Commercial route development began with review and analysis of adagrasib's reported route (Figure ). Iterative side-chain appendage to bicyclic pyrimidine core 2 resulted in a modular and convergent synthesis, and reparation required a longest linear sequence (LLS) of 8 synthetic step from available building blocks. Synthesis commenced by forming a methanol adduct of 2 at the northern aryl chloride's position. Blocking this site preserved SNAr reactivity at a later point in the synthesis and allowed regioselective prolinol attachment at the southeastern aryl chloride's location forming 5. Palladium hydroxide debenzylation and the ensuing Buchwald-Hartwig amination enabled the subsequent naphthyl chloride installation (8). Only piperazine appendage remained with two of the three side-chains affixed. This however necessitates demethylation and activation of the previously installed ether, adding to the LLS. Once this is done, chiral piperazine 11 can be connected to the pyrimidine ring via a SNAr reaction. This nucleophilic attack shows intriguing regioselectivity despite addition as the naked diamine and modest yield. Reaction with 2fluoroacrylic acid (13) completed the synthesis without exposing the sensitive acrylamide warhead to multiple synthetic operations.