Notwithstanding this synthesis, which remains as of this writing the most effective to date, the need for 7 steps, which includes a protecting group removal (i.e., the N-Boc group from the starting N-Boc-tleucine), provided the incentive to further streamline the route to nirmatrelvir. Moreover, the sequence as developed was hampered by our inability to make the corresponding thioester using the alternative educt, the trifluoroacetamide derivative of t-leucine, which would avoid both N-Boc deprotection and insertion of the required amide, thereby shortening the route by two steps. In this report we describe the successful search, and reduction to practice, for a 1-pot synthesis using an alternative, green coupling technology that affords the targeted drug as its MTBE solvate 4 in 53% overall isolated yield and >99.9% purity by HPLC.