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0 °C

To a solution of (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3-methyl-4-oxobutanoic acid (Preparation 66, 713 mg, 2.11 mmol) in DMF (15 mL) was added NMM (267 mg, 2.64 mmol) and the mixture was cooled to 0° C. HATU (871 mg, 2.29 mmol) was added and the reaction stirred warming to room temperature for 2 hours. 3′,4′-diamino-3-fluoro-[1,1′-biphenyl]-4-carbonitrile (Preparation 81, 400 mg, 1.76 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was collected, dried over Na2SO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 20-40% EtOAc in heptanes. The residue was dissolved in AcOH (10 mL) and heated to 40° C. for 2 days. The reaction was cooled and concentrated in vacuo, azeotroping with DCM to afford a foam. The residue was purified using silica gel column chromatography eluting with DCM:EtOAc 94:6 to afford the title compound.

1. temperaturewarming to room temperature for 2 hours
2. stirringthe reaction stirred at room temperature for 18 hours
3. extractionextracted with EtOAc
4. customThe organic layer was collected
5. dry with materialdried over Na2SO4
6. concentrationconcentrated in vacuo
7. customThe residue was purified
8. washeluting with 20-40% EtOAc in heptanes
9. dissolutionThe residue was dissolved in AcOH (10 mL)
10. temperatureheated to 40° C. for 2 days
11. temperatureThe reaction was cooled
12. concentrationconcentrated in vacuo
13. customazeotroping with DCM
14. customto afford a foam
15. customThe residue was purified
16. washeluting with DCM:EtOAc 94:6