Retrosynthetic planning often produces a multitude of potential synthetic routes, creating challenges for chemists in selecting the most viable options. Existing clustering approaches used in tools like ASKCOS and AiZynthFinder rely on abstract or computationally intensive metrics that often lack chemical interpretability. In this work, we propose a novel, chemically intuitive clustering methodology implemented in the SynPlanner retrosynthetic tool, based on the concept of Strategic Bond Patterns (SBPs). By extending the Condensed Graph of Reaction (CGR) formalism to multi-step retrosynthetic pathways, we introduce the RouteCGR and its simplified variant, SB-CGR, which encodes the key disconnections leading to a target molecule. This two-level clustering strategy - first by SBP, then by generalized pseudo-reactions - groups routes by their underlying synthetic logic while tolerating variations in the reactions’ order and application of non-strategic steps (protection/deprotection). Comparison against clustering algorithms from ASKCOS and AiZynthFinder demonstrates that the SBP-based method produces fewer, more interpretable clusters and aligns more closely with chemists’ reasoning and intuition. SynPlanner’s SBP approach uncovers a broader diversity of unique synthetic strategies and demonstrates faster, more meaningful clustering. This framework facilitates efficient exploration of synthetic options, enhances interpretability, and offers a practical solution for navigating the combinatorial complexity of retrosynthetic planning.
Gainullin et al. (Tue,) studied this question.