The reduction of N-benzyloxycarbonylprolinamide (I) with H2 over Pd/c in methanol gives prolinamide (II), which is condensed with N-benzyloxycarbonylhistidyl hydrazide (III) by means of NaNO2 - HCl in ethyl acetate yielding N-benzyloxycarbonylhistidylprolinamide (IV), The hydrolysis of (IV) with HBr in acetic acid affords histidylprolinamide (V), which is finally condensed with gamma-carboxy-gamma-butyrolactone (VI) by means of pentachlorophenol and dicyclohexylcarbodiimide in DMF. Compound (VI) is prepared by reaction of alpha-aminoglutaric acid (VII) with NaNO2 and 2N H2SO4 in water.
The condensation of o-chloronitrobenzene (I) with 2-amino-5-methylthiophene-3-carbonitrile (II) by means of lithium hydroxide in DMSO gives 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (III). The reductive cyclization of (III) using stannous chloride in aqueous ethanolic hydrochloric acid gives the primary amidine hydrochloride (IV), which is condensed with N-methylpiperazine (V) in a mixture of 4:1 toluene:DMSO.