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𝗜𝗻𝘃𝗲𝘀𝘁𝗶𝗴𝗮𝘁𝗶𝗼𝗻 𝗼𝗳 𝘁𝗵𝗲 𝗦𝘆𝗻𝘁𝗵𝗲𝘁𝗶𝗰 𝗦𝘁𝗿𝗮𝘁𝗲𝗴𝗶𝗲𝘀 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗪𝗥𝗡 𝗶𝗻𝗵𝗶𝗯𝗶𝘁𝗼𝗿 𝗛𝗥𝗢𝟳𝟲𝟭 𝗯𝘆 𝗡𝗼𝘃𝗮𝗿𝘁𝗶𝘀

ChemAIRS proposed a feasible 13-step synthetic route (Scheme 1) wherein the final target compound was synthesized through an amide coupling reaction between intermediates 13a and 13b, closely mirroring the methodology reported by 诺华.

𝘔𝘰𝘳𝘦𝘰𝘷𝘦𝘳, 𝘊𝘩𝘦𝘮𝘈𝘐𝘙𝘚 𝘪𝘥𝘦𝘯𝘵𝘪𝘧𝘪𝘦𝘥 𝘢 𝘱𝘰𝘵𝘦𝘯𝘵𝘪𝘢𝘭 𝘳𝘪𝘴𝘬 𝘪𝘯 𝘵𝘩𝘦 𝘧𝘪𝘯𝘢𝘭 𝘴𝘵𝘦𝘱, 𝘴𝘱𝘦𝘤𝘪𝘧𝘪𝘤𝘢𝘭𝘭𝘺 𝘢 𝘱𝘰𝘴𝘴𝘪𝘣𝘭𝘦 𝘴𝘪𝘥𝘦 𝘳𝘦𝘢𝘤𝘵𝘪𝘰𝘯 𝘢𝘴 𝘥𝘦𝘱𝘪𝘤𝘵𝘦𝘥 𝘪𝘯 𝘍𝘪𝘨𝘶𝘳𝘦 1. Notably diverging from the existing patent, ChemAIRS suggested a 3-step synthesis for the key intermediate 13b. This procedure commenced with a Suzuki coupling reaction to form the chloropyrimidine derivative 2b, which was subsequently transformed into the corresponding methyl ester 3a via palladium-catalyzed carbonylation.

𝗥𝗲𝘃𝗶𝘀𝗲𝗱 𝗦𝘆𝗻𝘁𝗵𝗲𝘁𝗶𝗰 𝗦𝘁𝗿𝗮𝘁𝗲𝗴𝘆 𝘁𝗼 𝗠𝗶𝗻𝗶𝗺𝗶𝘇𝗲 𝗥𝗲𝗮𝗰𝘁𝗶𝗼𝗻 𝗥𝗶𝘀𝗸𝘀

Acknowledging a risk associated with the final step of Scheme 1, which involved an amide coupling reaction between intermediate 13a and pyrimidine-carboxylic acid 13b, we tasked ChemAIRS to propose an alternative approach as illustrated in Scheme 2. In this revised scheme, the pyrimidine moiety was introduced earlier in synthesis via an amide coupling reaction between 11a and 11b, followed by a demethylation step to yield 13b. In the final step, trifluoromethylaniline 13a reacted with the intermediate 13b, a strategy intended to minimize the risk of the side reaction mentioned in Figure 1.

In conclusion, the ChemAIRS Retrosynthesis tool demonstrated its robust capability in identifying potential risks and proposing innovative solutions. Its capability to deviate from existing patents and suggest a synthesis for key intermediates underscores its value in accelerating synthetic organic chemistry projects and ensuring successful outcomes.