AbSynth: A Century of Total Syntheses as a Machine-Readable Resource for Analyzing Strategic Logic in Organic Chemistry.
4 affiliations
- 11904 Undergraduate Chemistry Club at the Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, Kraków30-387, Poland.
- 2Allchemy, Inc. , Highland, Indiana46322, United States.
- 3Institute of Organic Chemistry, Polish Academy of Sciences , Warsaw01-224, Poland.
- 4Center for Algorithmic and Robotized Synthesis (CARS), Institute for Basic Science (IBS), Ulsan44919, Republic of Korea.
Abstract
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, we 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, our 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. We identify several such multistep heuristics, including tolerable lengths of nonskeletal disconnections and the "longevity" of functional groups across routes, and anticipate that AbSynth will serve as a resource for uncovering additional trends in synthesis design. 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.
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BibTeX
@article{czuba2026absynth,
title = {{AbSynth: A Century of Total Syntheses as a Machine-Readable Resource for Analyzing Strategic Logic in Organic Chemistry.}},
author = {Maciej Czuba and Konrad Barnowski and Karol Molga and Zofia Pławecka and Agnieszka Wołos and Szymon Stodółkiewicz and Sebastian Baś and Wojciech Petrykowski and Wiktor Beker and Evan Saillard and Konrad Łęgowski and Rafał Roszak and Paweł Kowalczyk and Barbara Mikulak-Klucznik and Piotr Janasz and Emilia Mielke and Patrycja Pietruszewska and Maja Łazuchiewicz and Sylwia Wójcik and Jakub Zabielski and Dariusz Nostkiewicz and Gabriela Smaga and Ahmad Makkawi and Louis P J-L Gadina and Jakub Skoczek and Tomasz Klucznik and Maxence Deschamps and Anna Żądło-Dobrowolska and Michał Michalak and Sara Szymkuć and Daniel T Gryko and Yasemin Bilgi-Gadina and Bartosz A Grzybowski},
journal = {Journal of the American Chemical Society},
year = {2026},
month = sep,
doi = {10.1021/jacs.6c08434},
url = {https://europepmc.org/article/MED/42915532},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - AbSynth: A Century of Total Syntheses as a Machine-Readable Resource for Analyzing Strategic Logic in Organic Chemistry.
AU - Maciej Czuba
AU - Konrad Barnowski
AU - Karol Molga
AU - Zofia Pławecka
AU - Agnieszka Wołos
AU - Szymon Stodółkiewicz
AU - Sebastian Baś
AU - Wojciech Petrykowski
AU - Wiktor Beker
AU - Evan Saillard
AU - Konrad Łęgowski
AU - Rafał Roszak
AU - Paweł Kowalczyk
AU - Barbara Mikulak-Klucznik
AU - Piotr Janasz
AU - Emilia Mielke
AU - Patrycja Pietruszewska
AU - Maja Łazuchiewicz
AU - Sylwia Wójcik
AU - Jakub Zabielski
AU - Dariusz Nostkiewicz
AU - Gabriela Smaga
AU - Ahmad Makkawi
AU - Louis P J-L Gadina
AU - Jakub Skoczek
AU - Tomasz Klucznik
AU - Maxence Deschamps
AU - Anna Żądło-Dobrowolska
AU - Michał Michalak
AU - Sara Szymkuć
AU - Daniel T Gryko
AU - Yasemin Bilgi-Gadina
AU - Bartosz A Grzybowski
PY - 2026
DA - 2026/09/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c08434
UR - https://europepmc.org/article/MED/42915532
AB - 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, we 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, our 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. We identify several such multistep heuristics, including tolerable lengths of nonskeletal disconnections and the "longevity" of functional groups across routes, and anticipate that AbSynth will serve as a resource for uncovering additional trends in synthesis design. 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.
SN - 0002-7863
SN - 1520-5126
ER -