Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)=O.N1C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=1)[CH2:29][N:30]1[CH2:35][C@H:34]([CH3:36])[NH:33][CH2:32][C@H:31]1[CH3:37].[Si]([O:48][C:49]1[CH:50]=[C:51]([Mg]Br)[CH:52]=[CH:53][CH:54]=1)(C(C)(C)C)(C)C.Cl>O1CCCC1.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=1)[CH2:29][N:30]1[CH2:35][C@H:34]([CH3:36])[NH:33][CH2:32][C@H:31]1[CH3:37].[F:25][C:26]1[CH:27]=[C:28]([CH:38]=[CH:39][CH:40]=1)[CH2:29][N:30]1[C@H:31]([CH3:37])[CH2:32][N:33]([C@@H:1]([C:53]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:48])[CH:54]=2)[C:3]2[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=2)[C@@H:34]([CH3:36])[CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc([Mg]Br)c1
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Agent: C[C@@H]1CN[C@@H](C)CN1Cc1cccc(F)c1
Agent: Cl
Agent: c1ccc2[nH]nnc2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Temperature: 25 °C

Procedure:
In a 3 L round bottom flask fitted with a condenser and Dean-Stark trap are combined 4-formyl-N, N-diethylbenzamide (20.53 g, 100 mmol), benzotriazole (11.91 g, 100 mmol), and (2R,5S)-1-(3-flourobenzyl)-2,5-dimethylpiperazine (22.23 g, 100 mmol, Chirotech Division of Dowpharma, The Dow Chemical Company, Cambridge, England) with 1000 mL of toluene. The reaction is heated to reflux under nitrogen until no additional water is observed in the trap (ca. 3 hours). The reaction is cooled to room temperature and concentrated under vacuum to leave a volume of approximately 300 mL. Anhydrous tetrahydrofuran (500 mL) is added to the benzotriazole adduct under nitrogen with stirring until dissolved. To this solution is added to the solution of 3-tert-butyldimethylsilyloxyphenylmagnesium bromide (from Method A) at room temperature via double-ended needle. After stirring for approximately 2 hours, the reaction is quenched by the addition of saturated aqueous ammonium chloride solution (50 mL) and stirred for 15 minutes. Anhydrous magnesium sulfate (50 g) is added, stirred for approximately 1 hour, and the reaction is filtered. The solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate (1000 mL). The ethyl acetate solution is washed with 1 M sodium hydroxide (5×400 mL), water (4×400 mL), and saturated aqueous sodium chloride solution (400 mL). The organic layer is dried over anhydrous magnesium sulfate and the solvent is removed to give a viscous oil. The oil is dissolved in 500 mL of tetrahydrofuran and 300 mL of 3 M hydrochloric acid and stirred for approximately 1.5 hours at room temperature. Upon completion of the desilylation, the reaction is diluted with water (300 mL) and concentrated under vacuum to about half the original volume. This solution is extracted with pentane (2×500 mL). The aqueous layer is adjusted to pH 8-9 with 5 M sodium hydroxide and extracted with ethyl acetate (250 mL). The layers are separated and the aqueous portion is extracted with more ethyl acetate (250 mL). The combined organic extracts are washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to give a viscous oil. This residue is dissolved in ethyl acetate (25 mL), seeded with crystals of the authentic compound, and allowed to crystallize overnight (seed crystals can be obtained from hot 2-propanol with addition of water). The crystals are filtered and washed sparingly with cold ethyl acetate. Drying under 5 mm Hg at room temperature yields the desired product 4-[(R)-((2S,5R)-4-(3-fluorobenzyl)-2,5-dimethyl-1-piperazinyl)-(3-hydroxy-phenyl)-methyl]-N,N-diethylbenzamide as tan to off-white crystals, free from the undesired epimer. This solid is dissolved in isopropanol (300 mL) upon heating to boiling, and water (200 mL) is added slowly while swirling and keeping the solution hot. Crystallization occurs as solution begins to cool and is allowed to proceed overnight. Crystals are collected and washed sparingly with cold isopropanol: water/1:1. Drying under 5 mm Hg at 40° C. for 48 hours yields 4-[(R)-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)(3-hydroxyphenyl)methyl]N,N-diethyl-benzamide as ivory colored crystals (expected yield ˜30% from 4-formyl-N,N-diethylbenzamide).