3.4. General Procedure for the Synthesis of 5-Aminoisoxazole-4-Carboxamides (8a–k)

A fresh solution of NaOEt in EtOH, prepared at room temperature from sodium (1.5 equiv.) and absolute EtOH (~40 equiv.), was added dropwise to a stirred solution of 2-cyanoacetamide (1.0 equiv.) in absolute EtOH at 50 °C. The resulting suspension was then cooled in an ice bath, and the solution of N-hydroxyimidoyl chloride (7a–k) (1.0 equiv.) in EtOH was added dropwise. The mixture was stirred for an additional 30 min at 0 °C and then refluxed for 18 h. After completion of the reaction, EtOH was removed under reduced pressure. If possible, the resulting solid was washed with H₂O and recrystallized from MeOH to yield a crystalline solid (8a–k). Otherwise, the solid was dissolved in EtOAc, washed with brine, and dried over anhydrous Na₂SO₄. EtOAc was removed under reduced pressure and the remaining solid was purified using flash column chromatography with gradient EtOAc/n-Hex as an eluent.

NaH (1.2 equiv.) was added to a stirred solution of 2-cyanoacetamide (1.0 equiv.) in anhydrous DMF. After 15 min, a solution of appropriate N-hydroxyimidoyl chloride (7a–k) in anhydrous DMF was added dropwise. The reaction mixture was stirred under an inert atmosphere for 2 h at room temperature and then at 70 °C for 18 h. After completion of the reaction H₂O was added and extracted with EtOAc. Combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, and the solvents were removed under reduced pressure to yield 5-aminoisoxazole-4-carboxamides (8a–k), which were used in the next step without any purification.