Bayesian probability

Flow chemistry

Yield (engineering)

Nanotechnology

Organic chemistry

Combinatorial chemistry

Microreactor

Engineering

Catalysis

Artificial intelligence

Biochemical engineering

Chemistry

Metallurgy

Materials science

Bayesian optimization

Sequence (biology)

Computer science

Continuous flow

Biochemistry

Angewandte Chemie International Edition

The optimization of multistep chemical syntheses is critical for the rapid development of new pharmaceuticals. However, concatenating individually optimized reactions can lead to inefficient multistep syntheses, owing to chemical interdependencies between the steps. Herein, we develop an automated continuous flow platform for the simultaneous optimization of telescoped reactions. Our approach is applied to a Heck cyclization-deprotection reaction sequence, used in the synthesis of a precursor for 1-methyltetrahydroisoquinoline C5 functionalization. A simple method for multipoint sampling with a single online HPLC instrument was designed, enabling accurate quantification of each reaction, and an in-depth understanding of the reaction pathways. Notably, integration of Bayesian optimization techniques identified an 81 % overall yield in just 14 h, and revealed a favorable competing pathway for formation of the desired product.

Bayesian Self‐Optimization for Telescoped Continuous Flow Synthesis