(Z)-3-(3-(3,5-bis(trifluoroMethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3,3-

Synthesis of (Z)-3 -(3 -(3 , 5 -bis(trifluoromethyl)phenyl)- 1 H- 1 , 2, 4-triazol- 1 -y 1) - 1 -(3 , 3 - difluoroazetidin- 1 -yl)prop-2-en- 1 -one: To a 3-L, four-necked, round-bottomed flask equipped with nitrogen inlet, addition funnel, thermometer socket, mechanical stirrer was added (Z)-3-(3-(3, 5- bis(trifluoromethyl)phenyl)-lH-l , 2, 4-triazol-l-yl)acrylic acid (100 g, 1.0 eq.) in DCM (1.8 L, 18 V). The reaction mixture was cooled to -lOoC. To the cooled solution, were added HOBT (4.4 g, 0.1 eq.), EDC-HC1 (80.6 g, 1.5 eq.) and 3, 3-difluoroazetidine hydrochloride (44 g, 1.2 eq.). To the resulting mixture at -10 oC, was added DIPEA (72 mL, 1.5 eq) dropwise over a period of 1.5 hours. The progress of the reaction was monitored by HPLC analysis which showed the completion of the reaction at the end of DIPEA addition. The reaction temperature was slowly raised to 15 °C to 20 °C (~ 2h). The reaction mixture was quenched with 1L ice-water slurry. The organic layer was separated and the aqueous layer was extracted with DCM (400 mL x 2). The organic layer was washed with saturated brine solution (2 x 500 ml), dried over anhydrous NaSynthesis of (Z)-3 -(3 -(3 , 5 -bis(trifluoromethyl)phenyl)- 1 H- 1 , 2, 4-triazol- 1 -yl)- 1 -(3 , 3 - difluorIn a 25-mL, three-necked, round-bottomed flask equipped with nitrogen inlet, 3-(3, 5- bis(trifluoromethyl)phenyl)-lH-l , 2, 4-triazole (0.18 g, 1.0 eq.) was dissolved in DMF (5.0 mL, 27.0 V), and DABCO (0.143 g, 2.0 eq) and (Z)-l-(3, 3-difluoroazetidin-l -yl)-3-iodoprop- 2-en-l -one (0.192 g, 1.1 eq) were added. The reaction mixture was stirred at RT for 2-3 hr. The progress of the reaction was followed by TLC analysis on silica gel with 80percent> ethyl acetate-hexane as mobile phase, SM Rf =0.60 and Product Rf = 0.4. Reaction mixture was poured in to ice water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine solution (3 x 25 mL), dried over MgS0(Z)-3-(3-(3, 5-Bis(trifluoromethyl)phenyl)-1H- 1, 2, 4-triazol- l-yl)acrylic acid (8) (30 g, 85.47 mmol) was dissolved in CH