Ethyl Acetate → (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

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(R)-Pyrrolidin-3-ol (9.55 g, 109.6 mmol) and DIPEA (35.1 ml, 201.3 mmol) were added to a suspension of 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 9.3, 37.7 g, 91.5 mmol) in iPrOH (65 mL) and stirred at 140° C. for 1 h. EtOAc (700 mL) was added and the solution was washed 1N HCl (2×200 mL), sat. NaHCO3 (200 mL) and brine (2×200 mL), dried over Na2SO4, and the solution was concentrated under reduced pressure until crystallization commenced. n-Heptane (1 L) were added and the mixture was stirred at RT for 30 min, filtered and washed with iPr2O (500 mL) to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR=6.68 min, UPLC-MS (Condition 3) tR=1.10 min, m/z=462.2/464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.01 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.66-3.75 (m, 1H) 3.79-3.93 (m, 2H) 4.34 (br. s, 1H) 4.98 (d, =3.13 Hz, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 2H) 8.33 (d, J=1.96 Hz, 1H) 8.66 (d, J=1.96 Hz, 1H) 10.21 (s, 1H).

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