An overview of two-heteroatom reagents and the retrosynthesis of five- to seven-membered heterocycles to building blocks with heteroatoms O, N and S in the 1,2-, 1,3- and 1,4-position is presented. Their use in the cyclization of medium-large rings is exemplified. Retrosyntheses and syntheses of biologically active heterocyclic compounds, lanycil, sulfisoxazole , sulfamethoxazole, primicarb, hydralazine and glutethimide, are presented. Cyclizations to three- to seven-membered heterocycles with one or more heteroatoms in the ring obey the Baldwin rules. The mechanistic origin of the favored route and heuristic value of the Baldwin rules are discussed.