The general procedure for the synthesis of 5-(1-((2-(4-cyclopropylpiperazin-1-yl)pyridin-4-yl)methyl)-5-methyl-1H-pyrazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1 ,2,4-oxadiazole from 1-ethoxy-1-trimethylsilanyloxycyclopropane and the compound (CAS:1227158-84-0) was as follows: in Example 65 Example 65, 66 mL (1.15 mmol) of glacial acetic acid, 13.9 g of dry powdered molecular sieves (3 ) and 139 mL (0.692 mol) of 1-ethoxy-1-(trimethylmethylsilyl)hydroxycyclopropane were sequentially added to a solution of 56.0 g (0.115 mol) of the compound of Example 64 in 1.13 L of methanol. After stirring for 10 minutes at room temperature, 21.7 g (0.346 mol) of solid sodium cyanoborohydride was added. The mixture was heated under reflux conditions for 1 hour. After cooling to room temperature, the undissolved material was removed by filtration and the filtrate was concentrated on a rotary evaporator. The residue was dissolved in 1 L of ethyl acetate and washed twice with 750 mL of saturated sodium bicarbonate solution for about 1 hour each time, followed by 750 mL of saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the mixture was filtered and the solvent was removed on a rotary evaporator. The residue (53 g) was recrystallized from a boiling mixture of 293 mL of ethanol and 59 mL of water. After crystallization was complete (about 20 hours at room temperature), the mixture was filtered. The solid was washed with 36 mL of ethanol/water (5:1) and then dried under high vacuum. 26.4 g of the target compound was obtained as the first product. The crystallized mother liquor was concentrated and another 20.3 g of product was obtained as formate by preparative HPLC (Method N). To release the base, a suspension of formate in 1 L of ethyl acetate was washed sequentially with 200 mL of saturated sodium bicarbonate solution, water and saturated sodium chloride solution. After drying with anhydrous sodium sulfate, it was filtered and concentrated. The residue (13 g) was recrystallized from a boiling mixture of 80 mL ethanol and 16 mL water. After crystallization was complete (about 4 hours at room temperature), the solid was filtered and dried to give an additional 11.2 g of the target compound (total yield 37.6 g, 62% of theoretical yield). Melting point: 140 °C. 1H-NMR (400 MHz, CDCl3, δ/ppm): 8.26 (d, 2H), 8.13 (d, 1H), 7.33 (d, 2H), 6.83 (s, 1H), 6.33 (d, 1H), 6.32 (s, 1H), 5.35 (s, 2H), 3.47 (dd, 4H), 2.69 ( dd, 4H), 2.30 (s, 3H), 1.65-1.60 (m, 1H), 0.48-0.42 (m, 4H).LC/MS (Method D, ESIpos): rt = 1.91 min, m/z = 526 [M + H]+.
