Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:36]=[CH:35][C:27]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[CH:11]=1.[I-].[Na+].C(N(CC)CC)C.[F:46][C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49]Br>C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:49][C:48]2[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=2[F:46])[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:35][CH:36]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:18])=[O:19])[CH:11]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OS(=O)(=O)C(F)(F)F)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: Fc1ccccc1CBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OS(=O)(=O)C(F)(F)F)c2)N2C[C@@H](C)N(Cc3ccccc3F)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-1-piperazinyl)-3-trifluoromethylsulfonyloxy-benzyl)-N,N-diethylbenzamide (from Example 10, 527.6 mg, 1.0 mmol) was dissolved in acetonitrile (4.0 mL) and sodium iodide (15 mg, 0.1 mmol) added. The suspension was stirred during the addition of triethylamine (500 □L (363 mg), 3.59 mmol), followed by 2-fluorobenzyl bromide (241 □L (378 mg), 2.0 mmol). The reaction mixture was sealed under nitrogen and stirred overnight at room temperature. The reaction mixture was evaporated to dryness and partitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (2.5 mL). The supernatant organic layer was removed, and the aqueous portion washed with ethyl acetate (3×10 mL). The combined organic extract and washings were dried over anhydrous sodium sulfate and evaporated to a golden oil. The residue was dissolved in ethyl acetate (7 mL), applied to a pre-packed (Biotage) column and eluted with ethyl acetate. Pure fractions containing desired product, as evidenced by t.l.c. (silica gel, EM60F264, 100% ethyl acetate, Rf=0.77) were evaporated to dryness to yield the intermediate 4-((alpha-R)-alpha-((2S,5R)-2,5-Dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-trifluoromethylsulfonyloxybenzyl)-N,N-diethylbenzamide (610 mg), as a yellow oil which was used without further purification. The oil was dissolved in ethanol (7 mL) and aqueous 2.5 M (10%) sodium hydroxide solution (5 mL, 12.5 mmol) was added. The reaction mixture was set aside at room temperature for 5 h, then the ethanol removed by evaporation. The oily suspension of the sodium salt was clarified by the addition of water (5 mL), and the pH of the solution adjusted to 9-10 by the passage of gaseous carbon dioxide (from dry ice). The copious white precipitate was washed well with water and dried under vacuum (2 mm Hg) at room temperature overnight to yield 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(2-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide as a white solid (431 mg, 85.6%). Calc. for C31H38FN3O2:C, 73.93; H, 7.61; N, 8.34; F, 3.77. Found C, 73.96; H, 7.67; N, 8.29; F, 3.75%. 1H NMR (CDCl3, 300 MHz); δ 1.05 (d, J=6.1 Hz, 3H); 1.09 (d, J=6 Hz, 3H); 1.12 (br m, 3H); 1.24 (br m, 3H); 1.96 (t, J=10 Hz, 1H); 2.07 (t, J=10 Hz, 1H); 2.56 (br m, 2H); 2.60 (d, J=11 Hz, 1H); 2.72 (d, J=11 Hz, 1H); 3.29 (br m, 2H); 3.36 (d, J=14 Hz, 1H); 3.55 (br m, 2H); 3.89 (d, J=14 Hz, 1H); 5.13 (s, 1H); 6.57 (s, 1H); 6.66 (d, J=10 Hz, 2H); 7.00 (t, J=9 Hz, 1H); 7.07 (t, J=7.5 Hz, 1H); 7.10 (t, J=8 Hz, 1H); 7.20 (m, 1H); 7.27 (d, J=8 Hz, 2H); 7.38 (t, J=7 Hz, 1H); 7.43 (d, J=7 Hz, 2H).