Cycloaddition of the azomethine ylide resulting from N-trimethylsilylmethyl-N-methoxymethyl-(R)-alpha-methylbenzylamine (II) to 5-methoxycoumarin (I) produced the chiral cis-benzopyranopyrrole system (III). Lactone reduction by means of LiAlH4 or LiBH4 afforded diol (IV). After conversion of the primary alcohol of (IV) to either the corresponding chloride or the mesylate, cyclization in the presence of potassium tert-butoxide generated the tricyclic compound (V). The alpha-methylbenzyl group of (V) was removed by catalytic hydrogenation to give amine (VI), which was alkylated with 4-bromobutyronitrile yielding (VII). Reduction of the cyano group of (VII) using LiAlH4 in the presence AlCl3 or by catalytic hydrogenation in the presence of Raney-Ni produced the primary amine (VIII).

The mixture of 5- and 6-phenyl regioisomers of 2-hydroxy-3-carboxamidopyrazine (IX) and (X), prepared by a known method, was treated with POCl3 and Et3N to produce the corresponding chloro nitriles (XI) and (XII). Condensation of this mixture with methyl thioglycolate in the presence of NaOMe, followed by chromatographic separation of isomers furnished the desired thienopyrazine intermediate (XIII).

In a regioselective synthetic method, phenyl glyoxime (XIV) was condensed with aminomalononitrile to produce the pyrazine N-oxide (XV). Reduction of the N-oxide of (XV) with triethyl phosphite yielded (XVI). Diazotization of the amino group of (XVI), followed by diazo displacement with CuBr2, furnished bromo pyrazine (XVII). This was then cyclized with methyl thioglycolate as above to yield the desired thienopyrazine intermediate (XIII).

In an alternative synthesis, phenylacetaldehyde (XVIII) was condensed with pyrrolidine (XIX) to give enamine (XX). Nitrosation of malononitrile (XXI), followed by treatment with tosyl chloride, produced the O-tosyl oxime (XXII). This was condensed with enamine (XX), and to the intermediate adduct (XXIII) was added thiophenol producing the phenylthiopyrazine (XXIV). Subsequent oxidation of the sulfide group of (XXIV) to sulfone (XXV), followed by condensation with methyl thioglycolate, gave the desired thienopyrazine (XIII).

The amino ester intermediate (XIII) was treated with phosgene and Et3N, and to the resulting isocyanate (XXVI) was added the primary amine (VIII), producing urea (XXVII). Then, cyclization of (XXVII) in refluxing toluene generated the desired compound, which was isolated as the hydrochloride salt.