Notably, the mainstream synthetic strategy relies on the derivatization of 1 via conversion into the corresponding chloride 3 as an additional non-constructive step that results in intermediate 5 with genotoxic properties (Scheme 3). The content of 5 as a trace impurity is strictly regulated in the final API (10 ppm limit). Similar to the model amide coupling of 1 with 8, EDC performed as the best amide coupler in combination with ethyl acetate as a LAG additive (η = 0.25 µL•mg -1 ) to enable the amide coupling reaction of 1 and 4. * The corresponding amide 6 was obtained with a high yield of 94% and 98% HPLC purity after washing of the reaction mixture with water, filtration, and drying (Table , Entry 1). The main impurities were unreacted amine 4 (0.9%) and ester by-product 18 (1.1%). The coupling efficiency of the COMU/K2HPO4 system was also tested and afforded 6 with a lower yield (81%) and purity because of the greater formation of 18 (Table , Entry 2; see Tables and in the ESI for additional data). Crystals of 6 suitable for single-crystal X-ray diffraction analysis were obtained by crystallization from a methanol solution and revealed a solid-state structure, in the form of its methanol solvate. Nucleophilic substitution of the hydroxyl group in amide 6 with 1-methylpiperazine (7) was undertaken to synthesize the target API (Table ). Amide 6 was utilized as obtained in the amide coupling reaction, without additional purification other than washing with water. Following the previously established protocol, the reaction involved the generation of a highly reactive isouronium intermediate (6a) and its subsequent reaction with amine 7 added to the same milling jar. The optimal reaction conditions affording the highest yield of 2 were established after performing several test runs and screening LAG additives (Table , see Table in the ESI for additional data). Activation of the hydroxyl group in 6 was performed with TFFH (2 equiv.), using K2HPO4 (2.5 equiv.) and in the presence of green and biobased dimethyl isosorbide (DMI, ƞ = 0.65 µL•mg -1 ) as the most effective LAG solvent. After 2 h of ball milling, an excess of 1-methylpiperazine (7) (10 equiv.) was added and the milling was continued for an additional hour. The excess of amine a General conditions: 6 (0.24 mmol, 100 mg), TFFH (2 equiv.), base (2-2.5 equiv.), LAG additive (η = 0.19-0.65 µL mg -1 ), ball milling at 30 Hz for 120 min, then, addition of 1-methylpiperazine (7) (1.5-10 equiv.), followed by ball milling at 30 Hz for 60 min. b Yield determined by HPLC analysis after washing of the reaction mixture with water and drying in air. Plausible structures of the main impurities 19 and 20 are shown below. c TFFH (1.5 equiv.).