Scheme 1.

Synthesis of substituted isoxazolo[3,4-d]pyridazinones. (A). Method A, direct metalation of 2a–f conducted in THF. (B). Method B, mono-substitution of acetal 5, followed by deprotection and cyclization of hydrazone 7. Reagents: a. corresponding ArNHNH₂ (Aryl hydrazine), b. non-nucleophilic base, THF, and low temperature, as noted in Table 1, allow to warm to ambient temperature, c. 2,2-dimethyl-propane-1,3- diol, p-Toluenesulfonic acid (PTSA), reflux, d. non-nucleophilic base, low temperature, THF, followed by electrophile, e. addition of corresponding ArNHNH₂, reflux.