Because of its low cost, availability, and extended use on scale as an activating agent for carboxylic acids, thionyl chloride was originally screened in anticipation that the resulting acid chloride would facilitate coupling of 1 with the bicyclic proline (as its lithium salt) to arrive at intermediate acid 3 following an acidic aqueous work up and precipitation by heptane (Scheme 1). However, it is important to note that even after several efforts at optimization, the yields of 3 were consistently low (see the SI, Table ) and several impurities could be detected by 1 H NMR. Aside from the difficulty associated with handling this highly activated acid chloride due to its sensitivity to moisture, especially on a smaller academic scale, the potential for the acid chloride to cyclize to form an oxazolone type intermediate was also appreciated. The possibility that residual LiOH was present from hydrolysis of the precursor methyl ester en route to the bicyclic proline lithium salt further encouraged investigation into an alternative strategy. Consideration of the numerous peptide coupling reagents in terms of both cost and "greenness" turned our focus to alkyl chloroformates, which have been widely used on scale for this purpose. They are known for minimizing racemization, while imparting far greater stability to the resulting intermediates, especially to adventitious moisture. The use of ethyl chloroformate (ECF), along with equimolar quantities of base (NMM or DIPEA), did not provide the desired high yields (Table , entries 1 and 2), although the overall cleanliness of the reaction and isolated product did improve relative to the acid chloride approach. The lower yields obtained were not due to incomplete conversion; rather, the issue stemmed from the regioselectivity of attack by the proline nitrogen on this unhindered alkyl chloroformate. In efforts to improve the regioselectivity by using the more sterically hindered, commercially available 2-ethylhexyl chloroformate, the yield, in fact, decreased by about 50%, forcing additional screening of coupling reagents to efficiently form the first peptide bond (entry 6). As illustrated in Table (see ESI), several other coupling reagents were screened, all of which gave varying results. For example, pivaloyl chloride resulted in pivalic acid impurities following acidic work-up. Both MsCl and TsCl, used by Pfizer, aside from giving only modest yields, were deemed less attractive from both an environmental and human health perspective. Eventually, it was found that propane phosphonic acid anhydride (T3P) showed considerable potential as a coupling regent that met our rigorous standards (i.e., efficiency, lack of stereochemical issues in terms of diastereomer formation, environmental concerns, economics, etc.), and thus, was subjected to intense evaluation (Table , entries 7 and 8). This coupling reagent, T3P, as an item of commerce, is offered as a 50 w/w% solution in ethyl acetate, which is a preferred green solvent. It has also been used extensively on a multi-kilogram scale, and leads to nontoxic water-soluble by-products that are low in carbon count following its downstream processing. Intermediates formed using this coupling reagent present no regioselectivity issues, and along with its easy handling during aqueous work-up qualifies this reagent from both a practical and sustainable perspective. To activate carboxylic acid 1, 1.2 equivalents of T3P in a 50 w/w % solution in EtOAc were added dropwise to a mixture of acid and base (DIPEA) at -15 to -10 o C. The concentrated mixture (1.4 M) was then allowed one hour to effect acid activation. Sub-zero temperatures were crucial here for best results, as higher temperatures are known to lead to cyclization to form oxazolone intermediates. After this period of time (i.e., 1 h), addition of the bicyclic proline as its Na salt 2 at the same sub-zero temperatures, with dilution by addition of EtOAc leading to a 0.7-0.8 M global concentration, the mixture was allowed to slowly warm to rt with stirring for a period of 20 hours. An in-flask acidic aqueous workup followed by precipitation of the product using heptane afforded crude carboxylic acid 3 in 79% yield as a single diastereomer (Scheme 2). Subsequent T3P-activated coupling using this material, 3, was also tested in making the second peptide bond. Perhaps not surprisingly given the greater reactivity of primary amine 4, after combining all reagents in the same pot at sub-zero temperatures with vigorous stirring, the TLC profile showed complete bond formation after only three hours at room temperature (Scheme 3), with full conversion being assessed via crude 1 H NMR. A straightforward acidic aqueous work up gave crude Nirmatrelvir, which was purified as its MTBE solvate following the Pfizer protocol. 4