Reaction SMILES: C([O:4][C@@H:5]([C@@H:9]([NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C(=O)C)[C:20]=1[CH3:29])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=O)(=O)C.N1C=CC=CC=1.O=S(Cl)Cl.Cl.[CH2:42]([NH:45][C:46]([C@@H:48]1[C:52]([CH3:54])([CH3:53])[S:51][CH2:50][NH:49]1)=[O:47])[CH:43]=[CH2:44].C(O[C@@H]([C@@H](NC(=O)C1C=CC=C(OC(=O)C)C=1C)CC1C=CC=CC=1)C(Cl)=O)(=O)C.C(NC([C@@H]1C(C)(C)SCN1)=O)C=C.[OH-].[K+].[OH-].[K+].CO.C(O[C@H](C(N1[C@H](C(=O)NCC=C)C(C)(C)SC1)=O)[C@@H](NC(C1C(C)=C(OC(=O)C)C=CC=1)=O)CC1C=CC=CC=1)(=O)C.Cl>C(OCC)(=O)C.O.CO.CC#N>[CH2:42]([NH:45][C:46]([C@@H:48]1[C:52]([CH3:54])([CH3:53])[S:51][CH2:50][N:49]1[C:6](=[O:8])[C@@H:5]([OH:4])[C@@H:9]([NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[C:20]=1[CH3:29])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:47])[CH:43]=[CH2:44]
Reactant: C=CCNC(=O)[C@H]1NCSC1(C)C
Reactant: CC(=O)Oc1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](OC(C)=O)C(=O)O)c1C
Agent: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](OC(C)=O)[C@H](Cc2ccccc2)NC(=O)c2cccc(OC(C)=O)c2C)CSC1(C)C
Agent: CC(=O)Oc1cccc(C(=O)N[C@@H](Cc2ccccc2)[C@H](OC(C)=O)C(=O)Cl)c1C
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: c1ccncc1
Product: C=CCNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(O)c2C)CSC1(C)C
Temperature: 15 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
A solution of (2S,3 S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyric acid (140 kg, 339 mol), CH3CN (560 L), and pyridine (64.3 kg, 813 mol) was cooled to 15° C. SOCl2 (44.3 kg, 373 mol) was charged while maintaining the temperature at 15° C. The mixture was held at 15° C. for 1 h. A separate reactor was charged with (R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide hydrochloride (96.6 kg, 408 mol), CH3CN (254 L), and pyridine (29.5 kg, 373 mol), and was then cooled to 15° C. The (2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyric acid chloride solution was added to the (R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide solution, while maintaining the temperature at 15° C. The mixture was held at 15° C. for 6 h. A separate reactor was charged with KOH (167 kg, 2709 mol) and methanol (280 L) using a 0° C. cooling jacket. The resulting KOH/methanol solution was cooled to 5° C. The crude acetic acid 3-{(1S,2S)-2-acetoxy-3-[(R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester mixture was added to the KOH/methanol solution while maintaining the temperature at 10° C. After addition was complete, the mixture was held at 25° C. for 3 h. The mixture was charged with H2O (840 L) and ethyl acetate (840 L), and was then followed by acidification to pH 5–6.5 with concentrated HCl (85 kg) while maintaining the temperature at 20° C. The resulting layers were separated. The organic fraction was sequentially washed with 6.8 wt. % aqueous NaHCO3 (770 L), an aqueous HCl/NaCl solution (H2O: 875 L; conc. HCl: 207 kg; NaCl: 56 kg), 8.5 wt. % aqueous NaHCO3 (322 L), and then with 3.8 wt. % aqueous NaCl (728 L). The resulting organic fraction was partially concentrated by distillation at one atmosphere. The solvent was exchanged with ethyl acetate by continuing distillation and maintaining the pot temperature at ≧70° C. Ethyl acetate was added such that the pot volume remained at approximately 840 L. The solution was then cooled to 20° C. and held at this temperature until crystallization was observed. n-Heptane (280 L) was added and the suspension was agitated at 15° C. for 4 h. The crystals were, using cold 2.4:1 (v/v) ethyl acetate/n-heptane for rinsing. The wet cake was dried under vacuum at 45° C. to provide crude (R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide. Decolorization and recrystallization was conducted as follows: A mixture of crude (R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide, ADP carbon (21 kg), Supercel (3 kg), and ethyl acetate (780 L) was heated to 70° C. CH3OH (40 L) was added to the mixture. The mixture was filtered, and the resulting clear filtrate was heated to reflux at one atmosphere to begin distillation. CH3OH was displaced as follows: ethyl acetate (388 L) was charged while maintaining the pot volume at approximately 840 L and at 70° C. The solution was slowly charged with n-heptane (316 L), while maintaining a temperature of 70° C. The mixture was then cooled to 20° C. and was held at this temperature for 4 h. The crystals were filtered, using cold 2.1:1 (v/v) ethyl acetate/n-heptane for rinsing. The wet cake was dried under vacuum at 45° C. to give 103 kg (59.6%) of (4R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide as a white crystalline solid: mp=173–175° C., 1H NMR (300 MHz, DMSO-d6) displayed a ˜10:1 mixture of rotamers, major rotamer resonances δ 9.35 (s, 1H), 8.04–8.15 (m, 2H), 7.13–7.38 (m, 5H), 6.96 (t, J=7.7 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H), 5.71–5.87 (m, 1H), 5.45 (br d, J=6.2 Hz, 1H), 4.98–5.27 (m, 4H), 4.38–4.52 (m, 3H), 3.58–3.86 (m, 2H), 2.68–2.90 (m, 2H), 1.84 (s, 3H), 1.52 (s, 3H), 1.37 (s, 3H) [characteristic minor rotamer resonances δ 9.36 (s), 8.21 (d, J=10.5 Hz), 7.82 (5, J=5.8 Hz), 4.89 (s), 4.78 (AB q, JAB=9.8 Hz, Δν=27.1 Hz), 4.17–4.24 (m), 2.93–3.01 (m), 1.87 (s), 1.41 (s)]; 13C NMR (75 MHz, DMSO-d6) displayed a ˜10: 1 mixture of rotamers, major rotamer resonances δ 170.4, 169.5, 168.2, 155.7, 139.6, 139.4, 135.5, 135.4, 129.9, 128.2, 126.2, 126.1, 121.9, 117.8, 115.6, 72.4, 72.1, 53.1, 51.4, 48.2, 41.3, 34.2, 30.5, 25.0, 12.6 [characteristic minor rotamer resonances δ 171.4, 169.7, 168.6, 139.0, 129.5, 128.4, 70.6, 54.2, 49.1, 41.5, 31.4, 24.8]; MS (CI) m/z 512.2224 (512.2219 calcd for C27H34N3O5S, M+H+), elemental analysis calcd for C27H33N3O5S: C, 63.38; H, 6.50; N, 8.22; found: C, 63.19; H, 6.52; N, 8.10.