Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[C:32]([CH:40]1[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:47])[CH2:42][CH2:41]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:32]([OH:39])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:40]3[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:47])[CH2:42][CH2:41]3)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: CC(=O)N1CCC(C(=O)c2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2ccc(C(O)(c3ccccc3)C3CCN(C(C)=O)CC3)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.208 mL, 0.333 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (150 mg, 0.350 mmol, Intermediate 16) in dry THF (3.5 mL) at −78° C. After 3 minutes, a solution of 1-(4-benzoylpiperidin-1-yl)ethanone (80.9 mg, 0.350 mmol, Intermediate 52) in dry THF (3.5 mL) was added dropwise. An additional 0.5 mL of dry THF was used to quantitate the transfer. The reaction mixture was stirred for 5 minutes at −78° C., and the flask was placed into an ice-water bath. After 30 minutes, water (5 mL) was added. The biphasic mixture was warmed to room temperature then partitioned between water (25 mL) and ethyl acetate (40 mL). The layers were separated. The organic layer was dried with sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate-hexanes initially, grading to 100% ethyl acetate) and then by reverse phase HPLC [5% acetonitrile-water (containing 0.05% TFA v/v) initially, grading to 5% water (containing 0.05% TFA v/v)-acetonitrile] to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 8.31-8.25 (m, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.80-7.72 (m, 1H), 7.71-7.61 (m, 2H), 7.59-7.47 (m, 4H), 7.39-7.29 (m, 4H), 7.27-7.19 (m, 1H), 6.46-6.40 (m, 1H), 4.76-4.62 (m, 1H), 4.31 (s, 2H), 4.05 (s, 3H), 3.83 (t, J=16.3 Hz, 1H), 3.17-3.00 (m, 1H), 2.83-2.71 (m, 1H), 2.66-2.53 (m, 1H), 2.06 (s, 3H), 1.75-1.29 (m, 4H). MS (ESI): mass calcd. C34H33ClN4O3, 580.2; m/z found, 581.2 [M+H]+. This racemate was separated by chiral HPLC (Chiralpak AD column, 250 gram, 50 mm×21 cm, ethanol eluent, 80 mL/minute, 240 nm wavelength) to give two enantiomers. The first eluting enantiomer was Example 83B: 1H NMR (500 MHz, CDCl3) δ ppm 8.29 (dd, J=8.1, 2.1 Hz, 1H), 7.87-7.82 (m, 1H), 7.79-7.72 (m, 1H), 7.71-7.61 (m, 2H), 7.59-7.48 (m, 4H), 7.38-7.29 (m, 4H), 7.26-7.18 (m, 1H), 6.46-6.39 (m, 1H), 4.75-4.61 (m, 1H), 4.31 (s, 2H), 4.05 (s, 3H), 3.81 (t, J=16.2 Hz, 1H), 3.14-3.00 (m, 1H), 2.82-2.69 (m, 1H), 2.64-2.51 (m, 1H), 2.03 (s, 3H), 1.76-1.20 (m, 4H); MS (ESI): mass calcd. C34H33ClN4O3, 580.2; m/z found, 581.2 [M+H]+ and the second eluting enantiomer was Example 83C: 1H NMR (500 MHz, CDCl3) δ ppm 8.29 (dd, J=8.1, 2.1 Hz, 1H), 7.85 (d, J=2.3 Hz, 1H), 7.79-7.72 (m, 1H), 7.71-7.61 (m, 2H), 7.59-7.48 (m, 4H), 7.38-7.29 (m, 4H), 7.26-7.18 (m, 1H), 6.45-6.40 (m, 1H), 4.75-4.60 (m, 1H), 4.31 (s, 2H), 4.05 (s, 3H), 3.89-3.75 (m, 1H), 3.15-2.98 (m, 1H), 2.82-2.70 (m, 1H), 2.64-2.49 (m, 1H), 2.04 (s, 3H), 1.75-1.28 (m, 4H); MS (ESI): mass calcd. C34H33ClN4O3, 580.2; m/z found, 581.2 [M+H]+.