Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]2[C:18](/[CH:19]=[C:20](\[CH3:30])/[C:21]([NH:23][CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([B:31]4[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]4)[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.C([O-])(=O)C.[K+].Br[C:48]1[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][N:49]=1>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:18](/[CH:19]=[C:20](\[CH3:30])/[C:21]([NH:23][CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([B:31]4[O:32][C:33]([CH3:39])([CH3:38])[C:34]([CH3:37])([CH3:36])[O:35]4)[CH:15]=3)[N:10]=2)=[CH:40][CH:41]=1.[CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][NH:8][C:9]2[C:18](/[CH:19]=[C:20](\[CH3:30])/[C:21]([NH:23][CH2:24][CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:22])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:48]4[C:53]([CH3:54])=[CH:52][CH:51]=[CH:50][N:49]=4)[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1cccnc1Br
Agent: CC(=O)[O-]
Agent: COc1ccc(CNc2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3cc2/C=C(\C)C(=O)NCCC(C)(C)C)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2nc3ccc(-c4ncccc4C)cc3cc2/C=C(\C)C(=O)NCCC(C)(C)C)cc1

Procedure:
Lithium chloride (2.41 g, 56.7 mmol) is stirred 4 h in MeCN (300 mL). To the cloudy solution was added 2-(4-methoxybenzylamino)-6-bromoquinoline-3-carbaldehyde 7 (10.5 g, 28.4 mmol, prepared as in scheme II), ethyl 2-(diethoxyphosphoryl)propanoate (7.4 L, 34.0 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (4.3 ml, 28.4 mmol) and the reaction is stirred 12 h. The reaction is partitioned between 10% sodium carbonate solution and EtOAc. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with 10% sodium carbonate, brine, dried over sodium sulfate, filtered, and concentrated. The crude mixture is purified by silica gel chromatography eluted with 4:1 Hexanes/EtOAc to afford (E)-ethyl 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylate (representative compound 14). Step 2 A 1M aqueous solution of LiOH (10.0 ml, 10.0 mmol) was added to a solution of (E)-ethyl 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylate ((representative compound 14; 3.6 g, 7.9 mmol) in MeOH (10 mL) and THF (30 mL) at RT. The reaction was stirred 1 h. The organic solvent was removed in vacuo and the remaining aqueous solution was brought to a pH ˜1 with 1N HCl and the solution was extracted with a 2:1 chloroform/i-PrOH mixture. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford (E)-3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylic acid (representative compound 15) which was used without further purification. Step 3 TBTU (1.2 g, 3.7 mmol) was added to (E)-3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylic acid (1.2 g, 2.8 mmol), 3,3-dimethylbutylamine (1.1 ml, 8.4 mmol), and DIEA (2.0 ml, 11 mmol) in NMP (10 mL) and the reaction was stirred 1 h. The reaction was poured into a vigorously stirred solution of saturated aqueous sodium bicarbonate and after 30 min was diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with water, brine, and dried over sodium sulfate, filtered, and concentrated to afford (E)-3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylacrylamide (representative compound 16) which was used without further purification. Step 4 (E)-3-(2-(4-methoxybenzylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylacrylamide (representative compound 17) was prepared as in Step 7 of Scheme II. Step 5 Bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)dichloropalladium (II) (0.041 g, 0.058 mmol) was added to a degassed solution of (E)-3-(2-(4-methoxybenzylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylacrylamide (0.65 g, 1.2 mmol), potassium acetate (0.23 g, 2.3 mmol), and 2-bromo-3-methylpyridine (0.20 mL, 1.8 mmol) in EtOH (12 mL) and water (2 mL). The resulting solution was refluxed for 12 h. Then the reaction mixture was cooled and partitioned between DCM and 9:1 saturated ammonium chloride/ammonium hydroxide aqueous solution. The aqueous layer was extracted with DCM and the combined organics were washed with a 9:1 saturated ammonium chloride/ammonium hydroxide solution, water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (1:1 Hex/EtOAc) to afford (E)-3-(2-(4-methoxybenzylamino)-6-(3-methylpyridin-2-yl)quinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylacrylamide (representative compound 18). Step 6 Palladium on carbon (0.71 g, 0.67 mmol) was added to a solution of (E)-3-(2-(4-methoxybenzylamino)-6-(3-methylpyridin-2-yl)quinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylacrylamide (0.35 g, 0.67 mmol) in EtOH (6 mL). The flask was degassed with hydrogen gas and then stirred under a balloon of hydrogen 12 h. The reaction was filtered through celite and washed with ethanol and ethyl acetate. The filtrate was concentrated to afford 3-(2-(4-methoxybenzylamino)-6-(3-methylpyridin-2-yl)quinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylpropanamide (representative compound 19) which was used without further purification. Step 7 TFA (6.0 mL, 78 mmol) was added to 3-(2-(4-methoxybenzylamino)-6-(3-methylpyridin-2-yl)quinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylpropanamide (0.30 g, 0.57 mmol) and the reaction was heated to 65° C. After 5 h, the reaction was concentrated and the crude material dissolved in DCM. The organic layers were washed with 1N NaOH and the aqueous layer was again extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (20:1 DCM/MeOH with 2M NH3) to afford 3-(2-amino-6-(3-methylpyridin-2-yl)quinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylpropanamide (representative compound 20). MS (ESI, pos. ion) m/z: 405 (M+1). Step 8 The product of step 7, a racemic mixture, was purified via preparative Supercritical Fluid Chromatography (SFC), to afford the individual enantiomers. SFC was conducted using 12% isopropanol with 0.2% diethylamine in supercritical carbon dioxide, which provided peak 1 at approximately 4.59 minutes elution time and peak 2 at approximately 5.55 minutes elution time. Peak 1 was identified as the S isomer 21, while peak number 2 was identified as the R isomer, compound 22.