Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Si:31]([O:48][C@@H:49]([CH2:86][F:87])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C@@H:59]([NH:68][C:69]2[CH:74]=[CH:73][C:72]([S:75]([NH2:78])(=[O:77])=[O:76])=[CH:71][C:70]=2[S:79]([C:82]([F:85])([F:84])[F:83])(=[O:81])=[O:80])[CH2:60][S:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:53][CH2:52]1)([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Si](O[C@H](CF)CN1CCN(CC[C@@H](NC2C=CC(S(N)(=O)=O)=CC=2S(C(F)(F)F)(=O)=O)CSC2C=CC=CC=2)CC1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Si:31]([O:48][CH:49]([CH2:86][F:87])[CH2:50][N:51]1[CH2:56][CH2:55][N:54]([CH2:57][CH2:58][C@@H:59]([NH:68][C:69]2[CH:74]=[CH:73][C:72]([S:75]([NH:78][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([N:18]4[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[OH:30])[CH2:16][CH2:17]4)=[CH:22][CH:23]=3)(=[O:77])=[O:76])=[CH:71][C:70]=2[S:79]([C:82]([F:84])([F:83])[F:85])(=[O:80])=[O:81])[CH2:60][S:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH2:53][CH2:52]1)([C:44]([CH3:45])([CH3:46])[CH3:47])([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(N2CCC([C@@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](O[C@@H](CF)CN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Si](O[C@H](CF)CN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(N)(=O)=O)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)[Si](OC(CF)CN1CCN(CC[C@H](CSc2ccccc2)Nc2ccc(S(=O)(=O)NC(=O)c3ccc(N4CCC([C@@H](O)c5ccccc5-c5ccc(Cl)cc5)CC4)cc3)cc2S(=O)(=O)C(F)(F)F)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 58 mg, 0.14 mmol), 4-((R)-4-(4-((R)-2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide and 4-((R)-4-(4-((S)-2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide mixture of diastereomers (INTERMEDIATE 39, 120 mg, 0.14 mmol), DMAP (34 mg, 0.28 mmol), and EDC (53 mg, 0.28 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (2.8 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with 1N aq. sodium bisulfate followed by a saturated aq. sodium bicarbonate. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give N-(4-((2R)-4-(4-(2-(tert-butyldiphenylsilyloxy)-3-fluoropropyl)piperazin-1-yl)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide (EXAMPLE 6, STEP 1, 180 mg), which was used in the preparation of EXAMPLE 6, STEP 2, without further purification.