Overview. Both linear and convergent routes were developed for consideration towards scaling up a synthesis of Pyronaridine 9 (Scheme 1A, 1B). Both share the same initial Cu(I)-catalyzed Ullmann coupling between commercially available dichlorobenzoic acid 1 and aminopyridine 2 to arrive at adduct 3, under aqueous micellar catalysis conditions derived from TPGS-750-M (Scheme 1C). Subsequent cyclization/deoxychlorination to afford the dichlorotricyclic heteroaromatic 4 required use of especially water-sensitive POCl3, and was, therefore, carried out in recyclable toluene. The linear route continues directly from here via a 2-step, 1-pot acid-induced SNAr involving 4 and p-aminophenol 5 leading to intermediate 6, which without isolation undergoes a double Mannich-like reaction. Both reactions take place smoothly in aqueous solution to cleanly afford Pyronaridine. Alternatively, the convergent sequence employs a 3-step tandem sequence involving an initial double Mannich-like reaction using phenol 10 as educt to install the two required methylpyrrolidine residues to arrive at 11. In this case, the reaction could be performed in the complete absence of a reaction medium (i.e., under neat conditions). Nitro group reduction of 11 to 12 is then readily effected in aqueous surfactant solution. An acid-induced SNAr reaction between 4 and 12 merges both components to afford Pyronaridine, 9.