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Macrocyclic molecules tend to give retrosynthesis a difficult time due to multiple bond-breaking positions, intramolecular interactions, and chirality. This week, we submitted a #KRAS #G12C inhibitor patented by 默克, a moderately complicated macrocycle, to stress test our #ChemAIRS platform.

Within a few minutes, we were able to find a synthetic route that closely aligns with the route patented by Merck. See the comment section for the enlarged write-up content and reference.

We found a few noteworthy highlights:

🔷 The algorithm proposed an alternative route to synthesize a key intermediate (6b, scheme 2).

🔷 Potential functional group compatibility issues with precursor 3a were alerted, with risk-mitigating suggestions to change reaction conditions.

🔷 Potential side reactions in the synthesis of 4b were also labelled at different reaction sites.

This demonstrates our retrosynthesis tool's ability to propose viable synthetic strategies for moderately complicated macrocycles, identify synthetic risks, and propose mitigating strategies.