1) Hydrogenation of 5-nitroisatoic anhydride (I) over Pd/C provided amine (II), which was acylated to amide (IV) with 4-cyanobenzoyl chloride (III). Subsequent reaction of (IV) with beta-alanine ethyl ester (V) yielded diamide (VI). The amino group of (VI) was then protected by alkylation with benzhydryl bromide (VII) yielding (VIII). Further condensation of (VIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide in the presence of Cs2CO3 afforded benzodiazepinedione (X). The benzhydryl protecting group of (X) was cleaved by treatment with HF in the presence of ethyl methyl sulfide and anisole to yield (XI). The tetrazole ring of (XII) was then constructed by treatment of (XI) with trimethylsilylazide under Mitsunobu conditions. Subsequent conversion of the cyano group of (XII) into amidine was effected by the sequence of H2S addition, followed by S-methylation with CH3I to give (XIII), and then substitution of the methylthio group of (XIII) for an amino group. Finally, basic hydrolysis with LiOH provided the target carboxylic acid.

2) An improved procedure consisted of condensation of 5-nitroisatoic anhydride (I) with beta-alanine ethyl ester (V) to give amide (XIV). The amino group of (XIV) was protected with benzhydryl bromide (VII) yielding (XV), and then the nitro group of (XV) was reduced to aniline (XVI) by catalytic transfer hydrogenation. Protection of the amine of (XVI) as the tert-butyl carbamate (XVIII) was effected using 2-(tert-butoxycarbonyloxymino)-2-phenylacetonitrile (XVII). The sequence of condensation of (XVIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide with DBU provided the benzodiazepinedione (XIX). Hydrogenolysis of the N-benzhydryl group of (XIX) in the presence of Pearlman's catalyst, followed by treatment with trimethylsilyl azide furnished the tetrazole (XX). The Boc group of (XX) was deprotected with trifluoroacetic acid, and subsequent coupling with 4-cyanobenzoyl chloride (III) gave amide (XXI). The cyano group was of (XXI) then converted to hydroxyamidine (XXII) with hydroxylamine. Catalytic hydrogenation of (XXII) in the presence of Ac2O and AcOH produced the corresponding amidine. Finally, the ester group was hydrolyzed with LiOH.