SNAr Reaction with 12 resulting in Pyronaridine. The SNAr reaction was performed in 2 wt % aqueous TPGS-750-M, under acidic conditions, using a 1:1 ratio of coupling partners 4 and 12. Pyronaridine 9 precipitated from the aqueous reaction mixture, and was isolated via centrifugation followed by washing the solid with water, leading to the targeted drug in 78% isolated yield. Interestingly, this yield is lower than would be expected from the 3-step tandem sequence in which Pyronaridine is obtained in 95% yield (vide infra). This suggests that in situ formation of the aniline salt, as in the tandem sequence, is preferrable to direct use of the isolated trihydrochloride salt.