4-Bromophenethyl amine (I) was refluxed with ethyl formate to afford formamide (II). Cyclization of (II) employing polyphosphoric acid and phosphorus pentoxide at 200 C furnished 7-bromo-3,4-dihydroisoquinoline, which was isolated as the corresponding hydrochloride salt (III). Reduction of (III) with NaBH4 gave the tetrahydroisoquinoline (IV), that was nitrated with KNO3 and H2SO4 to provide (V). After protection of (V) as the N-Boc derivative (VI), reduction of the nitro group with concomitant hydrogenolysis of the bromine by hydrogenation over Pd/CaCO3 yielded aminoisoquinoline (VII). This was coupled with 4?(trifluoromethyl)biphenyl-2-carboxylic acid (VIII) by means of EDC to produce amide (IX). Cleavage of the Boc group of (IX) with trifluoroacetic acid gave amine (X). Finally, reductive alkylation of (X) with imidazole-2-carbaldehyde (XI) and sodium cyanoborohydride furnished the title compound.

Condensation of 2-chloro-4-nitrobenzoic acid (XII) with dimethyl malonate produced the arylmalonate (XIII). Hydrolysis and subsequent decarboxylation of (XIII) afforded diacid (XIV). This was converted into cyclic anhydride (XV) upon refluxing with Ac2O and then reduced to diol (XVI) with borane in THF. Optionally, diol (XVI) was obtained by direct reduction of diacid (XIV) with borane. After conversion of (XVI) to dimesylate (XVII), cyclization with ammonia produced tetrahydroisoquinoline (XVIII). This was protected as the N-Boc derivative (XIX) and the nitro group was reduced to the target amine (VII) by hydrogenation over Pt/C .

In a further procedure, nitro diol (XVI) was hydrogenated over Pt/C, and the resulting amine (XX) was condensed with acid chloride (XXI) (prepared from carboxylic acid (VIII) and SOCl2) to afford amide (XXII). After conversion of (XXII) to dimesylate (XXIII), cyclization with ammonia furnished intermediate (X).