Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=O.[CH3:13][C@@H:14]1[C@@H:19]([NH:20][C:21]([CH:23]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[N:24]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][C@H:39]([CH2:47][N:48]([CH3:50])[CH3:49])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:32]=2)=[O:22])[CH2:18][C@H:17]2[CH2:51][C@@H:15]1[C:16]2([CH3:53])[CH3:52].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[CH3:13][C@@H:14]1[C@@H:19]([NH:20][C:21]([CH:23]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[N:24]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]([CH2:4][C:3]3[C:6]([O:11][CH3:12])=[CH:7][CH:8]=[C:9]([F:10])[C:2]=3[F:1])[C@H:39]([CH2:47][N:48]([CH3:49])[CH3:50])[CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:32]=2)=[O:22])[CH2:18][C@H:17]2[CH2:51][C@@H:15]1[C:16]2([CH3:52])[CH3:53]
Reactant: COc1ccc(F)c(F)c1C=O
Reactant: C[C@@H]1[C@@H](NC(=O)C2CCS(=O)(=O)N2Cc2cccc(CN[C@@H](Cc3ccccc3)CN(C)C)c2)C[C@H]2C[C@@H]1C2(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(F)c(F)c1CN(Cc1cccc(CN2C(C(=O)N[C@H]3C[C@H]4C[C@@H]([C@@H]3C)C4(C)C)CCS2(=O)=O)c1)[C@@H](Cc1ccccc1)CN(C)C
Yield: 40.7 %

Procedure:
2,3-Difluoro-6-methoxy-benzaldehyde (from Step 1; 29 mg, 0.17 mmol) was added to a solution of 2-{3-[((S)-1-dimethylaminomethyl-2-phenyl-ethylamino)-methyl]-benzyl}-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicylo[3.1.1]hept-3-yl)amide (Intermediate 5; 90 mg, 0.16 mmol) in methanol (3 mL) at room temperature under argon. The mixture was stirred for a few minutes and then sodium cyanoborohydride (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 5 mg, 0.08 mmol) and glacial acetic acid (78 μL) were added. The mixture was stirred for 4 h at room temperature. 2,3-Difluoro-6-methoxy-benzaldehyde (from Step 1; 5 mg, 0.03 mmol) was added, followed by sodium cyanoborohydride (3 mg, 0.05 mmol) was added. The mixture was stirred for 4 h at room temperature. The mixture was stirred overnight at room temperature, and it was then concentrated under reduced pressure to remove methanol. Ethyl acetate (50 mL) was added and the mixture was washed with water (2×25 mL), and brine (25 mL). The aqueous layers were back-extracted with ethyl acetate (50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give crude product. Chromatography on a 12 gm silica column, eluting with 0-10% methanol/dichloromethane, followed by trituration with ether/pentane (1/1, 2 mL) to give partially purified material. Ethyl acetate (3 mL) and saturated sodium bicarbonate solution (2 mL) were added and the mixture was stirred for 30 min. The mixture was extracted with ethyl acetate (2×25 mL) and the organic layers were washed with brine, then dried, filtered and evaporated to give 2-(3-{[(2,3-difluoro-6-methoxy-benzyl)-((S)-1-dimethylaminomethyl-2-phenyl-ethyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (48 mg, 42%) as a white solid. HRMS: calcd for C41H55F2N4O4S. Calc [M+H+] 737.3907. found 737.3906.