We report a mild and efficient approach to the optically pure 6H-oxazolo[3,2-f]pyrimidine-5,7-dione scaffold via the unexpected rearrangement and ring contraction of 2,3-dihydropyrimido[6,1-b][1,5,3]dioxazepine-7,9(5H,8H)-diones derived from nucleoside precursors. The developed procedure enables the synthesis of a wide range of compounds with great structural diversity. The structure of the obtained compounds was confirmed by NMR spectroscopy and single crystal X-ray structural analysis. The final products were tested for cytotoxic effect on one non-cancerous (fibroblasts) and six cancer cell lines of different origin (colon, glioma, breast, cervix, vulvar, and lung). The synthesized products are low molecular weight compounds with lead-like properties suitable for a medicinal chemistry optimization program.