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The design of synthetic routes to complex, stereochemically rich targets remains one of the most demanding  challenges in organic chemistry. To interrogate the strategic logic underlying such efforts, authors curated and digitized over 3,000 classical total syntheses comprising close to 60,000 individual steps, now freely available as the AbSynth collection. Analyses across this data set reveal that synthesis planning cannot be reduced to purely local, one-step-at-a-time decision-making: known complexity metrics and scoring functions fail to vary monotonically along synthetic trajectories, and conventional bond-disconnection heuristics apply only sporadically and lack the specificity required for automation. Instead, the study shows that nearly half of all steps correspond to structurally unproductive − yet strategically essential − plateaus of skeletal complexity. Navigating these plateaus requires retrosynthetic algorithms to embrace multistep reasoning rather than incremental scoring. By providing a century- spanning, machine-readable data set of complete routes, this work offers a foundation for advancing chemical AI toward the complexity of human expert planning.

Several PhD-students from our institute, many student from Jagiellonian University and employees of Allchemy Inc. participated in this project.

M. Czuba, K. Barnowski, K. Molga, Zofia Pławecka, A. Wołos, S. Stodółkiewicz, S. Baś, W. Petrykowski, W. Beker, E. Saillard, K. Łęgowski, R. Roszak, P. Kowalczyk, B. Mikulak-Klucznik, P. Janasz, E. Mielke, P. Pietruszewska, M. Łazuchiewicz, S. Wójcik, J. Zabielski, D. Nostkiewicz, G. Smaga, A. Makkawi, L.-P. J.-L. Gadina, J. Skoczek, T. Klucznik, M. Deschamps, A. Żądło-Dobrowolska, M. Michalak, S. Szymkuć, D. T. Gryko, Y. Bilgi-Gadina, B. A. Grzybowski, „AbSynth: A Century of Total Syntheses as a Machine-Readable Resource for Analyzing Strategic Logic in Organic Chemistry”, J. Am. Chem. Soc.