Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines

High‐throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new click able building blocks remain exceedingly challenging. Here in , we describe a double‐click strategy that enables the sequential ligation of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO 2 NCO) via a modular amidation/SuFEx process. This method provides facile access to chemical libraries of N‐fluorosulfonyl amides (RCONHSO 2 F) and N‐acylsulfamides (RCONHSO 2 NR ´ R ´´ ) in near‐quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96‐well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compound s exhibit high antimicrobial activities against Gram‐positive bacterium S. aureus and drug‐resistant MRSA (MIC up to 6.25·μg mL‐1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high‐throughput medicinal chemistry.