Other innovative aspects of Chematica's plans are manifest in the routes to prepare the side-chain of the HCQ which, as we saw before, is the major factor driving availability/cost of the overall synthesis. The machine's proposals include, for example, opening of a lactam with Grignard reagent (paths 1 and 16), or alkylation of a lactone followed by ring-opening to install a primary iodide functionality -which is a very convenient group for subsequent alkylation (path 13). Other interesting approaches use multicomponent Mannich reaction. In pathway 2 this reaction is combined with subsequent Henry reaction, and in pathway 10 it follows a Curtius rearrangement.