[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.[Br:25][C:26]1[C:27]([C:33]#[N:34])=[N:28][CH:29]=[C:30](F)[CH:31]=1.Cl>CN1C(=O)CCC1.ClCCl>[Br:25][C:26]1[CH:31]=[C:30]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:29]=[N:28][C:27]=1[C:33]#[N:34]This example describes the procedure for conversion of (A1) to (A3) as shown in Scheme 1. Tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate was purchased from Small Molecules, Inc. (CAS: 365996-30-1, Hoboken, N.J.). DIPEA (18.5 mL, 106 mmol) and tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (17.7 g, 82.7 mmol) were added to 3-bromo-5-fluoropyridine-2-carbonitrile (Frontier Scientific; CAS: 950670-18-5, Logan, Utah) (16.4 g, 81.6 mmol) dissolved in NMP (16.3 mL) in a 150 mL sealed tube. The reaction was heated to 120° C. for 24 hours before cooling to ambient temperature. Hydrochloric acid (1.0 M in water, 100 mL, 100 mmol) was added. Dichloromethane was then added dropwise until a freely stirring suspension was formed. The precipitate was collected by filtration, washed with cold diethyl ether (30 mL), and dried under reduced pressure to afford a portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)-amino]cyclohexyl}carbamate. The mother liquors were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and water to yield an additional portion of tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate. MS ESI calc'd. for C17H24BrN4O2 [M+H]+ 395 and 397. found 395 and 397. 1H NMR (500 MHz, CD3OD) δ 8.02 (d, J=2.3 Hz, 1H), 7.23 (br s, 1H), 6.59-6.46 (m, 1H), 3.83 (s, 1H), 1.65 (s, 6H), 1.56-1.17 (m, 11H).
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