At the onset, a model amide coupling reaction of 1 and 4-bromo-3-methylaniline (8) (Table ) was investigated. The aromatic amine 8 was selected as a model compound because of its reduced nucleophilic properties compared to the N-Boc piperazine that we used in a previous study (Scheme 1). Several known mechanochemical amidation protocols were screened to identify the conditions that enable a high-yielding preparation of amide 9. The test reactions were performed in a Form-Tech Scientific FTS1000 shaker mill at a 30 Hz milling frequency on a 100 mg scale in 14 mL zirconia-coated milling jars with a single 10 mm ZrO2 (weight ca. 3 g) milling ball (see Electronic Supporting Information (ESI) for experimental details). We expected that the free hydroxyl of 1 could act as a competitive nucleophile that might result in a lower yield of amide 9 because of the generation of ester by-products. However, we observed various side processes, the prevalence of which was influenced by the specific coupling conditions employed. In the first experiment (Table , Entry 1), a combination of the TCFH reagent and K2HPO4 as a base in the presence of ethyl acetate as a LAG additive (η = 0.19 µL•mg -1 ) was tested. In contrast to the high-yielding coupling of 1 with N-Boc piperazine (Scheme 1), amide 9