Investigation of reactivity between pyrimidine 14 (MR84906) and chiral piperazine 15 (MR84905) kicked-off the new route's exploration. The reaction worked excellently, in parallel to the high-yielding formation of the methanol adduct. Product was isolated in 90% yield after crystallization. Byproducts associated with incorrect regiochemical addition (18) and unmasking of free piperidine (19) were held to less than 1% each and most often, less than 0.2%. Even more strikingly, free-piperazine (MR849109, 11) successfully reacted with 14, without impurities related to nucleophilic attack by the undesired amine (20). Neither amine nor pyrimidine reactive sites required protection. The amine could then be capped with a Cbz group in situ to intercept the same intermediate as Route 1, MR84907. Ability to use free diamine is particularly important since its synthetic preparation is much shorter than that of the protected piperazine, 4 and its molecular weight is half that of the Cbz protected fumarate salt thus reducing consumption of this expensive ingredient (Figure ). This provides an option which significantly reduces cost. Successful high-yielding installation of the piperazine represented a major program accomplishment. This resolved the low yield associated with the hydroxyl activation and ensuing SNAr (9.7% yield over two steps). It also negated multiple operations related to use of an ether protection group.