Multistep Library Synthesis in Flow: Production of Matrix Libraries in an Assembly Line

In drug discovery, automated library synthesis has traditionally focussed on established chemistry such as amide formation or Suzuki coupling. However, to explore a broader chemical space, recent automated protocols have emphasized on increasing the fraction of sp3 hybridized carbons to move beyond the limitations of planar molecules. Herein we present a novel approach for multistep library synthesis in continuous flow, enabling the linkage of three different elements in a combinatorial way. To achieve this synthesis, we employed nine different reactions in various combinations. Initially, we constructed a full combinatorial library, followed by the development of multi-transformation libraries where disparate reactions were integrated into a single experimental setup, prioritizing chemistries capable of introducing C(sp3) fragments while maintaining efficiency. By integrating diverse reactions and optimization capabilities, our method offers a powerful means to expand chemical diversity in drug discovery libraries.