Changing the sequence of bond-forming events led to a robust and scalable production route for MRTX849. Yield of API increased to 32% while reducing the sequence to six GMP steps (Figure ). Intermediate production was conducted at scales of up to 300 kg with 100 kg batches of final API, and metric-ton quantities were made to supply clinical and commercial needs. A doubly regioselective SNAr provides the option to reduce consumption of an expensive chiral intermediate, reaction optimization led to parts per million palladium catalysis, and a new method to deprotect Cbz-groups was developed to mitigate the risks associated with benzyl iodide generated under conventional TMSI deprotection strategy.