# SynthStrategy: Extracting and Formalizing Latent Strategic Insights from LLMs in Organic Chemistry

arXiv: https://arxiv.org/abs/2512.01507 · HTML: https://mlsanity.com/paper/2512.01507/

## Key facts

- Cited by 3 papers in the map (data through 14 Oct 2026).
- Builds on 21 of its 54 references that are in the map.
- First posted on arXiv 1 Dec 2025.

## Builds on (most cited first, 21 of 21)

- [Evaluating Large Language Models Trained on Code](https://mlsanity.com/paper/2107.03374/) (2021)
- [Gemini 2.5: Pushing the Frontier with Advanced Reasoning, Multimodality, Long Context, and Next Generation Agentic Capabilities](https://mlsanity.com/paper/2507.06261/) (2025)
- [Knowledge Distillation: A Survey](https://mlsanity.com/paper/2006.05525/) (2020)
- [StarCoder: may the source be with you!](https://mlsanity.com/paper/2305.06161/) (2023)
- [ChemCrow: Augmenting large-language models with chemistry tools](https://mlsanity.com/paper/2304.05376/) (2023)
- [Molecular Transformer - A Model for Uncertainty-Calibrated Chemical Reaction Prediction](https://mlsanity.com/paper/1811.02633/) (2018)
- [What can Large Language Models do in chemistry? A comprehensive benchmark on eight tasks](https://mlsanity.com/paper/2305.18365/) (2023)
- [Learning to Plan Chemical Syntheses](https://mlsanity.com/paper/1708.04202/) (2017)
- [Predicting Organic Reaction Outcomes with Weisfeiler-Lehman Network](https://mlsanity.com/paper/1709.04555/) (2017)
- [Molecule Edit Graph Attention Network: Modeling Chemical Reactions as Sequences of Graph Edits](https://mlsanity.com/paper/2006.15426/) (2020)
- [14 Examples of How LLMs Can Transform Materials Science and Chemistry: A Reflection on a Large Language Model Hackathon](https://mlsanity.com/paper/2306.06283/) (2023)
- [Retro*: Learning Retrosynthetic Planning with Neural Guided A* Search](https://mlsanity.com/paper/2006.15820/) (2020)
- [Training a Scientific Reasoning Model for Chemistry](https://mlsanity.com/paper/2506.17238/) (2025)
- [Re-evaluating Retrosynthesis Algorithms with Syntheseus](https://mlsanity.com/paper/2310.19796/) (2023)
- [Double-Ended Synthesis Planning with Goal-Constrained Bidirectional Search](https://mlsanity.com/paper/2407.06334/) (2024)
- [LLM-Augmented Chemical Synthesis and Design Decision Programs](https://mlsanity.com/paper/2505.07027/) (2025)
- [AOT*: Efficient Synthesis Planning via LLM-Empowered AND-OR Tree Search](https://mlsanity.com/paper/2509.20988/) (2025)
- [DirectMultiStep: Direct Route Generation for Multistep Retrosynthesis](https://mlsanity.com/paper/2405.13983/) (2024)
- [Tango*: Constrained synthesis planning using chemically informed value functions](https://mlsanity.com/paper/2412.03424/) (2024)
- [TempRe: Template generation for single and direct multi-step retrosynthesis](https://mlsanity.com/paper/2507.21762/) (2025)
- [Retro-BLEU: Quantifying Chemical Plausibility of Retrosynthesis Routes through Reaction Template Sequence Analysis](https://mlsanity.com/paper/2311.06304/) (2023)

## Built on by (most cited first, 3 of 3)

- [The Latent Space: Foundation, Evolution, Mechanism, Ability, and Outlook](https://mlsanity.com/paper/2604.02029/) (2026)
- [Agentic generation of verifiable rules for deterministic, self-expanding reaction classification](https://mlsanity.com/paper/2607.01061/) (2026)
- [Strategy-first synthesis planning for complex natural products](https://mlsanity.com/paper/2608.07454/) (2026)

## Abstract (arXiv)

Modern computer-assisted synthesis planning (CASP) systems show promises at generating chemically valid reaction steps but struggle to incorporate strategic considerations such as convergent assembly, protecting group minimization, and optimal ring-forming sequences. We introduce a methodology that leverages Large Language Models to distill synthetic knowledge into code. Our system analyzes synthesis routes and translates strategic principles into Python functions representing diverse strategic and tactical rules, such as strategic functional group interconversions and ring construction strategies. By formalizing this knowledge as verifiable code rather than simple heuristics, we create testable, interpretable representations of synthetic strategy. We release the complete codebase and the USPTO-ST dataset -- synthesis routes annotated with strategic tags. This framework unlocks a novel capability for CASP: natural language-based route retrieval, achieving 75% Top-3 accuracy on our benchmark. We further validate our library through temporal analysis of historical trends and chemically intuitive route clustering that offers more granular partitioning than common previous methods. This work bridges the tactical-strategic divide in CASP, enabling specification, search, and evaluation of routes by strategic criteria rather than structure alone.