A solution of 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid (360 mg, 0.84 mmol) in 5.0 mL of DCM was treated with oxalyl chloride (0.84 mL of 2.0 M in DCM solution, 1.68 mmol) followed by two drops of DMF while cooling in an ice bath at 0° C. It was stirred at this temperature for 15 min then allowed to stir at RT for 45 min. The reaction mixture was then concentrated under reduce pressure to remove the excess oxalyl chloride. The residue was dissolved in 5.0 mL of DCM, treated with 3-aminoisoxazole (212 mg, 2.52 mmol) followed by Et3N (0.18 mL, 1.26 mmol) and stirred for 18 h. The reaction mixture was treated with 15 mL saturated NaHCO3 and extracted with DCM (2×15 mL). The combined DCM layers were dried over MgSO4. Purification on the ISCO (12 g column, 20-70% EtOAc in hexanes) afforded 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide as a light yellow amorphous solid. MS (ES+): 495.1 (M+H)+.
