Reaction SMILES: O=C1CCC2=CN(C3C=CC=CC=32)CCCCCCN1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.[C:43]([O:47][C:48](=[O:79])[CH:49](C)[C@H:50]([C:55](=[O:77])[NH:56][C@H:57]1[CH2:74][C:73]2=[CH:75][N:66]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][C:72]=32)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][NH:59][C:58]1=[O:76])[CH2:51][CH:52]([CH3:54])[CH3:53])(C)(C)C.C(OC(=O)C[C@H](C(=O)N[C@H]1CC2=CN(C3C=CC=CC=32)CCCCCCNC1=O)CC(C)C)(C)(C)C>CN(C=O)C>[CH3:43][O:47][C:48](=[O:79])[CH2:49][C@H:50]([C:55](=[O:77])[NH:56][C@H:57]1[CH2:74][C:73]2=[CH:75][N:66]([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][C:72]=32)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][NH:59][C:58]1=[O:76])[CH2:51][CH:52]([CH3:54])[CH3:53]
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O)C(C)C(=O)OC(C)(C)C
Agent: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: O=C1CCc2cn(c3ccccc23)CCCCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h

Procedure:
Alternatively, to (2R)-4-methyl-2-(t-butoxy-carbonylmethyl)pentanoic acid (1 g, 4.34 mmol) in dry THF (100 mL) at -78° C. under argon was added NaN(TMS)2 (1.0M in THF, 10.9 mL, 2.5 eq) dropwise and the mixture was stirred for 1 hour. Iodomethane (0.33 mL, 1.2 eq) was added and the resulting mixture was stirred overnight from -78° C. to room temperature. The next day the reaction was quenched with water (100 mL). After extracting with ether (3×100 mL), the aqueous layer was combined with ethyl acetate and with stirring was added 4N HCl to pH=2. Sodium chloride was also added to saturation and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give (2R)-4-methyl-2-((1-methyl-1-t-butoxy-carbonyl)methyl)pentanoic acid as a dark brown oil (1 g). To this crude reaction product (500 mg) and (10S)-10-amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (399 mg, 0.7 in dry DMF at 0° C. under argon was added HOBt-H2O (1.1 eq, 234 mg), followed by EDCI (663 mg, 2.5 eq). The resulting mixture was stirred overnight from 0° C. to room temperature. Most of the DMF was removed by pump distillation at 65° C. Then, the residue was partitioned between CH2Cl2 (150 mL). After washing with 0.5N HCl (2×75 mL), saturated NaHCO3 (2×75 mL) and brine (1×75 mL), the organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash column chromatography on silica eluting with 30% ethyl acetate in petroleum ether to yield a mixture of three compounds, the two individual stereoisomers of (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diaza-tricyclo-[10.6.1.013,18 ]nonadeca-12(19),13(18), 14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester and (3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo-[10.6.1.013,18 ]nonadeca-12(19),13(18), 14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester. Further purification provided separation of the three compounds; (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl ester (13 mg) as a white solid; 1:1 mixture of the stereoisomers (5 mg) as a white solid; and the less polar stereoisomer of (3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo-[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) hexanoic acid t-butyl ester (15 mg); 300 MHz 1H NMR in CDCL3 (less polar diastereomer): δ(-0.2)-(-0.05) (m, 1H); 0.5-0.7 (m, 1H); 0.9 (dd, J=4 Hz, J=6.7 Hz, 6H); 1.15 (d, J=8.4 Hz, 3H); 1.18-1.4 (m, 3H); 1.41 (s, 9H); 1.45-1.73 (m, 4H); 1.75-1.8 (m, 2H); 2.5-2.7 (m, 3H); 2.89 (dd, J=10.9 Hz, J=15 Hz, 1H); 3.34-3.5 (m, 2H); 3.95-4.1 (m, 1H); 4.25-4.4 (m, 1H); 4.72-4.82 (m, 1H); 5.22-5.3 (m, 1H); 6.52 (d, J=7.5 Hz, 1H); 6.91 (s, 1H); 7.13 (dd, J=6.7 Hz, J=8.4 Hz, 1H); 7.22 (dd, J=5 Hz, J=7.1 Hz, 1H); 7.34 (d, J=8.4 Hz, 1H); 7.84 (d, J=8.4 Hz, 1H).