Step, 1-pot sequence en route to nirmatrelvir (1) Intermediate 9 was initially dried azeotropically using recoverable toluene. N-Boc Deprotection was then carried out using a concentrated solution of HCl/dioxane in CH3CN. All attempts using standard conditions involving TFA were quite low-yielding and involved creation of multiple sideproducts, presumably including various materials resulting from epimerization due to the presence of TFA. Use of HCl, however, was very clean and led to an initial mixture of conformers, likely to be a rotameric mix associated with the tertiary amide present (10a and 10b, Scheme 2) as seen by Pfizer with related compounds bearing the same bicyclic proline moiety, 8a and supported by variable temperature H NMR (see SI-1, section 3.7). Remarkably, and unexpectedly, it was also observed that greater degrees of epimerization occurred during subsequent trifluoroacetylation when the kinetically formed proportion of the minor conformer was used. Interestingly, equilibration of the N-Boc deprotected material, which was a 70:30 mixture of the initially formed HCl salt, at rt overnight reproducibly led to a ratio of conformers between 94:6 and 96:4. After equilibration, the solvent and excess HCl were removed in vacuo and the resulting amine hydrochloride salt was subjected to trifluoroacetic anhydride (TFAA) and NMM to install the trifluoroacetamide moiety. Removal of TFAA and NMM via aqueous washes afforded nirmatrelvir (1) in 95% yield over this 1-pot, 2 step approach, and with 95% purity by HPLC. Small amounts of the undesired diastereomer could be effectively removed by formation and recrystallization of the MTBE solvate, as described previously by Pfizer. The resulting nirmatrelvir was isolated seemingly as a pure rotamer based on NMR data (see Figure in SI-1).