4-(tert-Butyl-dimethyl-silanyloxy)-benzaldehyde oxime (which may be prepared according to the procedure described in Kao, Y. T. R. et al. US 20110212975 page 17; ˜20 g, ˜80 mmol) was dissolved in DMF (50 mL) and the solution was cooled to 0° C. N-Chlorosuccinimide (12.8 g, 96 mmol) was added in portions. The reaction mixture was stirred at 0° C. for 30 min, allowed to warm to room temperature and stirred at room temperature for 1.5 h. The reaction mixture was poured into ice-water (100 mL) and the resulting suspension was extracted with EtOAc (100 mL). The organic extract was dried over Na2SO4, filtered, and evaporated. Et2O (120 mL) was added to the residue, and then a solution of ethyl propiolate (16 mL, 158 mmol) and triethylamine (12 mL) in Et2O (120 mL) was added dropwise. The mixture was stirred at room temperature for 48 h. The reaction mixture was filtered and the filtrate was evaporated to give a brown oil which was purified by filtration through a silica gel plug (eluting with 12% EtOAc/hexanes) followed by silica gel chromatography. Final purification was accomplished using preparatory supercritical fluid chromatography (100 bar CO2 modified with 10% MeOH, flow rate of 2 mL/min at 30° C.) to give 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-isoxazole-5-carboxylic acid ethyl ester (600 mg, 2%).
