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A general method for the synthesis of 8hydroxy6substituted1,7naphthyridines is described using acylation of the dianion derived from tertbutylamide 1, followed by cyclization of the resulting intermediate ketones 2with ammonium acetate.

A practical synthesis of N-4-(6-cyclobutylamino-9H-purin-2-ylamino)-phenyl-N-methyl acetamide (QAB205, 5a), an antiasthmatic agent, is described from 2,6-dichloropurine (1) by base-assisted substitution of the 6-chloro substituent with cyclobutylamine (2a) followed by a new trimethylsilyl chloride-catalyzed displacement of the 2-chloro group in intermediate 6-cycbutylamino-2-chloropurine (3a) with an aromatic amine. Both steps can also be carried out in one pot without isolating the intermediate 6-cyclobutylamino-2-chloropurine (3a). The general synthetic utility of this route is demonstrated by synthesizing several 2-arylamino-6-alkylaminopurines (5).

Palladiumcatalyzed amination of 7bromo4methyl2,1,3benzothiadiazole 7 with benzophenone imine as an ammonia equivalent is described as a new, safe and practical alternative to nitration for the synthesis of 7amino4methyl2,1,3benzothiadiazole 1 in high yield. This methodology was successfully scaledup in the pilot plant on 14.0kg scale of 7and was also utilized for the synthesis of 7amino4,6dimethyl2,1,3benzothiadiazole 12 by the amination of 7bromo4,6dimethyl2,1,3benzothiadiazole 10.

Lithiation of Nprotected2,3dihydro1,4benzoxazines is described. Lithiation of Ntertbutoxycarbonyl2,3dihydro1,4benzoxazine 1 with BuLiTMEDA occurred in the αposition to nitrogen on the heterocyclic ring, leading to the unexpected ringopened product 3. On the other hand, lithiation of Nmethyl2,3dihydro1,4benzoxazine 4 took place at the oxygenadjacent orthoposition of the aromatic ring.