This key change allowed us to directly use morpholine by harnessing the reactivity of the chloropyridine moiety. Using phthalazinone 9 with morpholine and DIPEA in DMAc led to the clean formation of 4-methyl-7-morpholinopyrido pyridazin-1(2H)-one 10 in 79% isolated yield. The compound was isolated via trituration of the crude solid -an acceptable replacement for the chromatographic purification previously needed. In order to introduce the chiral benzylic amine, compound 10 was activated to the corresponding chlorophthalazine 11 by treatment with phosphorus oxychloride in acetonitrile in 78% isolated yield. Unfortunately, obtaining compound of high purity required chromatographic purification. Compound 11 was taken to the final SNAr reaction with the expensive (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride 3 in the presence of DIPEA and MgCl2 in tAmOH to afford MRTX0902 free base 8 in 72% isolated yield via trituration. The introduction of the costly chiral benzylic amine at the later stage improved cost-efficiency as compared to the initial approach. 3 Last, the preparation of MRTX0902 fumarate 12 from the free base 8 was explored. Due to the poor solubility of MRTX0902 free base, the crystallization process required significant amount of solvent (EtOAc) even at elevated temperature. In addition, the process required several days for the salt formation to complete. Solvent and temperature screening afforded two alternative hits: THF at room temperature or EtOH at 75 °C. Both solvents afforded MRTX0902 fumarate 12 in a couple of hours while keeping concentrations at acceptably high level. However, it was found that residual solvent was challenging to completely remove from the salt. EtOH was ultimately selected for the salt formation. 4 MRTX0902 free base 8 was treated in EtOH at 75 °C with solid fumaric acid to afford MRTX0902 fumarate 12 in 76% isolated yield via filtration. Non-negligible losses were observed in the mother liquor, an issue which was addressed in the subsequent iterations of process development work.