A simple and efficient method for the combinatorial synthesis of highly substituted thiopyrano[3,4-b]pyridin-5(4H)-one, thiopyrano[3,4-b]quinoline-4,6(3H,5H)-dione, dithiopyrano[3,4-b:4',3'-e]pyridine-4,6(1H,3H)-dione, and pyrazolo[3,4-b]thiopyrano[4,3-e]pyridin-5(1H)-one derivatives has been developed. The synthesis was achieved via one-pot multicomponent reaction of aromatic aldehyde, 2H-thiopyran-3,5(4H,6H)-dione and enamine (such as the derivatives of amine and 1,3-dicarbonyl compounds and 3-methyl-1-phenyl-1H-pyrazol-5-amine) in glacial acetic acid. This procedure features short reaction time, generally good to excellent yields, easily available starting materials, and operational simplicity. This chemistry provides an efficient and promising synthetic strategy to diversity-oriented construction of the thiopyrano[3,4-b]pyridine skeleton.