The initial development made use of a Pd2(dba)3/RuPhos catalyst system. With Cs2CO3 MR84915 was obtained in moderate yield with improvement desired. RuPhos, Cs2CO3 and toluene were replaced with (R)-BINAP, K3PO4, and 2-MeTHF. Again, wet-milling the phosphate improved robustness. These modifications substantially increased the assay yield. The installation of naphthylamine proceeded cleanly, but with only modest to good efficiency (80-90% assay yield, Figure ). The kinetic studies showed that productive and product decomposition pathways are competing with the latter becoming more dominant at high conversions (>90% of MR84910, Figure ). To prevent MR84915 assay loss the stirout time had to be limited to less than 30 hr. MR84915 product resisted crystallization as a freebase and amorphous precipitations (e.g. 2-MeTHFheptane) offered little in a way of impurity control resulting in MR84915 of suboptimal quality (~93% LC, 300 ppm Pd). While the salt screening identified only one crystalline hit -MR84915-p-toluenesulfonate -it satisfied the criteria of developability (robust crystallinity, thermal stability up to 140 °C, 1:1 stoichiometry, solubility profile, impurity rejection). Exploration of suitable crystallization solvents eventually led to 2-MeTHF-acetone mixtures which provided excellent impurity rejection, acceptable recovery, with minimal processing complexity. Finding optimal 2-MeTHF-acetone ratio (50:50 v/v) required balancing recovery (better at higher 2-MeTHF) and good crystallization kinetics (better at lower 2-MeTHF). In addition, ensuring the ratio of p-TSA to freebase (FB) is sightly below unity was critical for the optimal conversion and recovery as the solubility of MR84915-p-TSA salt curves up right past the equivalency point (Figure ). Step 5: