Phthalazinone 10 Core Formation. The last step of our envisioned synthesis to compound 10 was the condensation of hydrazine hydrate with compound 17. 7 Using standard conditions with hydrazine hydrate in EtOH at high temperature, the corresponding hydrazone was cleanly generated. However, the final cyclization to the phthalazinone was found to be sluggish and proceeded to decent conversion only after extended reaction time of over 24 to 48 h (see Scheme 4). Several approaches were proposed to circumvent this issue. The use of higher boiling point solvent such as the longer chain alcohol n-butanol or carbonyl activator such as a Brønsted acid were tested. The later was found to be the most effective and using 1 equivalent of acetic acid, the cyclization rate could be drastically increased leading to complete reaction in 5 hours at 75 °C. Deprotection of the tBu ester to the corresponding carboxylic acid or enhanced hydrazone isomerization cannot be ruled out with certainty under these reactions conditions. However, treatment of compound 17 in absence of hydrazine hydrate with acetic acid in EtOH at 75 °C showed complete stability of the tBu ester moiety. The final optimized conditions were applied to compound 7 and hydrazine hydrate in the presence of acetic acid in EtOH to generate 4methyl-7-morpholinopyrido pyridazin-1(2H)-one 10 in 94% corrected isolated yield. It is worth noting that due to the very low solubility of the azaphthalazinone core, this step is extremely efficient at removing impurities carried over the previous steps granting perfect entry into the endgame. Endgame Optimization. The last 3 steps to MRTX0902 fumarate salt were already well established, see Scheme 2, but some attention was brought to polish them, especially increasing the yield at every step, crucial for cost-effectiveness and removing tedious purification methods.