Re-evaluating Retrosynthesis Algorithms with Syntheseus
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Abstract (arXiv)
Automated Synthesis Planning has recently re-emerged as a research area at the intersection of chemistry and machine learning. Despite the appearance of steady progress, we argue that imperfect benchmarks and inconsistent comparisons mask systematic shortcomings of existing techniques, and unnecessarily hamper progress. To remedy this, we present a synthesis planning library with an extensive benchmarking framework, called syntheseus, which promotes best practice by default, enabling consistent meaningful evaluation of single-step models and multi-step planning algorithms. We demonstrate the capabilities of syntheseus by re-evaluating several previous retrosynthesis algorithms, and find that the ranking of state-of-the-art models changes in controlled evaluation experiments. We end with guidance for future works in this area, and call the community to engage in the discussion on how to improve benchmarks for synthesis planning.
Key facts. Cited by 26 papers in the map (data through 7 Oct 2026). Builds on 30 of its 77 references that are in the map. First posted on arXiv 30 Oct 2023.
Builds on
30 of 77 references.
References · 30
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- 2023GPT-4 Technical Reportcited by 18,132
- 2019Optuna: A Next-generation Hyperparameter Optimization Frameworkcited by 2,455
- 2016Automatic chemical design using a data-driven continuous representation of moleculescited by 762
- 2017Deep Reinforcement Learning that Matterscited by 727
- 2017Learning to Plan Chemical Synthesescited by 175
- 2020Retrosynthesis Prediction with Conditional Graph Logic Networkcited by 103
- 2020Molecule Edit Graph Attention Network: Modeling Chemical Reactions as Sequences of Graph Editscited by 87
- 2017Retrosynthetic reaction prediction using neural sequence-to-sequence modelscited by 82
- 2020Retro*: Learning Retrosynthetic Planning with Neural Guided A* Searchcited by 75
- 2021Learning to Extend Molecular Scaffolds with Structural Motifscited by 70
- 2020RetroXpert: Decompose Retrosynthesis Prediction like a Chemistcited by 66
18 more
- 2022Root-aligned SMILES: A Tight Representation for Chemical Reaction Predictioncited by 49
- 2021Amortized Tree Generation for Bottom-up Synthesis Planning and Synthesizable Molecular Designcited by 44
- 2023RetroBridge: Modeling Retrosynthesis with Markov Bridgescited by 35
- 2020Barking up the right tree: an approach to search over molecule synthesis DAGscited by 31
- 2021How Much Space Has Been Explored? Measuring the Chemical Space Covered by Databases and Machine-Generated Moleculescited by 27
- 2021Self-Improved Retrosynthetic Planningcited by 23
- 2022RetroGraph: Retrosynthetic Planning with Graph Searchcited by 23
- 2023Retrosynthetic Planning with Dual Value Networkscited by 20
- 2023Retro-fallback: retrosynthetic planning in an uncertain worldcited by 16
- 2023Retrosynthesis Prediction with Local Template Retrievalcited by 15
- 2023Models Matter: The Impact of Single-Step Retrosynthesis on Synthesis Planningcited by 15
- 2021Modern Hopfield Networks for Few- and Zero-Shot Reaction Template Predictioncited by 13
- 2021RetroComposer: Composing Templates for Template-Based Retrosynthesis Predictioncited by 13
- 2022SemiRetro: Semi-template framework boosts deep retrosynthesis predictioncited by 13
- 2017Generating Focussed Molecule Libraries for Drug Discovery with Recurrent Neural Networkscited by 12
- 2022MechRetro is a chemical-mechanism-driven graph learning framework for interpretable retrosynthesis prediction and pathway planningcited by 9
- 2022Mind the Retrosynthesis Gap: Bridging the divide between Single-step and Multi-step Retrosynthesis Predictioncited by 7
- 2023Recent advances in artificial intelligence for retrosynthesiscited by 5
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Citing papers per year: 2024: 8; 2025: 10; 2026: 8.
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- 2025KL-Regularized Reinforcement Learning is Designed to Mode Collapsecited by 29
- 2024Double-Ended Synthesis Planning with Goal-Constrained Bidirectional Searchcited by 24
- 2025LLM-Augmented Chemical Synthesis and Design Decision Programscited by 13
- 2025AOT*: Efficient Synthesis Planning via LLM-Empowered AND-OR Tree Searchcited by 13
- 2024RetroGFN: Diverse and Feasible Retrosynthesis using GFlowNetscited by 10
- 2024Equivariant Denoisers Cannot Copy Graphs: Align Your Graph Diffusion Modelscited by 7
- 2024Tango*: Constrained synthesis planning using chemically informed value functionscited by 7
- 2024Preference Optimization for Molecule Synthesis with Conditional Residual Energy-based Modelscited by 6
- 2025TempRe: Template generation for single and direct multi-step retrosynthesiscited by 6
- 2024Chemist-aligned retrosynthesis by ensembling diverse inductive bias modelscited by 5
- 2025SynCoGen: Synthesizable 3D Molecule Generation via Joint Reaction and Coordinate Modelingcited by 5
- 2025Procrustean Bed for AI-Driven Retrosynthesis: A Unified Framework for Reproducible Evaluationcited by 4
14 more
- 2025Trustworthy Retrosynthesis: Eliminating Hallucinations with a Diverse Ensemble of Reaction Scorerscited by 3
- 2025Fast and scalable retrosynthetic planning with a transformer neural network and speculative beam searchcited by 2
- 2025Retrosynthesis Planning via Worst-path Policy Optimisation in Tree-structured MDPscited by 2
- 2025SynthStrategy: Extracting and Formalizing Latent Strategic Insights from LLMs in Organic Chemistrycited by 2
- 2026SynRXN: An Open Benchmark and Curated Dataset for Computational Reaction Modelingcited by 1
- 2024It Takes Two to Tango: Directly Optimizing for Constrained Synthesizability in Generative Molecular Designcited by 0
- 2024Generative Model for Synthesizing Ionizable Lipids: A Monte Carlo Tree Search Approachcited by 0
- 2026RxnNano:Training Compact LLMs for Chemical Reaction and Retrosynthesis Prediction via Hierarchical Curriculum Learningcited by 0
- 2026ConRetroBert: EMA Stabilized Dual Encoders for Template-Based Single-Step Retrosynthesiscited by 0
- 2026Margin-calibrated Classifier Guidance for Property-driven Synthesis Planningcited by 0
- 2026Bridging Chemists and AI: An Expert-Augmented Framework for Interpretable Route Evaluationcited by 0
- 2026URSA: Chemistry-Aware Benchmark for Utilitarian Retrosynthesis Assessmentcited by 0
- 2026Strategy-first synthesis planning for complex natural productscited by 0
- 2026RetroMPA: A Molecular Property-Aware Auxiliary Framework for Enhancing Retrosynthesis Predictioncited by 0
- 2026RetroMPA: A Molecular Property-Aware Auxiliary Framework for Enhancing Retrosynthesis Prediction17 Aug 2026
- 2026Strategy-first synthesis planning for complex natural products7 Aug 2026
- 2026URSA: Chemistry-Aware Benchmark for Utilitarian Retrosynthesis Assessment6 Jul 2026
- 2026Bridging Chemists and AI: An Expert-Augmented Framework for Interpretable Route Evaluation27 May 2026
- 2026Margin-calibrated Classifier Guidance for Property-driven Synthesis Planning13 May 2026
- 2026ConRetroBert: EMA Stabilized Dual Encoders for Template-Based Single-Step Retrosynthesis12 May 2026
- 2026RxnNano:Training Compact LLMs for Chemical Reaction and Retrosynthesis Prediction via Hierarchical Curriculum Learning10 Feb 2026
- 2026SynRXN: An Open Benchmark and Curated Dataset for Computational Reaction Modeling5 Jan 2026
- 2025Procrustean Bed for AI-Driven Retrosynthesis: A Unified Framework for Reproducible Evaluation8 Dec 2025
- 2025SynthStrategy: Extracting and Formalizing Latent Strategic Insights from LLMs in Organic Chemistry1 Dec 2025
- 2025KL-Regularized Reinforcement Learning is Designed to Mode Collapse23 Oct 2025
- 2025Trustworthy Retrosynthesis: Eliminating Hallucinations with a Diverse Ensemble of Reaction Scorers12 Oct 2025
14 more
- 2025AOT*: Efficient Synthesis Planning via LLM-Empowered AND-OR Tree Search25 Sep 2025
- 2025Retrosynthesis Planning via Worst-path Policy Optimisation in Tree-structured MDPs1 Sep 2025
- 2025Fast and scalable retrosynthetic planning with a transformer neural network and speculative beam search2 Aug 2025
- 2025TempRe: Template generation for single and direct multi-step retrosynthesis29 Jul 2025
- 2025SynCoGen: Synthesizable 3D Molecule Generation via Joint Reaction and Coordinate Modeling16 Jul 2025
- 2025LLM-Augmented Chemical Synthesis and Design Decision Programs11 May 2025
- 2024Chemist-aligned retrosynthesis by ensembling diverse inductive bias models6 Dec 2024
- 2024Tango*: Constrained synthesis planning using chemically informed value functions4 Dec 2024
- 2024Generative Model for Synthesizing Ionizable Lipids: A Monte Carlo Tree Search Approach1 Dec 2024
- 2024It Takes Two to Tango: Directly Optimizing for Constrained Synthesizability in Generative Molecular Design15 Oct 2024
- 2024Double-Ended Synthesis Planning with Goal-Constrained Bidirectional Search8 Jul 2024
- 2024RetroGFN: Diverse and Feasible Retrosynthesis using GFlowNets26 Jun 2024
- 2024Preference Optimization for Molecule Synthesis with Conditional Residual Energy-based Models4 Jun 2024
- 2024Equivariant Denoisers Cannot Copy Graphs: Align Your Graph Diffusion Models27 May 2024
- 2025KL-Regularized Reinforcement Learning is Designed to Mode Collapsecited by 29
- 2024Double-Ended Synthesis Planning with Goal-Constrained Bidirectional Searchcited by 24
- 2025LLM-Augmented Chemical Synthesis and Design Decision Programscited by 13
- 2025AOT*: Efficient Synthesis Planning via LLM-Empowered AND-OR Tree Searchcited by 13
- 2024RetroGFN: Diverse and Feasible Retrosynthesis using GFlowNetscited by 10
- 2024Tango*: Constrained synthesis planning using chemically informed value functionscited by 7
- 2024Preference Optimization for Molecule Synthesis with Conditional Residual Energy-based Modelscited by 6
- 2025TempRe: Template generation for single and direct multi-step retrosynthesiscited by 6
- 2024Chemist-aligned retrosynthesis by ensembling diverse inductive bias modelscited by 5
- 2025SynCoGen: Synthesizable 3D Molecule Generation via Joint Reaction and Coordinate Modelingcited by 5
- 2025Procrustean Bed for AI-Driven Retrosynthesis: A Unified Framework for Reproducible Evaluationcited by 4
- 2025Trustworthy Retrosynthesis: Eliminating Hallucinations with a Diverse Ensemble of Reaction Scorerscited by 3
12 most cited of 25 All 25 (JSON)
- 2026RetroMPA: A Molecular Property-Aware Auxiliary Framework for Enhancing Retrosynthesis Prediction17 Aug 2026
- 2026Strategy-first synthesis planning for complex natural products7 Aug 2026
- 2026URSA: Chemistry-Aware Benchmark for Utilitarian Retrosynthesis Assessment6 Jul 2026
- 2026Bridging Chemists and AI: An Expert-Augmented Framework for Interpretable Route Evaluation27 May 2026
- 2026Margin-calibrated Classifier Guidance for Property-driven Synthesis Planning13 May 2026
- 2026ConRetroBert: EMA Stabilized Dual Encoders for Template-Based Single-Step Retrosynthesis12 May 2026
- 2026RxnNano:Training Compact LLMs for Chemical Reaction and Retrosynthesis Prediction via Hierarchical Curriculum Learning10 Feb 2026
- 2026SynRXN: An Open Benchmark and Curated Dataset for Computational Reaction Modeling5 Jan 2026
- 2025Procrustean Bed for AI-Driven Retrosynthesis: A Unified Framework for Reproducible Evaluation8 Dec 2025
- 2025SynthStrategy: Extracting and Formalizing Latent Strategic Insights from LLMs in Organic Chemistry1 Dec 2025
- 2025KL-Regularized Reinforcement Learning is Designed to Mode Collapse23 Oct 2025
- 2025Trustworthy Retrosynthesis: Eliminating Hallucinations with a Diverse Ensemble of Reaction Scorers12 Oct 2025
12 newest of 25 All 25 (JSON)