Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[N:24]([CH2:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30][CH2:29]2)[CH2:25][CH3:26])=[N:10][CH:11]=1.[H-].[Na+].Br[CH:43]([C:45]1[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[C:47]([C:55]([F:58])([F:57])[F:56])[CH:46]=1)[CH3:44].O>O1CCCC1.CN(C)C=O>[F:52][C:51]([F:53])([F:54])[C:49]1[CH:50]=[C:45]([CH:43]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:22])([F:21])[F:23])[CH:17]=[CH:16][C:15]=2[N:24]([CH2:27][C@H:28]2[CH2:29][CH2:30][C@H:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH2:33]2)[CH2:25][CH3:26])[C:9]2[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=2)[CH3:44])[CH:46]=[C:47]([C:55]([F:56])([F:57])[F:58])[CH:48]=1.[F:56][C:55]([F:58])([F:57])[C:47]1[CH:46]=[C:45]([CH:43]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=2[N:24]([CH2:27][C@H:28]2[CH2:33][CH2:32][C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:30][CH2:29]2)[CH2:25][CH3:26])[C:9]2[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=2)[CH3:44])[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CNc2ncc(OCCSC)cn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCSC)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(C(F)(F)F)cc2CN(c2ncc(OCCSC)cn2)C(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl trans-{4-[({2-[({5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetate (10.2 mg, 0.018 mmol) in tetrahydrofuran (0.3 mL) under ice cooling was added sodium hydride (50% in oil, 3.4 mg, 0.072 mmol), and the mixture was stirred at room temperature for 30 minutes. After cooling to −78° C., to the reaction mixture was added a solution of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane (6.9 mg, 0.021 mmol) in N,N-dimethylformamide (0.3 mL), and the mixture was stirred for 14 hours with warming to room temperature. The reaction mixture was added with water, and extracted with ethyl acetate, and the organic layer was washed twice with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→chloroform:methanol=20:1) to obtain ethyl trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetate (compound of Example 43, 1.8 mg, 12%) as a pale yellow oil, and trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylthio)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (compound of Example 44, 3.2 mg, 23%) as a pale yellow oil.