may also be used. Preferred catalysts include dibutyltin oxide, dibutyltin laurate, dibutyltin acetate, and sodium hydride. In general, for base catalysts, if the ester hydrochloride salt is used, from about 1 mole to about 3 moles of catalyst per mole of S6b ester hydrochloride salt (S6b-HCI) may be used; preferably, from about 1.0 moles to about 2.5 moles of catalyst per mole of S6b ester hydrochloride salt (S6b-HCl) may be used. In general, if the neutral form of the ester is used, from about 0.01 mole to about 0.3 mole of catalyst per mole of S6b neutral form may be used; preferably, from about 0.05 moles to about 0.2 moles of catalyst per mole of S6b neutral form may be used. In general, for Lewis acid catalysts, from about 0.05 mole to about 0.5 mole of catalyst per mole of S6b (neutral form) or S6b ester hydrochloride salt (S6b-HCl) may be used; preferably, from about 0.1 mole to about 0.3 mole of catalyst per mole of S6b (neutral form) or S6b ester hydrochloride salt (S6b-HCl) may be used.

[0074] The reaction of Scheme Six is conducted in the presence of a solvent. Examples of solvents are 1,4-di oxane, tetrahydrofuran (“THF”), 2-methyltetrahydrofuran (“2-MeTHF”), dibutyl ether, acetonitrile (“ACN”), cyclopentyl methyl ether (“CPME”), anisole, diphenyl ether, cyclohexane, xylenes, mesitylene, 1,2-dichlorethane (“DCE”), trifluorotoluene, toluene, chlorobenzene, dichlorobenzene, benzonitrile. Optionally, mixtures of solvents may be used. The preferred solvent includes xylenes.

[0075] The reaction of Scheme Six may be conducted at temperatures from about 25 °C to about 120 °C, preferably from about 40 °C to about 100 °C, and from about 1 kilopascal (kPa) to about 200 kPa or from about 1 kPa to about ambient pressure (usually about 101 kPa). However, higher and lower temperatures and pressures may be used.

[0076] A solution containing SI may be converted to the hydrochloride salt S1-HC1 by the addition of hydrogen chloride as a gas or as a solution in organic solvent or water.

[0077] A solution containing S1-HC1 or other acceptable salt may be converted to the neutral form of SI by addition of a solution of sodium hydroxide or other acceptable base.

[0078] A solution containing the neutral form of SI may be crystallized into a solid form of SI by the use of an appropriate solvent and anti-solvent, by employing a seed material as needed, and by modifying the temperature of the mixture. Examples of solvents include dichloromethane (“DCM”), isobutyl acetate, isopropyl acetate, isopropanol, ethyl acetate, methyl / c / 7-butyl ether (“MTBE”), toluene, and dibutyl ether. Examples of anti-solvents include cyclohexane, heptane, Isopar-C®, petroleum ether, and water. Examples of solvent-anti -solvent mixtures include ethereal solvent-hydrocarbon solvent mixtures. Examples of such mixtures are dibutyl ether-w-heptane and methyl tert-butyl ether (“MTBE”)-w-heptane. Examples of seed material may be the particles of previously crystallized SI, further processed as needed. The crystallization may be conducted at temperatures from about 60 °C to about -20 °C. One skilled in the art would recognize that this crystallization method may provide increased yield and / or purity or may avoid oiling of the product.

[0079] A solution containing the acceptable salt form of SI (e.g., S1-HC1) may be crystallized into a solid form of S1-HC1 by the use of an appropriate solvent, containing an appropriate moisture content, and optionally, an anti-solvent, by employing a seed material as needed, and by modifying the temperature of the mixture. Examples of solvents include isobutyl acetate, isopropyl acetate, isopropanol, and ethyl acetate. Examples of anti-solvents include cyclohexane, heptane, Isopar-C®, and petroleum ether. Examples of seed material may be the particles of previously crystallized S1-HC1, further processed as needed. The crystallization may be conducted at temperatures from about 60 °C to about -20 °C.

[0080] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0081] JH NMR spectral data are in ppm (5) and were recorded at 400 and 500 MHz;13C NMR spectral data are in ppm (5) and were recorded at 101 and 126 MHz; and19F NMR spectral data are in ppm (8) and were recorded at 376 and 471 MHz, unless otherwise stated.

[0082] In the examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.equiv = equivalentmg = milligramsg = gramkg = kilogramwt % = weight percenth = hoursmin = minutessec = secondsRT = room temperaturerpm = revolutions per minuteHC1 = hydrochloric acidHPLC = high-performance liquid chromatography UPLC = ultra-performance liquid chromatography kPa = kilopascalsLCMS = liquid chromatography mass spectrometry M = molarN = normalmmol = millimolespM = micromolarmL = milliliterL = litersvol = volumes (mL / g)EtOAc = ethyl acetateDCM = dichloromethaneTHF = tetrahydrofuranMeOH = methanolEtOH = ethanol / -PrOH= isopropanolMTBE = methyl Zt77-butyl etheraq = aqueousEXAMPLE 1

[0083] Synthesis of 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2)

[0084] Preparation 1, Step A: Synthesis of methyl (2,5-dimethylphenyl)carbamate (S4)

[0085] To a solution of 2, 5 -dimethylaniline (S3, 12.1 g, 100 mmol) in DCM (64.3 mL, 1000 mmol) was added pyridine (9.71 mL, 120 mmol). The mixture was cooled to 0 °C, and methyl chloroformate (8.91 mL, 115 mmol) was added dropwise over 30 min, maintaining an internal temperature below 10 °C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Upon reaction completion as measured by UPLC, water (100 mL) was added to the mixture, and the organic and aqueous layers were separated. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic extracts were dried by being passed through a phase separator and concentrated under vacuum to obtain methyl (2,5-dimethylphenyl)carbamate (S4, 17.3 g, 96% yield): ¹H NMR (400 MHz, DMSO-d₆) 58.77 (s, 1H), 7.15 (s, 1H), 7.05 (d, J= 7.7 Hz, 1H), 6.90 - 6.83 (m, 1H), 3.63 (s, 3H), 2.23 (s, 3H), 2.13 (s, 3H);13C NMR (126 MHz, DMSO-d₆) 5 155.30, 136.62, 135.50, 130.54, 128.86, 125.91, 125.56, 52.04, 21.05, 17.77; MS (ESI) m / z calcd for C10H13NO2[M+H]+180, found 180.

[0086] Preparation 1, Step B: Synthesis of 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2)

[0087] To a solution of methyl (2,5-dimethylphenyl)carbamate (S4, 5.38 g, 30 mmol) in DCM (38.6 mL, 600 mmol) cooled to 0 °C was added aluminum trichloride (10.0 g, 75 mmol). A solution of oxalyl dichloride (6.56 mL, 75 mmol) in DCM (19.3 mL, 300 mmol) was added over 30 min at 0 °C. The mixture was stirred at 0 °C with routine monitoring by UPLC. Upon reaction completion, the mixture was poured into water and the phases were separated. The aqueous layer was extracted with DCM (20 mL), and the combined organic extracts were dried over magnesium sulfate, fdtered, and concentrated under vacuum to provide 4-((methoxycarbonyl)amino)-2, 5-dimethylbenzoic acid (S2, 4.55 g, 66.6% yield): ¹H NMR (500 MHz, DMSO-d₆) 88.98 (s, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 3.68 (s, 3H), 2.47 (s, 3H), 2.21 (s, 3H);13C NMR (126 MHz, DMSO-d₆, 8 168.62, 154.93, 140.12, 137.95, 133.17, 127.78, 126.07, 125.98, 52.27, 21.69, 17.68; MS (ESI) m / z calcd for C11H13NO4[M+H]+224, found 224.EXAMPLE 2

[0088] Synthesis of 4-amino-2, 5-dimethylbenzoic acid (S5)S2 S5

[0089] Preparation 1: To a solution of 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2, 1.07 g, 4.79 mmol) in THF (12 mL) and MeOH (12 mL) was added sodium hydroxide (1 M, 9.6 mL, 9.6 mmol) to give a colorless solution. The flask was fitted with a condenser, and the mixture was heated to 60 °C for 48 h. Upon reaction completion, the solution was brought to pH 5 using 1 M HCl (~5.5 mL), and the reaction mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under vacuum to provide 4-amino-2, 5-dimethylbenzoic acid (S5, 0.73 g, 92% yield): ’H NMR (500 MHz, DMSO-Je) 87.55 (s, 1H), 6.43 (s, 1H), 5.47 (s, 2H), 2.40 (s, 3H), 2.03 (s, 3H);13C NMR (126 MHz, DMSO-d₆) 8 168.83, 150.80, 139.76, 134.03, 117.94, 116.55, 116.35, 22.33, 17.28; MS (ESI) m / z calcd for C9H11NO2+[M+H]+166, found 166.

[0090] Preparation 2, Step A: Synthesis of methyl (2,5-dimethylphenyl)carbamate (S4)

[0091] A solution of DCM (318 mL) and 2, 5 -dimethylaniline (S3, 100 g, 0.83 mol) in a three-neck round bottom flask with mechanical stirrer, base scrubber, temperature probe, and nitrogen inlet at ambient temperature was stirred for 10 min. Anhydrous pyridine (78 g, 0.99 mol) was added over 10-15 min before the reaction mixture was cooled to 0-5 °C. Methyl chloroformate (89.7 g, 0.95 mol) was added dropwise maintaining the internal temperature below 5 °C. The temperature was raised to 25-30 °C, and the mixture was stirred for 2-3 h withprogress monitored by HPLC. After complete conversion, the reaction mixture was cooled to 0-5 °C. DCM (200 mL) was added to the reaction mixture, and the mixture was stirred for 5-10 min. HCl (2 M, 454 mL) was added at 0–5 °C, and the reaction mixture was stirred for 30 min. The layers were separated, and the organic layer was transferred to a round bottom flask and partially concentrated at 45 °C under atmospheric pressure. The water content was checked (<0.2 wt %) before isolating the resulting material in DCM to afford methyl (2,5-dimethylphenyl)carbamate (S4, -471 g solution) which was taken directly into the next step.

[0092] Preparation 2, Step B: Synthesis of 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2)

[0093] A solution of aluminum trichloride (253 g, 1.90 mol) in DCM (532 mL) in a three-neck round bottom flask equipped with mechanical stirrer, base scrubber, temperature probe, and nitrogen inlet, at ambient temperature was stirred. The reaction mixture was cooled to 0-5 °C before oxalyl dichloride (136 g, 1.07 mol) was added slowly at 0-5 °C over 20-30 min. The reaction mixture was stirred for an additional 15-20 min. The reaction mixture was further cooled to -5 to 0 °C. Methyl (2,5-dimethylphenyl)carbamate in DCM (S4 in DCM, 466 g solution, -148 g of S4, 0.825 mol) was added at -5 to 5 °C over 90 min. The reaction mixture was stirred at 0-5 °C for 1-3 h with progress monitored by HPLC. A solution of HCl (2 M, 1480 mL) was added to a separate round bottom flask and was cooled to 0-5 °C. The above reaction mixture was added to the 2 M HC1 solution over the course of 3-4 h while maintaining an internal temperature of 0-5 °C. After complete addition, the reaction mixture was stirred for 1 h at 0-5 °C. The reaction mixture was heated to 30-35 °C, and the solvent was distilled under vacuum (95-45 kPa / 950-450 mbar). The resulting solid was filtered, and the wet cake was washed twice with water (2 x 300 mL). 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2, -286 g) was isolated as a wet cake which was taken directly into the next step without further purification.

[0094] Preparation 2, Step C: Synthesis of 4-amino-2,5-dimethylbenzoic acid (S3)

[0095] A solution of 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2, 222 g damp, assumed 184 g dry weight, 0.825 mol) in water (921 mL) was added to a jacketed reactor with temperature probe and base scrubber, and the mixture was stirred for 10 min at ambienttemperature. Aqueous sodium hydroxide solution (132 g NaOH in 829 mL water, 3.30 mol) was added over 30-45 min at ambient temperature. The reaction mixture was heated to 60-65 °C and was stirred for 3-5 h with reaction progress monitored by HPLC. After complete conversion, the reaction mixture was cooled to 0-5 °C and was stirred for 15-30 min. The pH was adjusted to 5-6 using HCl (330 mL concentrated HCl diluted in 330 mL water). The reaction mixture was warmed to 25-30 °C and stirred for 2-3 h. The resulting solids were filtered, and the wet cake was washed with water (368 mL) before drying further for 30 min. The solids were dried in a vacuum tray dryer at 65-70 °C with 1 kPa (10 mbar) vacuum for 8-12 h before checking water content (<0.5 wt %) to afford 4-amino-2,5-dimethylbenzoic acid (S5, 108 g, 75% yield over three steps) as an off-white solid. Analytical data matched those above.EXAMPLE 3

[0096] Synthesis of N-methylethanamine (S13)1. Step APh O → HN CH₃2. Step BS11 S13

[0097] Preparation 1, Step A: Synthesis of N-methyl-1-phenylmethanimine (S12a)

[0098] A round-bottom flask with a stir bar was charged with benzaldehyde (Sil, 53.1 g, 500 mmol). The flask was placed in an ice bath and cooled to 5-10 °C. Methylamine (aqueous, 40 wt %, 38.8 g, 525 mmol) was added slowly through an addition funnel, and the temperature of the reaction mixture was maintained below 20 °C. The reaction mixture was warmed to ambient temperature and was stirred for another 3 h. The reaction mixture was partitioned, and the organic layer was collected. Toluene (50 mL) was added to the organic layer, and the mixture was concentrated under vacuum to azeotrope water. Once the mixture was concentrated, this procedure was repeated. Additional toluene (20 mL) was added, and the mixture was concentrated under vacuum.. V-Methyl-I -phenylmethanimine (S12a) was isolated as a colorless oil (59.6 g, 85% yield):1H NMR (500 MHz, CDCl3) δ 8.28 (t, J = 1.7 Hz, 1H), 7.70 (dd, J = 6.7, 3.0 Hz, 2H), 7.40 (p, J = 3.4 Hz, 3H), 3.51 (d, J = 1.7 Hz, 3H);13C NMR (126 MHz, CDCl3) δ162.48, 136.25, 130.51, 128.60, 127.87, 48.23; MS (EI) calcd for C8H9N+[M]+119.1; found 118.1.

[0099] Preparation 1, StepB: Synthesis of N-methylethanamine (S13)

[0100] A round-bottom flask with a stir bar was charged with A-methyl-1 -phenylmethanimine (S12a, 85 wt %, 14.0 g, 100 mmol). Diethyl sulfate (15.4 g, 100 mmol) was added via syringe over 2 min. The reaction mixture was heated to 60 °C and was stirred for 5 h. The mixture was cooled to ambient temperature, water (10 g) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was partitioned, and the aqueous layer was extracted with toluene (2 x 5 mL). The resulting aqueous mixture was transferred to a roundbottom flask, and the mixture was cooled to 5-10 °C in an ice bath. To this mixture was added sodium hydroxide solution (aqueous, 50 wt %, 20 g) slowly over 5 min, and the internal temperature was maintained below 20 °C. Short-path distillation and condensation with ice water provided A-methylethanamine (S13) as a colorless oil (3.91 g, 66% yield):1H NMR (500 MHz, CDCl3) δ 2.62 (qd, J = 7.1, 0.7 Hz, 2H), 2.44 (d, J = 0.7 Hz, 3H), 1.10 (td, J = 7.2, 0.7 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 46.29, 36.37, 15.17; bp 30-33 °C; MS (EI) m / z calcd for C3H9N+[M]+59.1, found 59.1.

[0101] Preparation 2, Step A: Synthesis of N-ethy l-l -phenylmethanimine (S12b)

[0102] A round-bottom flask with a stir bar was charged with benzaldehyde (53.1 g, 500 mmol). The flask was placed in an ice bath and cooled to 5-10 °C. Ethylamine (69 wt % aq, 34.3 g, 525 mmol) was added through an addition funnel over 20 min, and the temperature of the reaction mixture was maintained below 20 °C. After complete addition, the reaction mixture was warmed to ambient temperature and was stirred for another 3 h. The reaction mixture was partitioned, the aqueous layer was removed, and the organic layer was collected. Toluene (20 mL) was added to the organic layer, and the mixture was concentrated under vacuum. Once the mixture was concentrated, this was repeated. Additional toluene (20 mL) was added, and the mixture was concentrated under vacuum. After concentrating, A-ethyl-1 -phenylmethanimine (S12b) was isolated as a colorless oil (71.5 g, 96% yield):1H NMR (500 MHz, CDCl3) δ 8.30 (t, J = 1.4 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.45 – 7.36 (m, 3H), 3.65 (qd, J = 7.3, 1.4 Hz, 2H), 1.31 (t,J = 7.3 Hz, 3H);13C NMR (126 MHz, CDCh) 5 160.46, 136.35, 130.47, 128.58, 127.99, 55.89, 16.31; MS (EI) calcd for C9H11N+[M]+133.1; found 132.1.

[0103] Preparation 2, Step B: Synthesis of N-methylethanamine (S13)

[0104] A round-bottom flask with a stir bar was charged with A-ethyl-l-phenylmethanimine (S12b, 89 wt %, 15.0 g, 100 mmol). Dimethyl sulfate (12.6 g, 100 mmol) was added via a syringe over 2 min. After complete addition, the reaction mixture was heated to 40 °C and was stirred for 3 h. The mixture was then cooled to ambient temperature, water (10 g) was added, and the reaction mixture was stirred for 30 min. The reaction mixture was partitioned, and the organic layer was removed. The aqueous layer was mixed with toluene (5 mL), and the resulting organic layer was removed. Additional toluene (5 mL) was added to extract the aqueous layer, and the organic layer was removed. The resulting mixture was transferred to a round-bottom flask placed in ice bath and cooled to 5-10 °C. To this mixture was added NaOH solution (50 wt % aq, 20 g) slowly over 5 min, and the internal temperature was maintained below 20 °C. After addition, the mixture was distilled via short-path distillation. N-Methylethanamine (S13) was isolated as a colorless oil (4.73 g, 80% yield). Analytical data matched those above.EXAMPLE 4

[0105] Synthesis of N-ethyl-N-methyl formamide (S14)

[0106] Method 1, Preparation 1: A reactor, under inert atmosphere and equipped with an overhead agitator, nitrogen inlet, and temperature probe, was charged with potassium tert-butoxide (12.3 g, 110 mmol) and THF (50 mL). The mixture was stirred at 25 °C. N-Methylformamide (S15, 5.84 mL, 100 mmol) was added to the reaction mixture slowly over 15 min. After complete addition, the mixture was stirred at 25 °C for 15 min. The reaction mixture was heated to 50 °C. Bromoethane (S16, 11.9 mL, 160 mmol) was added slowly over 15 min, maintaining a temperature of 50 °C. After complete addition, the mixture was stirred for an additional 16 h at 50 °C. After >98% conversion was observed by GC, the reaction mixture was cooled to 25 °C. The reactor was drained, the mixture was filtered to remove solids, and thesolids were washed with THF (50 mL). Subsequently, the filtrate was distilled under vacuum (approximately 10 kPa (100 mbar)) and distillation fractions were collected and analyzed.Fractions with product were combined to afford N-ethyl-N-methyl formamide (S14, 6.63 g, 76% yield) as a colorless oil: Observed as a mixture of rotamers:1H NMR (500 MHz, CDCl3) δ 8.07 (s, 0.6H), 8.00 (s, 0.4H), 3.39 (q, J= 7.2, 0.8H), 3.30 (q, J= 7.2 Hz, 1.2H), 2.93 (s, 1.2H), 2.86 (s, 1.8H), 1.20 (t, J = 7.2, 1.1 Hz, 1.9H), 1.13 (t, J= 7.2, 1.2 Hz, 1.2H);13C NMR (126 MHz, CDCl3) (mixture of rotamers) δ 162.35, 162.20, 44.26, 38.79, 33.93, 28.92, 14.13, 11.91; MS (EI) m / z calcd for C4H9NO+[M]+87.1, found 87.1.

[0107] Method 1, Preparation 2: In a 500 mL jacketed reactor with a positive nitrogen inlet, tetrabutylammonium bromide (TBABr, 1.29 g, 4.0 mmol) and THF (100 mL) were charged and stirred at 250 rpm. The internal temperature was adjusted to 30 °C before sodium / c / 7-butoxide (21.1 g, 220 mmol) was added in three portions over 1 min. N-Methylformamide (S15, 11.7 mL, 200 mmol) was added via a syringe over 5 min. The mixture was stirred at 30 °C for 15 min before bromoethane (S16, 17.9 mL, 240 mmol) was added using a syringe pump over 20 min. The resulting mixture was stirred overnight at 30 °C. The reaction mixture was drained and filtered into a round-bottom flask under vacuum. Additional THF (100 mL) was used to wash the reactor and the filter cake. The filtrate was sampled providing an assay yield of S14 product as 96%.

[0108] Method 2, Preparation 1: To a 1 L reactor, N-methylformamide (S15, 23.4 mL, 400 mmol) and toluene (400 mL) were added at ambient temperature. The reaction mixture was heated to 50 °C with stirring at 500 rpm. Sodium te / 7-butoxide (42.3 g, 440 mmol) was added. Diethyl sulfate (S17, 52.4 mL, 400 mmol) was then added over the course of 1 h. The reaction temperature was maintained at 50 °C and stirred overnight. The reaction mixture was filtered under vacuum. The filter cake was washed twice with toluene (2 x 100 mL), and an aliquot from the combined filtrate was analyzed by GC with an assay yield of 85%. Subsequently, the postfiltration mixture was transferred to a round-bottom flask for distillation. Fractions containingproduct were combined to afford N-ethyl-N-methylformamide (S14, 22.5 g, 65% yield) as a colorless oil. Analytical data matched those above.

[0109] Method 2, Preparation 2: A 50 mL three-neck round-bottom flask with a condenser and under nitrogen was charged with / -butanol ( / -BuOH, 10 mL). Sodium metal (138 mg, 6.0 mmol) was added to the flask. The reaction mixture was heated to 80 °C and stirred for 5 h, and the reaction mixture became a white slurry. The reaction mixture was cooled to 30 °C before N-methylformamide (S15, 290 μL, 5.0 mmol) was added dropwise over 1 min. The mixture was stirred for 15 min before diethyl sulfate (S17, 980 μL, 7.5 mmol) was added dropwise over 1 min. The reaction mixture was stirred at 30 °C overnight. The reaction mixture was filtered through a fritted funnel into a round-bottom flask under vacuum. The filter cake was washed with additional / -BuOH (5 mL). The filtrate was sampled and analyzed to provide an assay yield of 87%.

[0110] Method 2, Preparation 3: A 500 mL jacketed reactor with a positive nitrogen inlet was charged with benzyltriethylammonium chloride (BTEAC, 13.0 g, 60.0 mmol) and / -butanol ( / -BuOH, 300 mL). The agitation rate was set as 400 rpm. The chiller’s temperature was adjusted to 15 °C before potassium hydroxide (67.3 g, 1.20 mol) was added in one portion. N-Methylformamide (35.1 mL, 600 mmol) was added via a syringe over 5 min. Diethyl sulfate (94.3 mL, 720 mmol) was dosed using a syringe pump over 2 h. During the dose, an exotherm was observed, and the internal temperature fluctuated between 17 to 25 °C. After the dose, the chiller’s temperature was raised to 25 °C, and the reaction mixture was agitated for another 2 h. The reaction mixture was drained and filtered into a round-bottom flask under vacuum.Additional / -BuOH (200 mL) was used to wash the reactor and the filter cake. The filtrate was sampled and analyzed by GC with DMF as the internal standard. The assay yield of product was determined as 78%, with 2% A-methylformamide remaining.

[0111] Method 3, Preparation 1: A round-bottom flask with a stir bar was charged with N-methylethanamine (S13, 2.96 g, 50.0 mmol). The flask was placed in an ice bath and cooled to<10 °C. Ethyl formate (S18, 3.89 g, 52.5 mmol) was slowly added via an addition funnel over 20 min, while carefully maintaining the temperature below 20 °C. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was concentrated under vacuum at 35 °C to remove ethanol. Once the mixture was concentrated, additional heptane (10 mL) was added and distilled until the heptane concentration was <5%. After concentrating, the desired product, A-ethyl-A-methyl formamide (S14), was isolated as a paleyellow oil (3.34 g, 77% yield). Analytical data matched those above.

[0112] Method 3, Preparation 2: A 10 mL microwave reactor vial was charged with formic acid (S19, 1.84 g, 1.0 equiv, 40 mmol). The reactor vial was cooled in an ice bath before addition of N-ethylmethylamine (S13, 2.36 g, 1.0 equiv, 40 mmol) slowly over 5 min. The reactor vial was then sealed and heated at 110 °C for 24 h in a microwave reactor. After 24 h, the reactor vial was cooled and opened, yielding a colorless liquid with a 93% assay yield of S14.

[0113] Method 4, Preparation 1: To a solution of N-methylformamide (S15, 2.95 mL, 50 mmol) in THF (41.0 mL, 500 mmol) was added sodium / c / 7-butoxide (5.29 g, 55.0 mmol). The mixture was stirred for 30 min. Iodoethane (S20, 4.44 mL, 55.0 mmol) was added dropwise, and the reaction mixture was heated to 50 °C overnight. The mixture was cooled to ambient temperature, and water (25 mL) was added dropwise. Methyl ter -butyl ether (MTBE, 50 mL) was added, and the layers were separated. The aqueous layer was thrice extracted with MTBE. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum (30 °C, 26.6 kPa (200 torr)) then at 40 °C, 1.3 kPa (10 torr)) to provide N-ethyl-N-methylformamide (S14, 1.95 g, 44.8% yield) as an orange / red oil. Analytical data matched those above.EXAMPLE 5

[0114] Synthesis of 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl)S5 S6a-HCI

[0115] A 50 mL three-neck round-bottomed flask under inert atmosphere equipped with temperature probe, nitrogen inlet, and scrubber was charged with N-ethyl-N-methylformamide (S14, 970 mg, 90 wt %, 10 mmol) and anhydrous DCM (10 mL). The mixture was cooled to 0 °C, and oxalyl dichloride (1.27 g, 880 pL, 10 mmol) was added dropwise over 5 min. The solution was stirred at ambient temperature for 30 min and was used directly in the next step without any further purification. In a separate 100 mL round-bottomed flask, 4-amino-2,5-dimethylbenzoic acid (S5, 830 mg, 5 mmol) was combined with anhydrous DCM (10 mL). At ambient temperature, the solution of Vilsmeier reagent (also known herein as reagent V) created by the combination of formamide and oxalyl dichloride (from above) was added dropwise to the benzoic acid solution. The reaction mixture became cloudy and was stirred at ambient temperature. Full conversion was observed after 15 min, at which time water (450 mg, 450 pL, 25 mmol) was added. Solids precipitated, and after stirring for 15 min, the suspension was concentrated under vacuum to remove DCM. Acetone (20 mL) was added, and the mixture was heated to near reflux (55 °C) and hot filtered to provide solids that after drying in a vacuum oven afforded the title compound (S6a-HCl, 1.16 g, 86% yield) as a white solid:1H NMR (500 MHz, DMSO-d6, mixture of rotamers) 8 12.95 (s, 1H), 11.69- 11.16 (m, 1H), 8.57 - 8.34 (m, 1H), 7.75 (s, 1H), 7.39 - 7.30 (m, 1H), 3.82 (q, J= 7.1 Hz, 1H), 3.66 (q, J= 7.1 Hz, 1H), 3.37 - 3.29 (m, 3H), 3.32 (d, J= 10.7 Hz, 3H), 2.51 (s, 3H), 2.38 (s, 3H), 1.26 (dt, J= 13.1, 7.1 Hz, 3H);13C NMR (126 MHz, DMSO-d6, mixture of rotamers) δ 167.93, 155.25, 155.06, 138.96, 138.05, 132.89, 132.84, 129.93, 129.66, 129.20, 129.12, 127.38, 127.12, 51.09, 44.57, 40.67, 35.06, 20.71, 17.20, 17.17, 13.10, 10.90; MS (ESI) m / z calcd for C13H19N2O2+[M+C1]+235, found 235.EXAMPLE 6

[0116] Synthesis of methyl 4-( ((ethyl(methyl)amino)methylene)amino)-2, 5 -dimethylbenzoate hydrochloride (S6bl-HCl)S5 S6b1-HCI

[0117] A four-neck round bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen tube, and ice bath was charged with N-ethyl-N-methyl formamide (S14, 48.5 g, 0.557 mol) and DCM (400 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mixture was cooled to 0 °C. Oxalyl dichloride (46.1 mL, 0.545 mol) was added to the above reaction mixture over 30 min. The reaction mixture was stirred below 0 °C for 30 min, then was warmed to ambient temperature and was stirred for 1 h. The reaction mixture (Vilsmeier reagent, also known herein as reagent V) was taken to the next part. A separate round bottom flask equipped with a mechanical stirrer, temperature probe, condenser, heating mantle, and nitrogen tube was charged with 4-amino-2,5-dimethylbenzoic acid (S5, 40 g, 0.242 mol) and DCM (400 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mixture was cooled to 18 °C. The Vilsmeier reagent was added to the above reaction mixture via an addition funnel over 1 h while maintaining the temperature below 20 °C. After addition, the reaction mixture was warmed to ambient temperature and stirred for 3 h. After complete conversion by HPLC, the DCM was distilled under reduced pressure to 200 mL while maintaining the reaction mixture temperature below 20 °C. Methanol (232.8 g, 7.26 mol) was added dropwise over 30 min at ambient temperature. The reaction mixture was stirred for 2 h, was heated to 50-55 °C, and was stirred for 14 h. After complete conversion by HPLC, the reaction mixture was concentrated under vacuum at 45 °C. The resulting product was obtained as a brown, thick liquid, which was cooled to 0 °C, and acetone (200 mL) was added. The mixture was stirred at -5 to 0 °C. Solid precipitated gradually, and the mixture appeared as a thick yellowslurry. The mixture was stirred at 0 °C for 1 h and was filtered. The product was washed with cold acetone (160 mL), was suction dried for 20 min, and was further dried at 45 °C under vacuum for 1 h. The title compound (S6bl-HCl, 63.5 g, 92% yield) was isolated as a pale yellow solid:1H NMR (400 MHz, CDCl3, mixture of rotamers) 5 11.91 -11.88 (m, 1H), 9.53 (s, 1H), 8.18 -8.09 (m, 1H), 7.72 - 7.712 (m, 1H), 7.33 - 7.28 (m, 1H), 4.00 - 3.98 (m, 1H), 3.85 (s, 3H), 3.76 - 3.71 (m, 1H), 3.50 (s, 2H), 3.40 (s, 1H), 3.04 (s, 1H), 2.93 - 2.88 (m, 2H), 2.53 - 2.50 (m, 3H), 2.43 -2.42 (m, 3H), 1.37 - 1.35 (m, 6H);13C NMR (101 MHz, CDCl3, mixture of rotamers) 5 167.02, 154.07, 139.38, 138.59, 138.53, 133.57, 133.49, 130.19, 129.99, 128.78, 127.25, 127.15, 52.30, 51.89, 46.22, 44.20, 41.56, 36.75, 32.18, 20.96, 17.90, 13.45, 11.21, 10.96; MS (ESI) m / z calcd for C14H21N2O2+[M+H]+249, found 249.

[0118] Synthesis of isopropyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S6b2-HCl)S5 S6b2-HCI

[0119] A four-neck round bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen tube, and ice bath was charged with N-ethyl-N-methylformamide (S14, 97.0 g, 1.11 mol, 2.3 equiv) and DCM (800 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mass was cooled to 0 °C. Oxalyl dichloride (92.2 mL, 1.09 mol, 2.25 equiv) was charged to the above reaction mass over 30 min. The reaction mixture was stirred below 0 °C for 30 min, then warmed to ambient temperature and stirred for 1 h. The reaction mixture (Vilsmeier reagent, also known herein as reagent V) was taken to the next part. A separate round bottom flask equipped with a mechanical stirrer, temperature probe, condenser, heating mantle, and nitrogen tube was charged with 4-amino-2,5-dimethylbenzoic acid (S5, 80 g, 0.484 mol, 1 equiv) and DCM (800 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mass was cooled to 18 °C. The Vilsmeier reagent was added to the abovereaction mixture through an addition funnel over 1 h while maintaining the temperature below 20 °C. After addition, the reaction mixture was warmed to ambient temperature and stirred for 3 h. After complete conversion by HPLC, the DCM was distilled under reduced pressure to 450 mL while maintaining the reaction mixture temperature below 20 °C. i-PrOH (873.18 g, 14.6 mol, 30 equiv) was charged dropwise over 30 min at ambient temperature. The reaction mixture was stirred at 25-30 °C for 2 h. The reaction mass was heated to 65-70 °C and stirred for 14 h. After complete conversion by HPLC, the reaction mass was fdtered, and the wet cake was washed with z-PrOH (80 mL). The wet cake was suction dried for 30 min and further dried at 45 °C under vacuum for 1 h. The fdtrate was concentrated at 45 °C under vacuum to obtain the resulting product as a brown, thick liquid (270 g), which was dissolved in water (1350 mL). The aqueous layer was washed with MTBE (2 x 540 mL). The aqueous layer was neutralized (pH 7-8) with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 810 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate solution (2 x 540 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated at 45 °C under reduced pressure to obtain the neutral form of the desired product as dark brown liquid. The neutral form (110 g) was dissolved in ethyl acetate (220 mL) at ambient temperature. The mass was cooled to 0 °C and HC1 in ethyl acetate (4 M, 220 mL) was added slowly. The temperature of the mass was gradually raised to ambient temperature. The mass was concentrated at 45 °C under vacuum which was chased with MTBE (2 x 550 mL). MTBE (330 mL) was charged to the mass and stirred for 30 min under the nitrogen atmosphere. The mass was filtered under nitrogen atmosphere and the product was washed with MTBE (110 mL). The product was suction dried for 20 min and further dried at 45 °C under vacuum for 1 h to afford the title compound (S6b2-HC1, 115 g, 38% yield) as an off-white solid: 'H NMR (400 MHz, CDCh, mixture of rotamers) 8 12.44 - 12.36 (m, 1H), 8.14 - 8.05 (m, 1H), 7.66 - 7.65 (d, 1H), 7.26- 7.17 (m, 1H), 5.20 -5.14 (m, 1H), 4.01 - 3.96 (m, 1H), 3.69 - 3.64 (m, 1H), 3.47 (s, 2H), 3.34 (s, 1H), 2.46 (s, 3H), 2.42 - 2.41 (m, 3H), 1.33 (m, 3H), 1.32 - 1.31 (m, 3H);13C NMR (101 MHz, CDCl3, mixture of rotamers) 8 166.37, 166.35, 154.12, 154.01, 138.83, 138.80, 138.51, 138.45, 133.37, 133.30, 130.30, 130.09, 129.76, 127.38, 127.27, 68.43, 52.17, 46.35, 41.42, 36.87, 21.86, 20.96, 18.00, 13.53, 11.28; MS (ESI) m / z calcd for C16H25N2O2+[M+H]+277, found 277.

[0120] Synthesis ofn-propyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S6b3-HCl)S5 S6b3-HCI

[0121] A four-neck round bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen tube, and ice bath was charged with A-ethyl-A-methyl formamide (S14, 84.9 g, 0.975 mol, 2.3 equiv) and DCM (700 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mass was cooled to 0 °C. Oxalyl dichloride (80.7 mL, 0.953 mol, 2.25 equiv) was charged to the above reaction mass over 30 min. The reaction mass was stirred below 0 °C for 30 min. The reaction mass warmed to ambient temperature and stirred for 1 h. The reaction mass (Vilsmeier reagent, also known herein as reagent V) was taken to the next part. A round bottom flask equipped with a mechanical stirrer, temperature probe, condenser, heating mantle, and nitrogen tube was charged with 4-amino-2,5-dimethylbenzoic acid (S5, 70 g, 0.424 mol, 1 equiv) and DCM (700 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mass was cooled to 18 °C. The Vilsmeier reagent was added to the above reaction mass through an addition funnel over 1 h while maintaining the temperature below 20 °C. After addition, the reaction mass was warmed to ambient temperature and stirred for 3 h. After complete conversion, the DCM was distilled under reduced pressure to 400 mL while maintaining the reaction mass temperature below 20 °C. / / -Propanol (764.03 g, 12.7 mol, 30 equiv) was charged dropwise in 30 min at ambient temperature. The reaction mass was stirred at ambient temperature for 2 h. The reaction mass was heated to 65 °C and stirred for 14 h. After complete conversion, the reaction mass was concentrated at 45 °C under vacuum to obtain a brown, thick liquid. The resulting product was cooled to 0 °C and acetone (350 mL) was added. The mass was stirred at -5 to 0°C. The solid precipitated out gradually and appeared as a thick, pale-yellow slurry. The mass was stirred at 0 °C for 1 h and filtered. The product was washedwith cold acetone (280 mL). The product was suction dried for 20 min and further dried at 45 °C under vacuum for 1 h to obtain a crude solid of the desired product. To purify, the solid (265 g) was dissolved in water (1325 mL). The aqueous layer was washed with MTBE (2 x 530 mL). The aqueous layer was neutralized (pH 7-8) with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 795 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate solution (2 x 530 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated at 45 °C under reduced pressure to obtain the neutral form of the desired product. The neutral form (148 g) was dissolved in ethyl acetate (296 mL) at ambient temperature. The mass was cooled to 0 °C and HC1 in ethyl acetate (4 M, 296 mL) was added slowly using an addition funnel. The temperature of the mass was gradually raised to 20-25 °C. The mass was concentrated at 45 °C under vacuum to obtain a white solid which was chased with MTBE (2 x 740 mL). MTBE (444 mL) was charged to the mass and stirred for 30 min under nitrogen atmosphere. The mass was filtered under the nitrogen atmosphere and the product was washed with MTBE (148 mL). The product was suction dried for 20 min and further dried at 45 °C under vacuum for 1 h to afford the title compound (S6b3-HCl, 161.1 g, 60.8% yield) as a white solid: 'H NMR (400 MHz, CDCI3, mixture of rotamers) 8 12.48 - 12.41 (m, 1H), 8.11 — 8.01 (m, 1H), 7.69 - 7.68 (d, 1H), 7.26 - 7.20 (m, 1H), 4.22 - 4.19 (m, 2H), 4.03 - 3.98 (m, 1H), 3.69 - 3.64 (m, 1H), 3.49 (s, 2H), 3.34 (s, 1H), 2.49 - 2.46 (m, 6H), 1.78 - 1.72 (m, 2H), 1.33 (m, 3H), 1.00 (m, 3H);13C NMR (101 MHz, CDCl3, mixture of rotamers) δ 166.83, 154.07, 153.97, 139.11, 139.08, 138.70, 138.63, 133.54, 133.47, 130.33, 130.12, 129.27, 127.34, 127.25, 66.54, 52.24, 46.41, 41.48, 36.95, 21.97, 21.03, 18.05, 13.50, 11.31, 10.54; MS (ESI) m / z calcd for C16H25N2O2+[M+H]+277, found 277.

[0122] Synthesis of n-butyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S6b4-HCl)S5 S6b4-HCI

[0123] A four-neck round bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen tube, and ice bath was charged with A-ethyl-A-methyl formamide (S 14, 97.0 g, 1.11 mol, 2.3 equiv) and DCM (800 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mass was cooled to 0 °C. Oxalyl dichloride (92.2 mL, 1.09 mol, 2.25 equiv) was charged to the above reaction mass over 30 min. The reaction mass was stirred below 0 °C for 30 min. The reaction mass was warmed to ambient temperature and stirred for 1 h. The reaction mass (Vilsmeier reagent) was taken to the next part. A separate round bottom flask equipped with a mechanical stirrer, temperature probe, condenser, heating mantle, and nitrogen tube was charged with 4-amino-2,5-dimethylbenzoic acid (S5, 80 g, 0.48 mol, 1 equiv) and DCM (800 mL) at ambient temperature under nitrogen atmosphere. The flask was evacuated and backfilled with nitrogen (3 times). The reaction mass was cooled to 18 °C. The Vilsmeier reagent was added to the above reaction mass through an addition funnel over 1 h while maintaining the temperature below 20 °C. After addition, the reaction mass was warmed to ambient temperature and stirred for 3 h. A small aliquot sample was quenched in / / -butanol and analyzed by HPLC. After complete conversion, the DCM was distilled under reduced pressure to 450 mL volume while maintaining the reaction mass temperature below 20 °C. / / -Butanol (1077 g, 14.6 mol, 30 equiv) was charged dropwise in 30 min at ambient temperature. The reaction mass was stirred at 25-30 °C for 2 h. The reaction mass was heated to 75-80 °C and stirred for 14 h. After complete conversion, the reaction mass was concentrated at 50 °C under vacuum to obtain a brown, thick liquid. The resulting product (220 g) was dissolved in water (1100 mL). The aqueous layer was washed with MTBE (2 x 440 mL). The aqueous layer was neutralized (pH 7-8) with saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 660 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate solution (2 x 440 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated at 45 °C under reduced pressure to afford the title compound (S6b4-HCl, 93 g, 66% yield) as a dark brown liquid: 'H NMR (400 MHz, CDCh, mixture of rotamers) 57.74 (s, 1H), 7.46 (s, 1H), 6.56 (s, 1H), 4.23-4.26 (m, 2H), 3.31-3.49 (m, 2H), 3.00 (s, 3H), 2.53 (s, 3H), 2.24 (s, 3H), 1.69-1.76 (m, 2H), 1.44-1.49 (m, 2H), 1.26 (m, 3H), 1.00 (m, 3H);13CNMR (101 MHz, CDCh, mixture of rotamers) 8 167.80, 154.29, 151.73, 139.14, 132.58, 132.28, 128.68,122.86, 121.90, 64.01, 30.83, 21.71, 19.49, 17.15, 13.73; MS (ESI) m / z calcd for C17H27N2O2[M+H]+291, found 291.

[0124] Synthesis of (4-difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI)S5 S1

[0125] A 100 mL round-bottom flask was charged with V-ethyl-A-methylformamide (S14, 5.8 g, 2.2 equiv, 66 mmol) and DCM (30 mL) under nitrogen. The flask was put in an ice bath and the mixture was cooled to 0 °C. Oxalyl dichloride (5.8 mL, 2.2 equiv, 66 mmol) was added dropwise over 5 min. The ice bath was removed and the reaction was stirred at ambient temperature for 30 min to form the Vilsmeier reagent, also known herein as reagent V. A separate 250 mL three-neck round bottom flask was charged with 4-amino-2,5-dimethylbenzoic acid (S5, 4.96 g, 1.0 equiv, 30 mmol) and DCM (30 mL) under nitrogen. The flask was put in an ice bath and the mixture was cooled to 0 °C. To this mixture was added the Vilsmeier reagent via syringe over 15 min. The ice bath was removed and stirred at ambient temperature for 2 h. (4-(Difluoromethoxy)phenyl)methanol (S9, 8.23 mL, 2.0 equiv, 60 mmol) was dosed over 5 min. The reaction was stirred at ambient temperature overnight. After 20 h, the mixture was concentrated under vacuum, and toluene (50 mL) and water (30 mL) were added, and the mixture was transferred to a separatory funnel. The toluene layer was removed, and the aqueous layer was washed four times with toluene (50 mL). The aqueous layer was then transferred to a round bottom flask and neutralized with 2 N NaOH solution (50 mL, 3.33 equiv). The mixture was then transferred to a separatory funnel and extracted with ethyl acetate (50 mL) twice. The organic layers are combined, dried with sodium sulfate, and concentrated under vacuum to afford the title compound (SI, 10.1 g, 75% yield) as a brown oil. Analytical data matched those below.EXAMPLE 7

[0126] Synthesis of 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl)S6b2-HCI S6a-HCI

[0127] Preparation 1: To a 40 mL vial with a stir bar was added isopropyl 4-(((ethyl (methyl )amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S6b2-HCl, 1.13 g, 3.62 mmol) and 37% hydrogen chloride aqueous solution (1.86 g, 4.25 mL, 12.0 molar, 51.0 mmol). The vial was capped, the reaction mixture was stirred at 600 rpm and was heated to 65 °C for 2 h. After 2 h, the solution was placed under vacuum to remove isopropanol (15 kPa (150 mbar) and a temperature of 60-65 °C). The solution was then heated at 65 °C for an additional 18 h. Upon analysis by HPLC that showed >95% conversion, the mixture was concentrated under vacuum. The mixture was cooled to 0 °C, and THF (4.18 g) was slowly added dropwise at 0 °C. The mixture was stirred for 2 h at 0 °C, and the solids were collected by filtration to afford the title compound after drying as an off-white solid (S6a-HCl, 0.77 g, 79% yield). Analytical data matched those above.

[0128] Preparation 2 To a 20 mL vial equipped with a stir bar was added isopropyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S6b2, 1.0 g, 3.62 mmol) and isopropanol (6.4 mL, 5.0 g). Sodium hydroxide (174 mg, 4.34 mmol) was then added to the solution. The vial was sealed, and the reaction mixture was stirred at 85 °C for 17 h. Upon completion, as confirmed by HPLC, the reaction mixture was allowed to cool to ambient temperature. The resulting reaction mixture was concentrated under a vacuum of 10 kPa (100 mbar) at 50 °C and reduced by approx. 50% volume. The resultant solution was cooled to 0 °C, and a solution of hydrogen chloride in isopropanol (317 mg, 2.17 mL, 4.0 molar, 8.68 mmol) was added dropwise. After the solution was stirred at 0 °C for 45 min, the ice bath was removed, and the solution was stirred an additional 2 h at ambient temperature. The solids were filtered,and the filter cake was rinsed with additional isopropanol (6.91 g) and methyl / e / 7-butyl ether (5.12 g). The collected solids were dried under vacuum to afford 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl, 1.16 g, 93% yield) as a white powder. Analytical data matched those above.EXAMPLE 8

[0129] Synthesis of sodium 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S6a-Na)S6b2 S6a-Na

[0130] To a 50 mL flask equipped with a stir bar was added isopropyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S6b2, 1.71 g, 6.07 mmol) and isopropanol (9.8 mL, 7.69 g). Sodium hydroxide (291 mg, 7.28 mmol) was added to the solution. The flask was equipped with a condenser, and the reaction mixture was stirred at 80 °C for 17 h. Upon completion, as confirmed by HPLC, the reaction mixture was allowed to cool to ambient temperature. The resulting reaction mixture was concentrated to approximately 73% mass under a vacuum of 10 kPa (100 mbar) at 50 °C. The resultant solution was heated to 50 °C, and then methyl te / 7-butyl ether (19.5 mL, 14.4 g) was added dropwise in 4 equal portions at time intervals of 10—15 min. The mixture was stirred at 50 °C for 30 min, after which the solution was allowed to cool to ambient temperature and stirred for an additional 2 h. The solids were filtered, and the filter cake was rinsed with additional methyl te / 7-butyl ether (30 mL, 22 g). The collected solids were dried to afford the title compound (S6a-Na, 1.55 g, 89% yield) as an off-white powder:1H NMR (500 MHz, DMSO-d6) δ 7.56 (br s, 1H), 7.40 (s, 1H), 6.40 (s, 1H), 3.34 (br s, 2H), 2.91 (br s, 3H), 2.41 (s, 3H), 2.09 (s, 3H), 1.11 (t, 7 = 7.08 Hz, 3H);13C NMR (126 MHz, DMSO-d6) δ 173.33, 150.04, 135.24, 134.96, 131.93, 126.32, 120.50, 49.21, 27.31, 25.91, 21.80, 17.91; MS (ESI) m / z calcd for C13H19N2O2+[M+H]+235; found 235.EXAMPLE 9

[0131] Synthesis of 4-(difluoromethoxy)benzaldehyde (S8)

[0132] A 2 -liter flask, equipped with a nitrogen gas inlet, overhead stirrer and temperature probe, was charged with potassium hydroxide (315 g, 5610 mmol) and water (468 mL).Acetonitrile (468 mL) and 4-hydroxybenzaldehyde (S7, 45.7 g, 374 mmol) were then sequentially added. The mixture was cooled to < 5 °C in an ice / water bath. Diethyl (bromodifluoromethyl)phosphonate (150 g, 561 mmol) was then added dropwise over 30 min. The reaction mixture was stirred in the ice / water bath for 30 min and then the ice bath was removed. The reaction mixture was stirred at ambient temperature for 3 h. The organic layer was collected, and the aqueous layer was extracted with MTBE (250 mL x 2). Organic layers were combined, dried over sodium sulfate, filtered and concentrated to afford the desired product, 4-(difluoromethoxy)benzaldehyde (S8, 60.5 g, 94% yield):1H NMR (500 MHz, CDCl3) δ 9.94 (s, 1H), 7.88 (d, J= 8.3 Hz, 2H), 7.21 (d, J= 8.3 Hz, 2H), 6.60 (t, J= 72.9 Hz, 1H);13C NMR (126 MHz, CDCl3) δ 189.14, 154.15 (t, J = 2.8 Hz), 131.76, 130.14, 117.47, 113.79 (t, J= 210 Hz);19F NMR (471 MHz, CDCl3) δ -82.45; MS (EI) calcd for [C8H6F2O2]+[M]+172.0, found 172.0.EXAMPLE 10

[0133] Synthesis of (4-(difluoromethoxy)phenyl)methanol (S9)

[0134] Preparation 1: A flask equipped with a nitrogen inlet, overhead stirrer and temperature probe was charged with 4-(difluoromethoxy)benzaldehyde (S8, 60 g, 349 mmol), followed by ethanol (611 mL). The mixture was cooled to < 5 °C in an ice / water bath. Sodium borohydride (13.2 g, 349 mmol) was added portion-wise, and the mixture was stirred for 1 h andallowed to warm to ambient temperature. Upon reaction completion, the mixture was quenched by the addition of 2 M HC1 (50 mL), concentrated under vacuum to 25% volume and extracted with ethyl acetate (300 mL x2). The combined organic extract was dried over magnesium sulfate and concentrated under vacuum to afford (4-(difluorom ethoxy )phenyl)methanol (S9, 55.1 g, 316 mmol, 91% yield):1H NMR (500 MHz, CDCl3) δ 7.37 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.5 Hz, 2H), 6.50 (t, J = 73.9 Hz, 1H), 4.68 (d, J= 4.4 Hz, 2H), 1.73 (d, J= 5.3 Hz, 1H);13C NMR (126 MHz, CDCl3) δ 150.58 (t, J= 2.8 Hz), 138.06, 128.47, 119.72, 115.91 (t, J=260Hz), 64.60;19F NMR (471 MHz, CDCl3) δ -80.75; MS (El) calcd for [C8H7F2O2]- [M-H]’ 173.0, found 173.0.

[0135] Preparation 2: A jacketed reactor equipped with a nitrogen inlet, outlet, overhead stirrer, and temperature probe was charged with ethanol (475 mL) and the jacket temperature was set to 3 °C. The mixture was stirred at 500 rpm. Once the internal temperature was below 5 °C, sodium borohydride (15.1 g, 0.33 equiv, 392 mmol) was added in portions over 2 min. 4-(Difluoromethoxy)benzaldehyde (S8, 215 g, 1.19 mol) was then added slowly over 90 min to keep the temperature below 5 °C. After addition of aldehyde was complete, the reaction was stirred for an additional 30 min and then analyzed by HPLC, showing >99% conversion. The reaction was quenched by slow addition of 2 M HC1 (200 mL) over 1 h. Solids were present, and the mixture was filtered through a fritted funnel and washed with water (50 mL) and DCM (50 mL). The filtrate was concentrated to remove most of the EtOH. The mixture was then diluted with DCM (400 mL) and 10 wt % brine solution (400 mL). The organic layer was collected, dried over sodium sulfate, filtered, and concentrated to afford (4- (difluorom ethoxy )phenyl)methanol (S9, 211 g, 1.18 mol, 98% yield). Analytical data matched those above.

[0136] Preparation 3 A 1 -liter reactor was charged with 4-hydroxybenzaldehyde (S7, 30.0 g, 246 mmol) and isopropyl alcohol (z-PrOH, 220 g) at ambient temperature. The reactor jacket temperature was increased to 50 °C. A parallel addition of NaOH (160 g, 25 wt %, 983 mmol) and Freon-22 (chlorodifluoromethane, 62.5 g, 722 mmol) was conducted over 70 min. During the parallel addition, the internal temperature rose to 55 °C. After the parallel addition was complete, the jacket temperature was reduced to 12 °C. When the internal temperature was below 40 °C, the reaction mass was filtered to remove inorganics. The filtrate was added backinto the reactor. GC-FID analysis showed >95% intermediate 4-(difluoromethoxy)benzaldehyde (S8). When the internal temperature of the above solution was below 15 °C, a solution of sodium borohydride (18.5 mL, 12 wt % aq with 14 M NaOH stabilizer, 81 mmol) was added over 15 min. During the addition, the internal temperature was maintained between 20 - 22 °C. After 30 min post addition, the jacket temperature was increased to 20 °C. Stirring was stopped, and the aqueous phase was separated. An aqueous wash was prepared (120 g water, saturated with 20 g NaCl) and added to the reaction mixture. The mixture was stirred for 5 min, and after stirring was stopped the phases readily settled. The aqueous phase was separated, and the / -PrOH phase was analyzed by GC-FID showing 98% (4-(difluoromethoxy)phenyl)methanol (S9). The organic phase was concentrated under vacuum. After most of the z-PrOH was removed, the vacuum was released, and toluene (150 mL) was added. The mixture was stirred and after 5 min, stirring was stopped and the phases were separated. The organic phase was transferred to a flask, concentrated under vacuum, and subjected to short path distillation. From the distillation, (4-(difluoromethoxy)phenyl)methanol (S9) was isolated (34.7 g, 81% yield over 2 steps) as a faintly orange oil. Analytical data matched those above.

[0137] Preparation 4: A flask equipped with a stir bar, temperature probe, gas inlet, and outlet to a scrubber was charged with 4-hydroxybenzaldehyde (S7, 5.0 g, 1 equiv, 40.9 mmol) and stirred in a mixture of isopropanol (40 mL) and water (10 mL). The solution was then heated to 60 °C and held for 30 min. A solution of 50 wt % aqueous sodium hydroxide (13.1 g, 4 equiv, 164 mmol) was added to the solution over 15 min, while maintaining the internal temperature <65 °C. After complete addition, chlorodifluoromethane (or Freon-22) (7.1 g, 2 equiv, 81.9 mmol) was bubbled through the reaction over 20 min. After 1 hour complete consumption of 4-hydroxybenzaldehyde was observed by HPLC, and the reaction was cooled to 25 °C. The reaction was concentrated under vacuum to remove most of the solvent. The resulting mixture was diluted with ethanol (40 mL) and 35 wt % aqueous formaldehyde (17.6 g, 5 equiv, 205 mmol) was added to the reaction slowly. While stirring in an ambient water bath, sodium hydroxide (16.4 g, 50 wt %, 5 equiv, 205 mmol) was added to the reaction dropwise over 20 min while maintaining the internal reaction temperature below 30 °C. The reaction was then stirred at 25 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with MTBE (80 mL).The combined organic layer was washed with 1 N HC1 solution (50 mL), followed by saturated sodium chloride solution (50 mL). The resulting organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain (4-(difluoromethoxy)phenyl)methanol as a thick orange oil (S9, 77% yield over 2 steps). Analytical data matched those above.EXAMPLE 11

[0138] Synthesis of l-(chloromethyl)-4-(difluoromethoxy)benzene (S10)S9 S10

[0139] Preparation 1: A flask equipped with nitrogen inlet, stir bar and temperature probe was charged with (4-(difluoromethoxy)phenyl)methanol (S9, 1.74 g, 10 mmol) and DCM (13.6 mL). The mixture was stirred and cooled to < 5 °C in an ice / water bath. Triethylamine (1.46 mL, 10.5 mmol) was then added. Thionyl chloride (0.95 mL, 13.0 mmol) was then added slowly over 1 h via syringe pump to keep the internal temperature < 5 °C. After 1 h, the reaction was quenched by addition of aqueous HC1 (I M, 10 mL). The organic layer was collected and washed with aqueous potassium carbonate (5 wt %, 10 mL). The organic layer was then dried over sodium sulfate, fdtered, and concentrated to afford the desired product, l-(chloromethyl)-4-(difluoromethoxy)benzene (S10, 1.74 g, 8.96 mmol, 90% yield): 'H NMR (500 MHz, CDCh) 8 7.42 - 7.36 (m, 2H), 7.14 - 7.08 (m, 2H), 6.51 (t, J = 73.7 Hz, 1H), 4.57 (s, 2H);19F NMR (471 MHz, CDCh) 8 -80.99;13C NMR (126 MHz, CDCh) 8 151.07 (t, J= 3.0 Hz), 134.70, 130.18, 119.77, 115.76 (t, J= 260 Hz), 45.38; MS (EI) calcd for [C8H7F2OCl]+[M]+192.0, found 192.0.

[0140] Preparation 2: A 1-L reactor was charged with 4-hydroxybenzaldehyde (S7, 30.0 g, 246 mmol) and / -PrOH (197 g). The reactor jacket temperature was increased to 50 °C. A parallel addition of NaOH (157 g, 25 wt % aq, 983 mmol, 4 equiv) and Freon-22 (64 g, 737 mmol, 3 equiv) was conducted over 75 min. After the parallel addition was complete, the jacket temperature was reduced to 12 °C. When the internal temperature was below 40 °C, the reaction mass was fdtered to remove inorganics. The fdtrate was added back into the reactor. After the layers settled, GC-FID analysis indicated 94% conversion. When the internal temperature wasbelow 15 °C, a solution of sodium borohydride (18.5 mL, 12 wt % aq with 14 MNaOH stabilizer, 81 mmol, 0.33 equiv) was added over 15 min. During the addition, the internal temperature was maintained between 20 - 22 °C. After 30 min post addition, the jacket temperature was increased to 20 °C. Stirring was stopped, and the aqueous phase was separated. An aqueous wash was prepared (150 g water, 12 mL concentrated HCl, saturated with 50 g NaCl). The acidic aqueous phase was added, resulting in minimal hydrogen evolution and a noticeable color change. The mixture was stirred for 5 min, and after stirring was stopped the phases readily settled. The aqueous phase was separated and the z-PrOH phase was analyzed by GC-FID showing 98% S9. The jacket temperature was increased to 60 °C and z-PrOH was removed under vacuum (9.33 kPa (70 torr)). After most of the z-PrOH was removed, the vacuum was released and toluene (111 g) was added. The mixture was stirred and after 5 min, stirring was stopped and the phases were separated. The organic phase was further distilled (140 g of distillate removed). After the distillation, the jacket temperature was set to 12 °C and DCM (300 mL) was added. GC-FID analysis of the DCM solution showed 93% (4-(difluoromethoxy)phenyl)methanol (S9). When the internal temperature was below 15 °C, thionyl chloride (24 mL, 332 mmol, 1.35 equiv) was added over 20 min. After 18 h, water (120 g) was added. After 5 min, stirring was stopped and the phases were separated. A rinse solution was prepared (200 g water, 21 g of 50 wt % NaOH) and added to the mixture. After 5 min, stirring was stopped and the phases were separated. The DCM was removed by vacuum distillation and GC-FID analysis indicated 76% conversion. The residue was transferred to a round bottom flask for short path distillation. From the distillation, l-(chloromethyl)-4-(difluoromethoxy)benzene was isolated (S10, 34 g, 72% yield over 3 steps). Analytical data matched those above.EXAMPLE 12

[0141] Synthesis of 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1)

[0142] Preparation P. A flask fitted with a stir bar was charged with 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl, 1.35 g, 5 mmol), anhydrous potassium carbonate (1.52 g, 11 mmol), benzyltriethylammonium chloride (57 mg, 0.25 mmol), and anhydrous ethyl acetate (10 mL). The reaction mixture was stirred at ambient temperature for 30 min before adding 1 -(chloromethyl)-4-(difluoromethoxy)benzene (S10, 1.06 g, 5.5 mmol). The reaction mixture was heated to 50 °C and stirred for 18-20 h. After complete conversion was observed, the mixture was diluted with water (10 mL) and was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (10 mL), and the organic layer was washed with brine (10 wt %, 10 mL). The solution was concentrated under vacuum to afford the title compound (S1, 1.8 g, 92% yield):1H NMR (400 MHz, CDCl3) 57.78 (s, 1H), 7.55 - 7.32 (m, 3H), 7.13 (d, J= 8.6 Hz, 2H), 6.75 - 6.23 (m, 2H), 5.28 (s, 2H), 3.62 - 3.23 (m, 2H), 3.01 (s, 3H), 2.54 (s, 3H), 2.23 (s, 3H), 1.22 (t, J= 7.1 Hz, 3H);13C NMR (126 MHz, CDCl3) δ 167.29, 154.83, 151.82, 150.93, 150.90, 150.88, 139.70, 133.99, 132.77, 129.76, 128.92, 122.11, 121.99, 119.56, 117.98, 115.92, 113.86, 65.16, 21.87, 17.46;19F NMR (376 MHz, CDCI3) 8 -80.75; MS (ESI) m / z calcd for C21H25F2N2O3+[M+H]+391, found 391.

[0143] Preparation 2, Step A: Synthesis of 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoyl chloride hydrochloride (S6c-HCl)

[0144] A 100 mL three-neck round bottom flask equipped with a condenser was charged with 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HC1, 1.35 g, 5.0 mmol) and DCM (10 mL) under nitrogen. Thionyl chloride (0.4 mL, 5.5 mmol) was added dropwise over 1 min. The reaction mixture was heated to 40 °C and was stirred for 3 h. Formation of the acid chloride hydrochloride (S6c-HCl) was detected as measured by HPLC with an alcohol quench.

[0145] Alternatively, S6c-HCl may also be isolated as follows. The reaction mixture was cooled to room temperature and concentrated to remove DCM, yielding a yellow solid (1.41 g, 97% yield): ’H NMR (500 MHz, CDC13, mixture of rotamers) 8 12.35 (d, J= 13.0 Hz, 1H), 12.29 (d, J= 12.8 Hz, 2.3H), 8.47 (d, J= 11.8 Hz, 2.3H), 8.39 (d, J= 12.0 Hz, 1H), 7.95 (s, 3.3H), 7.42 (s, 2.3H), 7.37 (s, 1H), 4.02 (q, J= 7.2 Hz, 2H), 3.76 (q, J= 7.2 Hz, 4.6H), 3.51 (s, 6.9H), 3.42 (s, 3H), 2.50 - 2.46 (m, 9.9H), 2.39 (s, 9.9H), 1.35 - 1.28 (m, 9.9H);13C NMR (126 MHz, CDCI3, mixture of rotamers) 8 166.68, 166.66, 154.54, 154.39, 140.84, 140.77, 140.56, 140.53, 136.82, 136.76, 131.19, 131.16, 131.00, 130.77, 127.51, 127.34, 52.47, 46.62, 41.68, 37.07, 21.30, 21.28, 18.38, 13.58, 11.40. MS (ESI) calculated for C13H18ClN2O+[M-Cl]+253.1102, found 253.1107.

[0146] Preparation 2, Step B: 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S1)

[0147] To the reaction mixture from Step A above was added (4-(difluoromethoxy)phenyl)methanol (S9, 0.75 mL, 5.5 mmol) over 1 min. The reaction mixture was stirred at 40 °C overnight. The mixture was concentrated under reduced pressure, ethyl acetate (30 mL) and water (30 mL) were added, and the mixture was transferred to a separatory funnel. The organic layer was removed, and the aqueous layer was washed twice with ethyl acetate (30 mL x 2). The aqueous layer was transferred to a round bottom flask and neutralized with 2 N NaOH solution (10 mL). The mixture was transferred to a separatory funnel and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), dried with sodium sulfate, and concentrated by rotary evaporation to provide 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S1, 1.61 g, 73% yield) as a yellow oil. Analytical data matched those above.EXAMPLE 13

[0148] Synthesis of 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S1)S1

[0149] Preparation 1: A 50 mL flask equipped with a stir bar, reflux condenser, and septum was charged with methyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S6bl, 0.32 g, 1.3 mmol), (4-(difluoromethoxy)phenyl)methanol (S9, 270 mg, 1.55 mmol), and dibutyltin oxide (32 mg, 0.13 mmol). The flask was evacuated and backfilled with nitrogen 3 times, and xylenes (2.6 mL) was added to this mixture. The reaction mixture was stirred at 130 °C for 24 h. The reaction mixture was cooled, diluted with EtOAc (50 mL), and washed with water (2 x 50 mL). The organic layer was separated, dried over sodium sulfate, and concentrated under vacuum to afford S1 (482 mg, 95% yield) as a pale-yellow oil. Analytical data matched those above.

[0150] Preparation 2: Representative procedure for base-catalyzed transesterification

[0151] A flask equipped with a stir bar and reflux condenser was charged with methyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S6bl, 2.00 g, 8.05 mmol), (4-(difluoromethoxy)phenyl)methanol (S9, 1.75 g, 10.1 mmol) and xylenes (27.2 mL). The contents of the reaction were heated to 80 °C, and NaOH (2 N, 0.40 mL, 0.81 mmol) was added. The reaction mixture was stirred at 80 °C with nitrogen purging. After 24 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The aqueous layer was extractedwith EtOAc (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting material was purified by column chromatography to afford S1 (2.65 g, 6.79 mmol, 84% yield) as a colorless oil. Analytical data matched those above.EXAMPLE 14

[0152] Preparing the 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)- 2,5-dimethylbenzoate (neutral form of S1) from 4-(difluoromethoxy)benzyl-4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1-HCl)S1

[0153] Preparation 1, Step A: To a solution of 4-(difluoromethoxy)benzyl 4- (((ethyl (methyl )amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1-HC1, 100 g, 234 mmol) in ethyl acetate (800 mL) at ambient temperature was slowly added a solution of water (800 mL) containing sodium hydroxide (11.2 g, 281 mmol), with continued mixing. After vigorous mixing, the phases were allowed to settle, and the organic layer was collected and washed with an aqueous solution of saturated sodium bicarbonate (100 mL). The organic layer was collected, dried over sodium sulfate, filtered through a pad of Celite®, and concentrated to give the title compound (S1, 89 g) as an amber honey-like oil.(400 MHz, CDCh) 8 7.78 (s, 1H), 7.55 - 7.32 (m, 3H), 7.13 (d,,7 = 8.6 Hz, 2H), 6.75 - 6.23 (m, 2H), 5.28 (s, 2H), 3.62 - 3.23 (m, 2H), 3.01 (s, 3H), 2.54 (s, 3H), 2.23 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).13C NMR(126 MHz, CDCl3) δ 167.29, 154.83, 151.82, 150.93, 150.90, 150.88, 139.70, 133.99, 132.77, 129.76, 128.92, 122.11, 121.99, 119.56, 117.98, 115.92, 113.86, 65.16, 21.87, 17.46.19F NMR (376 MHz, CDCl3) δ -80.75. MS (ESI) m / z calcd for C21H25F2N2O3+[M+H]+391, found 391.

[0154] Preparation 1, Step B: Preparing crystalline SI

[0155] To S1 (158 g, 404.7 mmol) oil, containing a trace amount of EtOAc (2.6 mL), at ambient temperature, was added methyl Zc / 7-butyl ether (72 mL) and / / -heptane (77.5 mL). The solution was warmed to 30 °C. After 1 h of mixing, the solution was cooled to 0 °C over 60 min. After nucleation was observed, ^-heptane (615 mL) at ambient temperature was added to the slurry over 5 h. If no nucleation was observed, 2.5 wt % of S1 seeds with respect to initial S1 can be added. After / / -heptane addition, the slurry was held at 0 °C for 2 h before being filtered and washed with cold / / -heptane (300 mL). The resulting wet cake was dried under vacuum at ambient temperature to yield S1 (145 g, 92% yield) as an off-white solid. Analytical data matched those above.

[0156] Preparation 2: 1 g of 4-(Difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S1) as a colorless oil was dissolved in ethyl acetate. The solution was concentrated under vacuum with stirring at 35 °C for 5 hours. The oil crystallized to an off-white solid upon cooling to room temperature.

[0157] Acid / Base extraction for purification of S1

[0158] To a stirred solution of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S1, 1.50 g, 3.84 mmol) in EtOAc (12 mL) was added HC1 in EtOAc (1 M, 4.6 mL, 4.61 mmol). The mixture was stirred for 15 min at ambient temperature, and the solution turned from clear yellow to opaque white. Water (12 mL) was added, and mixing was continued for 30 min. The mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was transferred to a flask before adding potassium carbonate (0.64 g, 4.61 mmol) and EtOAc (12 mL). The mixture was stirred at ambient temperature for 1 h before transferring to a separatory funnel. The layers were separated, and the organic layer was concentrated under vacuum and then was dried under vacuum at 35 °C to provide S1 (1.39 g, 93% yield) as a white solid. Analytical data matched those above.EXAMPLE 15

[0159] Preparation of crystalline S1-HCl from S1S1-HCI

[0160] Preparation 1: To a solution of (4-difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S1, 200 g, 0.51 mol) in ethyl acetate (400 mL) at ambient temperature in a glass-lined reactor, water (4 mL) was added at ambient temperature. The reaction mixture was cooled to < 5 °C. A solution of HC1 in ethyl acetate (138 mL, 4 M, 0.51 mol) was added to the mixture at < 5°C over 4-5 h to adjust the pH (2.5 to 3.5). The reaction mass was stirred for 30 min at < 5 °C before gradually allowing the reaction mixture to warm to ambient temperature. The reaction mixture was stirred for 16-18 h at ambient temperature. The reaction mixture was then cooled to < 5 °C and stirred for 2 h. The solids were filtered, and the slurry was washed with pre-cooled ethyl acetate (200 mL). The wet cake was allowed to set for 30 min on vacuum to dry. Afterwards, the solid was dried at 50-55 °C under vacuum for 2-3 h to afford the title compound (S1-HCl, 187.4 g, 86% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6, mixture of rotamers) 8 11.18 - 10.79 (m, 1H), 8.54 - 8.27 (m, 1H), 7.79 (s, 1H), 7.55 (d, J= 8.2 Hz, 2H), 7.38 - 7.33 (m, 1H), 7.26 (t, J= 74.1 Hz, 1H), 7.22 (d, J= 8.2 Hz, 2H), 5.32 (s, 2H), 3.75 - 3.61 (m, 2H), 3.32 - 3.25 (m, 3H), 2.52 - 2.49 (m, 3H), 2.38 - 2.32 (m, 3H), 1.30 - 1.23 (m, 3H);19F NMR (376 MHz, DMSO-d6) δ -82.14; mp 95- 100 °C.

[0161]

[0162] Preparation 2: A reactor equipped with overhead agitator, temperature probe, and nitrogen inlet was charged with crude 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI, 10 g, 26 mmol), ethyl acetate (28 mL) and HCl (1 M in ethyl acetate, 31.2 mmol, 31.2 mL). The reaction mixture was stirred at 20 °C before seeds of 4-(difluoromethoxy)benzyl-4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1-HC1, 0.11 g) were added after solids had begun to form. The mixture was stirred for 19 h. The mixture was vacuum filtered, and the solids were dried in a vacuum oven to afford 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1-HCl, 6.09 g, 45% yield). Analytical data matched those above.EXAMPLE 16

[0163] Synthesis of 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl)S6b2-HCI S6a-HCI

[0164] To a 40-mL vial equipped with a stir bar was added isopropyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S6b2-HCl, 1.5 g, 1.0 equiv, 4.8 mmol) and aqueous 6 M HCl (6.0 mL, 4.5 wt equiv, 7.5 equiv). The vial was capped, and the reaction mixture was stirred (600 rpm) at 65 °C for 18 h. Upon completion, as confirmed by HPLC, the reaction mixture was cooled to 0 °C in an ice bath. The solids were filtered, and the filter cake was rinsed with acetone (14.8 mL, 11.6 g, 7.7 wt equiv). The collected solids were dried to afford 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl, 1.1 g, 4.2 mmol, 87% yield, 99 wt % purity) as a white powder.EXAMPLE 17

[0165] Synthesis of 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl)S6b2-HCI S6a-HCI

[0166] To a 1-L jacketed reactor equipped with a vacuum distillation system, a solution of isopropyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S6b2-HCl, 409 g total, 9.3 wt % S6b2-HCl, 38.0 g S6b2-HCl, 121 mmol, 1.0 equiv) and aqueous 6 M HCl (140 g, 3.7 wt equiv, 6.3 equiv HCl) were added at 25 °C. The mixture was stirred at 300 rpm. The jacket temperature was adjusted to 40 °C for 20 min and then 60 °C for 30 min. As the temperature increased, the organic solvent was distilled off under atmospheric pressure. Once most of the di chloromethane was removed, the jacket temperature was increased to 110 °C. When the internal temperature stabilized at 100 °C, most of the organic fractions were distilled (330 g). The reaction mixture was stirred at this temperature for 18 hours, until S6b2-HCl was less than 1.0 area percent (A%) by HPLC. Upon completion, as confirmed by HPLC, 1% sodium chloride (1.3 g, 23 mmol) was added to the reaction mixture. The slurry was cooled to 0 °C over 1 hour and held for 3 hours. The solids were filtered, and the filter cake was rinsed with acetone (154 mL, 121 g, 3.2 wt equiv). The collected solids were dried to afford 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl, 26.7 g, 97.9 mmol, 81% yield, 99 wt % purity) as a white powder. Analytical data matched those above.EXAMPLE 18

[0167] Synthesis of 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl)S6b2 S6a-HCI

[0168] To a 20-mL vial equipped with a stir bar were added isopropyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S6b2, 1.0 g, 3.6 mmol, 1.0 equiv) and isopropanol (6.4 mL, 5.0 g, 5.0 wt equiv). Sodium hydroxide (179 mg, 4.4 mmol, 1.2 equiv) was added to the solution. The vial was sealed, and the reaction mixture was stirred at 85 °C for 19 h. Upon completion, as confirmed by HPLC, the reaction mixture was cooled to 0 °C and a solution of hydrogen chloride in isopropanol (319 mg, 2.2 mL, 4 M, 8.7 mmol, 2.4 equiv) was added dropwise. After the solution was stirred at 0 °C for 40 min, the ice bath was removed, and the solution was stirred an additional 1.5 h at ambient temperature. The solids were filtered, and the filter cake was rinsed with additional isopropanol (3.6 g, 3.6 wt equiv) followed by deionized water (2.6 g, 2.6 wt. equiv). The collected solids were dried under reduced pressure to afford 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (also known as 4-carboxy-A-((ethyl(methyl)amino)methylene)-2,5-dimethylbenzenaminium chloride, S6a-HCl, 748 mg, 2.8 mmol, 75% yield, 96 wt % purity) as a white powder. Analytical data matched those above.EXAMPLE 19

[0169] General Procedure for Synthesis of (4-(difluoromethoxy)phenyl)methanol (S9)S7 S9

[0170] A 1-L reactor was charged with 4-hydroxybenzaldehyde (S7, 30.0 g, 246 mmol) and isopropanol (220 g, 280 mL, 9.3 vol). The jacket temperature was increased to 50 °C. A parallel addition of NaOH solution (40 wt %, 3-4 equiv) and Freon-22 (4 - 6 equiv) was conducted for the specified time. During the parallel addition, the internal temperature was maintained at < 56°C. After the parallel addition was complete, the jacket temperature was reduced to 10 °C. When the internal temperature was below 40 °C, the reaction mass was filtered to remove inorganics. The filtrate was re-added to the reactor. After the layers settled, the bottom aqueous phase was removed. HPLC analysis of both the aqueous and organic layers showed excellent partition of 4-(difluoromethoxy)benzaldehyde (S8) into the organic isopropanol layer. When the internal temperature was below 15 °C, a solution of sodium borohydride (NaBH₄, 12 wt % aq with 40 wt % NaOH stabilizer, approx. 0.3 equiv NaBH₄, 1 equiv NaOH) was added over 25 min. During the addition, the internal temperature was maintained between 20-25 °C. After addition, the jacket temperature was increased to 25 °C, and the reaction mixture was stirred for an additional 2 h prior to quench and further processing (below) afforded (4-(difluoromethoxy)phenyl)methanol (S9) as an unpurified oil that was taken directly into the next step without further purification. Analytical data matched those above.

[0171] Isolation of (4-(difluoromethoxy)phenyl) methanol (S9) via acid-base wash

[0172] The general procedure for synthesis of 4-(difluoromethoxy)benzaldehyde (S8) using NaOH (98 g, 40 wt %, 983 mmol, 4 equiv) and Freon-22 (117 g, 1355 mmol, 5.5 equiv) was conducted over 7 h. Reduction to S9 was carried out using a solution of NaBH₄ (12 wt % aq with 40 wt % NaOH stabilizer, 25.1 g, 18.3 mL, 79.7 mmol, 0.32 equiv NaBH₄), and the reaction mixture was stirred at 10 °C for 18 h. The internal temperature was increased to 25 °C, and the mixture was stirred for 2 h. Upon reaction completion, 2 N HCl (120 mL, 4 vol) was slowly charged to the reactor in 10 mL portions over 10 min. Gas generation and an exotherm were observed; the internal temperature reached 30 °C. After addition, the layers were allowed to settle, and the bottom aqueous layer was removed. Isopropanol was removed from the organic layer under vacuum (9.33 kPa (70 torr), 45 °C) to afford a heterogeneous slurry of unpurified S9.DCM (120 mL, 4 vol) was charged to the reactor followed by 1 M NaOH (120 mL, 4 vol). The solutions were stirred for 5 min and allowed to settle. After the layers were separated, the remaining organic layer was washed with 15% brine (60 mL, 2 vol). The organic solvents were removed under vacuum. A light-yellow oil of (4-(difluoromethoxy)phenyl)methanol (S9) was obtained in 72% yield and 95 wt % purity. Analytical data matched those above.EXAMPLE 20

[0173] Preparation of -(chloromethyl)-4-(difluoromethoxy)benzene (S10)S21 S10

[0174] A 2-dram vial was charged with l-difluoromethoxy-4-methylbenzene (S21, 0.20 mL), trichloroisocyanuric acid (48.5 mg, 0.21 mmol, 0.33 equiv), azobisisobutyronitrile (AIBN, 10.4 mg, 0.063 mmol, 0.1 equiv) and chlorobenzene (0.80 mL). The vial was heated to 65°C and the mixture was stirred overnight. An aliquot of the reaction was sampled for GC analysis to determine yield and conversion. The reaction mixture was washed with 10% aqueous sodium thiosulfate and concentrated in vacuo. The resulting product was purified via flash column chromatography using hexanes and DCM as the eluent to afford 1-(chloromethyl)-4-(difluoromethoxy)benzene (S10, 55% yield). Analytical data matched those above.EXAMPLE 21

[0175] Synthesis of 1-(chloromethyl)-4-(difluoromethoxy)benzene (S10)S9 S10

[0176] A 250-mL round-bottom flask was charged with thionyl chloride (SOCl₂, 3.6 mL, 49 mmol, 1.3 equiv) and dichloromethane (28 g, 21 mL, 3 vol). The flask was placed in an ice bath to maintain internal temperature ~0 °C. A solution of (4-(difluoromethoxy)phenyl)methanol (S9, 7.0 g, 94 wt %, 37.8 mmol, 1.0 equiv) in DCM (11 g, 8 mL, 1.1 vol) was added over 1 h. After addition, the solution was warmed to ambient temperature, and the reaction mixture was stirred for an additional 2 h. Water (28 mL, 4 vol) was slowly added to the reaction mass. After 30 min, stirring was stopped and the phases were separated (aqueous pH < 2). A rinse solution of 10% sodium bicarbonate (28 mL, 4 vol) was prepared and added to the organic layer. After 5 min, stirring was stopped, and the phases were separated (aqueous pH 7-8). The di chloromethane waswashed with a 25% brine solution (28 mL, 4 vol). After the aqueous phase was removed, dichloromethane was removed by vacuum distillation to afford 1-(chloromethyl)-4-(difluoromethoxy)benzene (S9, 92% yield, 95 wt % purity) as a brown oil. Analytical data matched those above.EXAMPLE 22

[0177] Synthesis of 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (S1)S1

[0178] A 500-mL jacketed reactor equipped with a temperature probe, nitrogen inlet, mechanical stirrer, and a water-cooled condenser was charged with 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl, 99 wt %, 13.5 g, 50 mmol, 1 equiv) and DCM (100 mL). Thionyl chloride (3.81 mL, 52.5 mmol, 1.05 equiv) was added at room temperature via syringe over 2 min with stirring. The reaction mixture was heated to 40 °C and stirred at reflux for 4 h. To the reaction mixture was added (4-(difluoromethoxy)phenyl)methanol (S9, 98 wt %, 9.85 g, 55.0 mmol, 1.1 equiv) via a syringe over 2 min. The mixture was stirred at reflux at 40 °C overnight. The reaction mixture was cooled to room temperature before addition of a potassium carbonate solution (13 wt % aq, 70 mL, 75 mmol, 1.5 equiv) over 5 min. After stirring for 5 min, the layers were separated, and the DCM layer was collected. The DCM layer was concentrated to afford unpurified 4-(difluorom ethoxy )benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate as a dark brown oil (SI, 21.3 g, 88% yield). Alternatively, an acid-base extraction according to that described in Example 14, Preparation 2 was conducted and resulted in a similar yield. Analytical data matched those above.EXAMPLE 23

[0179] Synthesis of 4-(difluoromethoxy) benzyl-4-( ( (ethyl(methyl)amino)methylene)amino)- 2, 5 -dimethylbenzoate (SI)S1

[0180] A 1-L Optimax 1001 reactor equipped with a temperature probe, nitrogen inlet, and mechanical stirrer was charged with 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoic acid hydrochloride (S6a-HCl, 98 wt %, 35 g, 127 mmol, 1 equiv), anhydrous potassium carbonate (38.5 g, 279 mmol, 2.2 equiv), benzyltriethylammonium chloride (BTEAC, 2.88 g, 12.66 mmol, 0.1 equiv), water (1.71 g, 95.0 mmol, 0.75 equiv) and anhydrous ethyl acetate (253 mL, 7.2 vol). The reaction mixture was stirred at room temperature for 30 min before adding l-(chloromethyl)-4-(difluoromethoxy)benzene (S10, 98 wt %, 24.9 g, 127 mmol, 1 equiv). The reaction mixture was stirred overnight at 55 °C. After complete consumption of S6a-HC1 was observed by UPLC, water (125 mL, 3.6 vol) was added, and the mixture was stirred for 10 min as it cooled to room temperature. The aqueous layer was removed before washing the organic layer with 1% potassium carbonate solution (125 mL, 3.6 vol). The organic layer wasconcentrated down to give the desired product, 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate as an oil (SI, 51 g, 91 wt % with remaining EtOAc, 95% yield). Analytical data matched those above.EXAMPLE 24

[0181] Synthesis of 4-(difluoromethoxy)benzyl-4-(((ethyl(methyl)amino)methylene)amino)- 2, 5 -dimethylbenzoate (SI)S1

[0182] Representative example of base-mediated transesterification of ester HCl-salt (S6 salt)

[0183] To a 100-mL two-neck round-bottom flask, equipped with a stir bar and a reflux condenser with an attached Dean-Stark trap, was added methyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S6bl-HCl, 1.00 g, 1 equiv, 3.51 mmol) in xylenes (12 mL) under nitrogen. The reaction mixture was stirred at room temperature for 5 min, and sodium methoxide (759 mg, 0.78 mL, 30 wt %, 1.2 equiv, 4.21 mmol) was added. The reaction mixture was stirred for 5 min, and (4-(difluoromethoxy)phenyl)methanol (S9, 795 mg, 1.3 equiv, 4.56 mmol) was added to this mixture. The combined reaction mixture was stirred at 65 °C for 3 h under nitrogen. The reaction showed 90% area under the curve (AUC) for SI after 3 h.

[0184] Using the general procedure above, SI was also generated (72% AUC) using the ethyl ester hydrochloride.

[0185] Using the general procedure above, SI was also generated (59% AUC) using the isopropyl ester hydrochloride (S6b2-HCl).

[0186] Consequently, in light of the above, the following additional non-exhaustive details (D) are provided.ID. A compound, 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2) having the following formulaS22D. A compound, 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoyl chloride (S6c), having the following formulaan acceptable salt thereof.3D. A process comprising:contacting S6a or an acceptable salt thereof with S10 to produce SI or an acceptable salt, solvate, or hydrate thereof in the presence of a base, a solvent, and optionally a phase-transfer catalystS1 or salt thereof4D. The process according to 3D, wherein from about 1.0 mole to about 5 moles of base per mole of S6a is used.5D. The process according to 4D, wherein from about 1.5 mole to about 3 moles of base per mole of S6a is used.6D. The process according to 3D, wherein from about 2.0 moles to about 5 moles of base per mole of an acceptable salt of S6a is used.7D. The process according to 6D, wherein from about 2.1 moles to about 4 moles of base per mole of an acceptable salt of S6a is used.8D. The process according to any one of 3D-7D, wherein the base is sodium methoxide, sodium ethoxide, N,N-diisopropylethylamine, triethylamine, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, or mixtures thereof.9D. The process according to 8D, wherein the base is potassium carbonate.10D. The process according to any one of 3D-9D, wherein the solvent is water, ethyl acetate, acetone, acetonitrile, methyl ethyl ketone, N,N-dimethylformamide, dimethyl sulfoxide, isobutyl acetate, tetrahydrofuran, or mixtures thereof.11D. The process according to 10D, wherein the solvent is acetone, acetonitrile, ethyl acetate, water, or mixtures thereof.12D. The process according to any one of 3D-11D, wherein from about 0.01 mole to about 0.5 mole of phase-transfer catalyst per mole of S6a or acceptable salt thereof is used.13D. The process according to 12D, wherein from about 0.05 mole to about 0.15 mole of phase-transfer catalyst per mole of S6a or acceptable salt thereof is used.14D. The process according to any one of 3D-13D, wherein the phase-transfer catalyst is tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, benzyl tri ethyl ammonium chloride, or mixtures thereof.15D. The process according to claim 14, wherein the phase-transfer catalyst is benzyl triethylammonium chloride.16D. A process comprising:contacting S6b or an acceptable salt thereof, wherein R¹ is C₁-C₈ alkyl, with S9 in the presence of a catalyst and a solvent to produce SI or an acceptable salt, solvate, or hydrate thereofS1 or salt thereof17D. The process according to 16D, wherein R¹ is C₁-C₃ alkyl.18D. The process according to 16D or 17D, wherein the catalyst is a base catalyst.19D. The process according to any one of 16D-18D, wherein the base catalyst is sodium methoxide (“NaOCHs”), potassium methoxide (“KOCH3”), sodium ethoxide (“NaOCTbCH ”), sodium pentoxide (“NaOCH2CH2CH2CH2CH3”), potassium ze / 7-butoxide (“KOf-Bu”), potassium / c / 7-amylate (“KO-t-Am”), sodium / c / 7-butoxide (“NaO / -Bu”), sodium hydroxide (“NaOH”), potassium hydroxide (“KOH”), sodium hydride (“NaH”), or mixtures thereof.20D. The process according to 19D, wherein the catalyst is sodium hydride or sodium methoxide.21D. The process according to any one of 16D-20D, wherein from about 1 mole to about 3 moles of base catalyst per mole of an acceptable salt of S6b is used.22D. The process according to 21D, wherein from about 1.0 mole to about 2.5 moles of base catalyst per mole of an acceptable salt of S6b is used.23D. The process according to any one of 16D-20D, wherein from about 0.01 mole to about 0.3 mole of base catalyst per mole of S6b is used.24D. The process according to 23D, wherein from about 0.05 mole to about 0.2 mole of base catalyst per mole of S6b is used.25D. The process according to 16D or 17D, wherein the catalyst is a Lewis acid catalyst. 26D. The process according to 16D, 17D or 25D, wherein the Lewis acid catalyst is dibutyltin oxide, dibutyltin laurate, dibutyltin acetate, titanium isopropoxide, aluminum isopropoxide, zirconium isopropoxide, or mixtures thereof.27D. The process according to any one of 16D-17D or 25D-26D, wherein from about 0.05 mole to about 0.5 mole of Lewis acid catalyst per mole of S6b or an acceptable salt of S6b is used.28D. The process according to 27D, wherein from about 0.1 mole to about 0.3 mole of Lewis acid catalyst per mole of S6b or an acceptable salt of S6b is used.29D. The process according to any one of 16D-28D, wherein the solvent is xylenes, mesitylene, 1,2-dichlorethane, trifluorotoluene, toluene, chlorobenzene, dichlorobenzene, benzonitrile, or mixtures thereof.30D. The process according to 29D, wherein the solvent is toluene or xylenes.31D. The process according to any one of 16D-30D, wherein the contacting is conducted at a temperature from about 25 °C to about 120 °C or from about 40 °C to about 100 °C.32D. The process according to any one of 16D-31D, wherein the contacting is conducted at pressures from about 1 kilopascal (kPa) to about 200 kPa or from 1 kPa to about 101 kPa.33D. The process according to 3D or 16D, wherein SI or an acceptable salt, solvate, or hydrate thereof is prepared as a solution.34D. A process to convert 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1-HCl) or an acceptable solvate or hydrate thereof to 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable solvate or hydrate thereof in the presence of a base.35D. A process to convert SI or an acceptable solvate or hydrate thereof to S1-HC1 or an acceptable solvate or hydrate thereof in the presence of hydrogen chloride, wherein the hydrogen chloride is a gas or in solution, wherein the solution comprises an organic solvent or water. 36D. A process to produce a crystalline form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1-HCl) or an acceptable solvate or hydrate thereof.37D. A process to produce a crystalline form of 4-(difluoromethoxy)benzyl 4- (((ethyl (methyl )amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable solvate or hydrate thereof.38D. A process comprising:(a) contacting S6a or an acceptable salt thereof, with a carboxylic acid activator in the presence of a solvent; and(b) contacting the reaction mixture of step (a) withi. S9 to provide SI or an acceptable salt, solvate, or hydrate thereof, or ii. an alcohol R3-OH to provide S6b or an acceptable salt thereof, wherein R3 is Ci-Cs alkylS6b or salt thereof39D. The process according to 38D, wherein the carboxylic acid activator is thionyl chloride, phosphorus pentachloride, or oxalyl dichloride.40D. The process according to 38D or 39D, wherein the solvent is toluene (“PI1CH3”), ethyl acetate (“EtOAc”), dichloromethane (“DCM”), or tetrahydrofuran (“THE”).41D. The process according any one of 38D-40D, wherein the process further comprising an optional base.42D. The process according to 4 ID, wherein the optional base is selected from the group consisting of triethylamine (“EtsN”), A, A-diisopropylethylamine (“DIPEA”), pyridine, sodium carbonate (“Na2CO3”), potassium carbonate (“K2CO3”), and sodium bicarbonate (“NaHCCh”).43D. The process according to 42D, wherein the optional base is selected from the group consisting of sodium carbonate and potassium carbonate.44D. The process according to any one of 38-43D, wherein the resulting mixture of step (a) comprising S6c or an acceptable salt thereof.45D. The process according to any one of 38D-44D, wherein the SI or acceptable salt, solvate, or hydrate thereof is isolated from the reaction mixture.46D. The process according to any one of 38D-44D, wherein the S6b or acceptable salt thereof is isolated from the reaction mixture.

[0187] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0188] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0189] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMSWhat is claimed is:

1. A compound, 4-((methoxycarbonyl)amino)-2,5-dimethylbenzoic acid (S2) having the following formulaS22. A compound, 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoyl chloride (S6c), having the following formulaan acceptable salt thereof.

3. A process comprising:contacting S6a or an acceptable salt thereof with S10 to produce SI or an acceptable salt, solvate, or hydrate thereof in the presence of a base, a solvent, and optionally a phase-transfer catalystS1 or salt thereof4. The process according to claim 3, wherein from about 1.0 mole to about 5 moles of base per mole of S6a is used or wherein from about 2.0 moles to about 5 moles of base per mole of an acceptable salt of S6a is used.

5. The process according to claim 3 or claim 4, wherein the base is sodium methoxide, sodium ethoxide, A'. A i isopropyl ethyl amine, triethylamine, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, or mixtures thereof.

6. The process according to any one of claims 3-5, wherein the solvent is water, ethyl acetate, acetone, acetonitrile, methyl ethyl ketone, / V, A i methyl form ami de, dimethyl sulfoxide, isobutyl acetate, tetrahydrofuran, or mixtures thereof.

7. The process according to any one of claims 3-6, wherein from about 0.01 mole to about 0.5 mole of phase-transfer catalyst per mole of S6a or acceptable salt thereof is used.

8. The process according to any one of claims 3-7, wherein the phase-transfer catalyst is tetramethylammonium bromide, tetraethyl ammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide, benzyl triethylammonium chloride, or mixtures thereof.

9. A process comprising:contacting S6b or an acceptable salt thereof, wherein R3 is Ci-Cs alkyl, with S9 in the presence of a catalyst and a solvent to produce SI or an acceptable salt, solvate, or hydrate thereofS1 or salt thereof10. The process according to claim 9, wherein R3 is C1-C3 alkyl.

11. The process according to claim 9 or claim 10, wherein the catalyst is a base catalyst selected from the group consisting of sodium methoxide, potassium methoxide, sodium ethoxide, sodium pentoxide, potassium / erLbutoxide, sodium Zert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, or mixtures thereof.

12. The process according to claim 9 or claim 10, wherein the catalyst is a Lewis acid catalyst selected from the group consisting of dibutyltin oxide, dibutyltin laurate, dibutyltinacetate, titanium isopropoxide, aluminum isopropoxide, zirconium isopropoxide, or mixtures thereof.

13. The process according to any one of claims 9-12, wherein the solvent is xylenes, mesityl ene, 1,2-dichlorethane, trifluorotoluene, toluene, chlorobenzene, dichlorobenzene, benzonitrile, or mixtures thereof.

14. A process to produce a crystalline form of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (S1-HCl) or an acceptable solvate or hydrate thereof.

15. A process to produce a crystalline form of 4-(difluoromethoxy)benzyl 4-(((ethyl (methyl )amino)methylene)amino)-2,5-dimethylbenzoate (SI) or an acceptable solvate or hydrate thereof.

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