Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:13]([CH2:14][OH:15])[CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
(1S,2R)-cis-2-Methoxycarbonyl-cyclohex-4-ene-1-carboxylic acid (66.0 g, see Bolm et al. J. Org. Chem. 2000, 65, 6984-6991) was dissolved in dry acetone (815 mL) prior to the addition of triethylamine (43.4 g). This solution was cooled to 0° C. and ethyl chloroformate (46.7 g) was added. The resulting solution was stirred 1 h before NaN3 (35.0 g) was added. The cooling bath was removed, and the reaction was warmed to rt overnight. All solid material was removed by filtration, and the solution was partially concentrated. Water was slowly added and the organic layer was separated. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine before they were dried, filtered, and concentrated. The resulting oil (66.1 g) was dissolved in benzene (800 mL) and was warmed to a gentle reflux. After 4 h, the solution was cooled back to rt. Benzyl alcohol (37.5 g) and p-TsOH (1.5 g) were added, and the solution was warmed back to a gentle reflux overnight. After cooling to rt, the reaction was washed with NaHCO3 and brine, dried, filtered, and concentrated to give (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid methyl ester (97.7 g). MS found: (M+H)+=290.2. (61b) A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid methyl ester (91.4 g) was dissolved in MeOH (500 mL) prior to the dropwise addition of NaOH (25.3 g) in water (95 mL). After 3 h, the solution was partially concentrated and an Et2O/water mixture was added. The aqueous layer was separated and was acidified (pH-2) with concentrated HCl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine before they were dried, filtered, and concentrated to give (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72.7 g). MS found: (M+H)+=276.2. (61c) A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72 g) was dissolved in CH2Cl2 (750 mL) prior to the addition of CDI (50.9 g). After 2.5 h water was added, and the solution was extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated. The resulting material was dissolved in CH2Cl2 and ammonia gas was bubbled through the solution for 1.5 h. After stirring overnight, the majority of the solvent was removed and Et2O was added. The product precipitated as a white solid and was collected to give (1R,6S)-6-carbamoylcyclohex-3-enyl)carbamic acid benzyl ester (61.5 g). MS found: (M+H)+=275.3. (61d) A sample of (1R,6S)-6-carbamoylcyclohex-3-enyl)-carbamic acid benzyl ester (30.7 g) was dissolved in THF (1100 mL) and NMP (220 rL). At −78° C., 2.3M n-BuLi (96.3 mL) was added dropwise. After 2 h, a solution of Boc20 (24.4 g) in THF (40 mL) was added dropwise. This solution was stirred 1.2 h before it was quenched with a saturated NH4Cl solution. Water and Et2O were added. The organic layer was filtered then washed with water, brine, dried, filtered, and concentrated. Flash chromatography of the resulting residue gave (1R,6S)-(6-tert-butoxycarbonylaminocarbonyl-cyclohex-3-enyl)-carbamic acid benzyl ester (29.2 g). MS found: (M+Na)+=397.4. (61e) A sample of (1R,6S)-(6-tert-butoxycarbonyl-aminocarbonylcyclohex-3-enyl)carbamic acid benzyl ester (29.0 g) was dissolved in THF (1290 mL). This was cooled in an ice/brine bath prior to the addition of n-BuLi (1.5 mL, 2.4 M). After 30 min, iodine (59.0 g) was added in a single portion. The bath was removed, and the reaction was warmed to rt overnight. The resulting solution was quenched with saturated thiosulfate solution. Water and EtOAc were added. The organic layer was washed with water, brine, dried, filtered, and concentrated. The resulting slurry was diluted with Et2O and (1R,2S,4S,5R)-2-benzyloxycarbonyl-amino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (22.8 g) was collected by vacuum filtration. MS found: (M−C5H8O2+H)+=401.1. (61f) A sample of (1R,2S,4S,5R)-2-benzyloxycarbonylamino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (43.3 g) was dissolved in benzene (580 mL) prior to the addition of Bu3SnH (27.8 g) and AIBN (0.7 g). The resulting mixture was warmed to a gentle reflux for 3 h. After cooling, the solvent was removed and hexane was added. The resulting white solid was collected by vacuum filtration to give (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (29.5 g). MS found: (M+Na)+=397.4. (61 g) A solution of (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (10.21 g, 27.3 mmol) in tetrahydrofuran (200 mL) was treated with water (40 mL) and then with sodium borohydride (5.16 g, 136 mmol). The mixture was stirred at room temperature for 2 h, then was treated with saturated aqueous sodium bicarbonate and stirred until the bubbling subsided. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to provide (1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamic acid tert-butyl ester as a white solid (6.8 g); additional product (2.1 g) was obtained by flash column chromatography of the residue from concentration of the mother liquors, eluting with 40%, then 50% ethyl acetate-hexane. MS found: (M+H)+=379.28. (61 h) A solution of (1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamic acid tert-butyl ester (3.49 g, 9.22 mmol) in tetrahydrofuran (40 mL) was treated with diphenyl disulfide (4.03 g, 18.4 mmol) and tri-n-butylphosphine (4.6 mL, 18.4 mmol) and the solution was heated at reflux for 17 h. The mixture was cooled and concentrated under vacuum, and the residue was purified by flash column chromatography, eluting with 10%, then 20% ethyl acetate-hexane, to provide (1S,2R,4R)-(4-tert-butoxycarbonylamino-2-phenyl-sulfanylmethylcyclohexyl)-carbamic acid benzyl ester (4.37 g) as a white glassy solid. MS found: (M+H)+=471.65. (61i) A solution of (1S,2R,4R)-(4-tert-butoxycarbonyl-amino-2-phenylsulfanylmethylcyclohexyl)carbamic acid benzyl ester (4.37 g, 9.22 mmol) in 2-propanol (100 mL) was treated with a solution of Oxone (11.34 g, 18.44 mmol) in water (60 mL). The mixture was stirred at room temperature for 18 h, then was diluted with water and extracted with ethyl acetate. The organic phases were washed with water, then with brine, then were dried over sodium sulfate and concentrated under vacuum to provide (1S,2R,4R)-(2-benzene-sulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl)-carbamic acid benzyl ester (4.77 g) as a white glassy solid, used without further purification. MS found: (M+H)+=503.6. (61j) A mixture of (1S,2R,4R)-(2-benzene-sulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl)carbamic acid benzyl ester (2.96 g, 5.9 mmol) and 20% palladium hydroxide on charcoal (Pearlman's catalyst, 2.0 g) in methanol (100 mL) was stirred under one atmosphere of hydrogen at room temperature for 16.5 h. The mixture was filtered through Celite, and the solids were washed with methanol. The filtrate was concentrated under vacuum and the residue was dissolved in dichloromethane. The solution was dried over sodium sulfate and concentrated under vacuum to provide (1R,3R,4S)-(4-amino-3-benzenesulfonylmethylcyclohexyl)-carbamic acid tert-butyl ester (2.02 g) as a white glassy solid, used without further purification. MS found: (M+H)+=369.62. (61k) This material (61j) was incorporated into Steps 52a to 52b (substituting N-Cbz-L-Met-OH for N-Boc-L-Met-OH) to give tert-butyl (1R,3R,4S)-4-((S)-2-oxo-3-(2-phenylacetamido)pyrrolidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate. MS found: (M+H)+=586.6. (61l) A portion of above material (61k) (2.0 g) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. prior to the addition of TFA (7 mL). After the reaction was warmed to rt over 1 h, it was concentrated and dried. This material, acetone (993 mg), and acetic acid (1 mL) in 1,2-dichloroethane (15 mL) was stirred for 3 min, then treated with sodium triacetoxyborohydride (1.4 g). After stirring for 20 h, MeOH (10 mL) was added followed by 37% aqueous formaldehyde (2 mL) and sodium cyanoborohydride (427 mg) were added. The mixture was stirred 3 h, and the solvent was removed under vacuum. The residue was dissolved in EtOAc (200 mL), washed with saturated NaHCO3, dried over Mg2SO4, filtered, and evaporated to provide N-((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-2-phenylacetamide (2.7 g). MS found: (M+H)+=542.2. (61m) A portion of above material (61l) (300 mg) was dissolved in 33% (wt) HBr/AcOH (3 mL). After 30 min, Et2O (20 mL) was added and a white solid precipitated from solution. This solid was collected to give (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one dihydrogen bromide (300 mg). MS found: (M+H)+=408.2. (61n) The above material (61m) was dissolved in EtOAc (8 mL) prior to the addition of saturated Na2CO3 solution (3 mL). The organic phase was dried (Na2CO3), filtered, and concentrated to afford free base (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (210 mg). MS found: (M+H)+=408.2. (61o) A portion of the above material (61n) (30 mg) was dissolved in DMF (1 mL) prior to the addition of NMM (29.3 mg) and 3,5-ditrifluoromethylbenzoic acid (16.2 mg). After cooling to 0° C., BOP reagent (38 mg) was added. The resulting mixture was warmed to rt and was stirred overnight. The solution was diluted with EtOAc and was washed with sat. NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (X.0 mg). MS found: (M+H)+=648.