The 34 selected combinations of molecules and carboxylic acids were subjected to screening of reaction conditions in a 24-well plate setup (Figure ), resulting in the formation of the desired product with ≥5% LCMS-yield for all substrate combinations. Based on these results, scale-up experiments for 14 novel MAGL inhibitors were performed following the streamlined synthesis route outlined in Figure . By employing a late-stage Minisci-type alkylation strategy, we reduced the synthesis of the alkylated intermediate from seven steps (orange) to three steps (blue), greatly enhancing efficiency. The left-hand building blocks were subsequently coupled with various right-hand side residues, yielding 14 new compounds (18-31) from commercially available starting materials (step h). Instead of alkylating the final compound, we synthesized the intermediate building blocks, allowing for diverse amide couplings to produce a broader array of analogs.