The amide coupling reaction is one of the most critical transformations in drug discovery, playing a pivotal role in the synthesis of numerous pharmaceutical compounds. Its significance in pharmaceutical chemistry is underscored by surveys indicating that amide coupling reactions frequently dominate among all reaction types. Despite the development of over 200 activators for amide coupling reactions, only a few are commonly used in large-scale amide synthesis due to their proven reliability, affordability, ease of handling, and other favorable attributes. However, when these coupling reagents are applied to challenging target substrates, it remains difficult to predict their effectiveness-particularly in couplings between acids and aromatic amines with weak nucleophilicity. The deactivation of aromatic amines by the aromatic system, combined with steric hindrance and electronic demands imposed by various substituents, complicates the selection of efficient coupling reagents. Furthermore, other aspects of reaction conditions, such as the choice of base and solvent, can also impact reactivity. Therefore, there is a pressing need for a strategy that can quickly explore chemical space and identify suitable conditions for amide coupling of challenging substrates, without resorting to time-consuming and labor-intensive experimental screening processes.