Knoevenagel condensation of 4-fluorobenzaldehyde (I) with ethyl cyanoacetate (A) gave adduct (II). Subsequent conjugate addition of NaCN to (II), followed by alkylation with ethyl 3-chloropropionate (B) furnished the dicyano diester (III). Acid hydrolysis of (III), with concomitant decarboxylation, afforded tricarboxylic acid (IV), which was further esterified with methanolic HCl to give ester (V). Dieckmann cyclization of (V) using NaOMe, and then hydrolysis and decarboxylation gave rise to the racemic trans ketoacid (VI). Esterification of (VI), and reduction of the resulting keto ester (VII) with NaBH4 produced a mixture of diastereomeric alcohols. The desired trans,trans-isomer (VIII) was then isolated by column chromatography. Ester hydrolysis of (VIII) and re-solution as the corresponding salt with (R)-alpha-methylbenzylamine furnished the (-)-hydroxy acid (IX) that was esterified to (X) with methanolic HCl.

Reduction of 3',5'-bis(trifluoromethyl)acetophenone (XI) with NaBH4 gave alcohol (XII). This was either converted to imidate (XIII) by addition of trichloroacetonitrile, or to bromide (XIV) upon treatment with triphenylphosphine dibromide. Condensation of the chiral hydroxy ester (-)-(X) with imidate (XIII) in the presence of triflic acid provided ether (XVa-b) as a diastereomeric mixture. Alternatively, (XV) was obtained by alkylation of alcohol (-)-(X) with bromide (XIV). Cromatographic separation of the diastereomeric mixture (XVa-b), followed by basic hydrolysis of the desired isomer yielded carboxylic acid (XVI). Activation of the carboxyl group of (XVI) as the corresponding acid chloride by means of oxalyl chloride, and subsequent treatment with NaN3 generated the acyl azide (XVII). Curtius rearrangement ot the acyl azide (XVII) in hot toluene provided isocyanate.

Addition of benzyl alcohol (C) to isocyanate (XVIII) gave rise to carbamate (XIX), which was further N-alkylated with iodomethane and NaH. Hydrogenolysis of carbamate (XX) over Pd/C produced methyl amine (XXI). This was then converted to the target triazolylmethyl derivative by alkylation with N-formyl-2-chloroacetamidrazone (XXII), followed by thermal cyclization in refluxing xylene.

Knoevenagel condensation of 4-fluorobenzaldehyde (I) with ethyl cyanoacetate (A) gave adduct (II). Subsequent conjugate addition of NaCN to (II), followed by alkylation with ethyl 3-chloropropionate (B) furnished the dicyano diester (III). Acid hydrolysis of (III), with concomitant decarboxylation, afforded tricarboxylic acid (IV), which was further esterified with methanolic HCl to give ester (V). Dieckmann cyclization of (V) using NaOMe, and then hydrolysis and decarboxylation gave rise to the racemic trans ketoacid (VI). Esterification of (VI), and reduction of the resulting keto ester (VII) with NaBH4 produced a mixture of diastereomeric alcohols. The desired trans,trans-isomer (VIII) was then isolated by column chromatography. Ester hydrolysis of (VIII) and re-solution as the corresponding salt with (R)-alpha-methylbenzylamine furnished the (-)-hydroxy acid (IX) that was esterified to (X) with methanolic HCl.

Reduction of 3',5'-bis(trifluoromethyl)acetophenone (XI) with NaBH4 gave alcohol (XII). This was either converted to imidate (XIII) by addition of trichloroacetonitrile, or to bromide (XIV) upon treatment with triphenylphosphine dibromide. Condensation of the chiral hydroxy ester (-)-(X) with imidate (XIII) in the presence of triflic acid provided ether (XVa-b) as a diastereomeric mixture. Alternatively, (XV) was obtained by alkylation of alcohol (-)-(X) with bromide (XIV). Cromatographic separation of the diastereomeric mixture (XVa-b), followed by basic hydrolysis of the desired isomer yielded carboxylic acid (XVI). Activation of the carboxyl group of (XVI) as the corresponding acid chloride by means of oxalyl chloride, and subsequent treatment with NaN3 generated the acyl azide (XVII). Curtius rearrangement ot the acyl azide (XVII) in hot toluene provided isocyanate.

Addition of benzyl alcohol (C) to isocyanate (XVIII) gave rise to carbamate (XIX), which was further N-alkylated with iodomethane and NaH. Hydrogenolysis of carbamate (XX) over Pd/C produced methyl amine (XXI). This was then converted to the target triazolylmethyl derivative by alkylation with N-formyl-2-chloroacetamidrazone (XXII), followed by thermal cyclization in refluxing xylene.

Knoevenagel condensation of 4-fluorobenzaldehyde (I) with ethyl cyanoacetate (A) gave adduct (II). Subsequent conjugate addition of NaCN to (II), followed by alkylation with ethyl 3-chloropropionate (B) furnished the dicyano diester (III). Acid hydrolysis of (III), with concomitant decarboxylation, afforded tricarboxylic acid (IV), which was further esterified with methanolic HCl to give ester (V). Dieckmann cyclization of (V) using NaOMe, and then hydrolysis and decarboxylation gave rise to the racemic trans ketoacid (VI). Esterification of (VI), and reduction of the resulting keto ester (VII) with NaBH4 produced a mixture of diastereomeric alcohols. The desired trans,trans-isomer (VIII) was then isolated by column chromatography. Ester hydrolysis of (VIII) and re-solution as the corresponding salt with (R)-alpha-methylbenzylamine furnished the (-)-hydroxy acid (IX) that was esterified to (X) with methanolic HCl.

Reduction of 3',5'-bis(trifluoromethyl)acetophenone (XI) with NaBH4 gave alcohol (XII). This was either converted to imidate (XIII) by addition of trichloroacetonitrile, or to bromide (XIV) upon treatment with triphenylphosphine dibromide. Condensation of the chiral hydroxy ester (-)-(X) with imidate (XIII) in the presence of triflic acid provided ether (XVa-b) as a diastereomeric mixture. Alternatively, (XV) was obtained by alkylation of alcohol (-)-(X) with bromide (XIV). Cromatographic separation of the diastereomeric mixture (XVa-b), followed by basic hydrolysis of the desired isomer yielded carboxylic acid (XVI). Activation of the carboxyl group of (XVI) as the corresponding acid chloride by means of oxalyl chloride, and subsequent treatment with NaN3 generated the acyl azide (XVII). Curtius rearrangement ot the acyl azide (XVII) in hot toluene provided isocyanate.

Addition of benzyl alcohol (C) to isocyanate (XVIII) gave rise to carbamate (XIX), which was further N-alkylated with iodomethane and NaH. Hydrogenolysis of carbamate (XX) over Pd/C produced methyl amine (XXI). This was then converted to the target triazolylmethyl derivative by alkylation with N-formyl-2-chloroacetamidrazone (XXII), followed by thermal cyclization in refluxing xylene.