Mannich-like reaction to form Pyronaridine. Initial screening of the double Mannich-like reaction between 6 and excess (10 equiv) pyrrolidine 7 and paraformaldehyde 8 under micellar catalysis conditions provided Pyronaridine, 9, in quantitative yield (Scheme 4). Reducing the loading of 7 and 8 from ten to four equivalents led to a precipitous drop in conversion, from 100% to 33%, due to poor solubility of educt 6. That is, the reaction containing 10 equiv pyrrolidine begins as a homogeneous emulsion, and then soon thereafter, Pyronaridine slowly precipitated to form a free-flowing suspension over the course of the reaction. The reaction containing four equivalents, however, did not afford an initial homogeneous mixture and instead, amine 6 formed a clump, thereby limiting the extent of conversion. This suggested that the excess pyrrolidine was acting either as a co-solvent, a base, or a combination thereof. The addition of 10 v/v % 2-MeTHF as co-solvent containing four equivalents of 7 and 8 did not improve the overall conversion. However, use of five equivalents each of 7 and 8 in combination with three equivalents of Et3N showed the same initial solubilization and eventual precipitation of 9. In this manner, Pyronaridine was isolated in quantitative yield.