The recently discovered pyrazolo[1,5-b][1,2,4,6]thiatriazine template was shown to possess four nucleophilic sites (N2, N4, C5, N7) that underwent a range of substitution reactions. Methylation occurred at both N4 and N7. Alkylation with benzylic halides occurred preferentially at N7, regardless of the solvent, but also occurred at C5, N4, and N2. Similar alkylation with -halo esters occurred at both N4 and N7, but the latter derivatives underwent a novel pyrazole ring expansion to afford pyrimido[1,6-b][1,2,4,6]thiatriazine derivatives. Bromination of pyrazolo[1,5-b][1,2,4,6]thiatriazines afforded unstable 5-bromo derivatives. Tosylation occurred selectively at C5, but in modest yield; catalysis with 1-methylimidazole also led to a low yield of the 5,5′-dimer. The action of HCl on N7-benzylated pyrazolo[1,5-b][1,2,4,6]thiatriazines readily caused extrusion of sulfur dioxide to produce pyrazolo-guanidines.