# Double-Ended Synthesis Planning with Goal-Constrained Bidirectional Search

arXiv: https://arxiv.org/abs/2407.06334 · HTML: https://mlsanity.com/paper/2407.06334/

## Key facts

- Cited by 24 papers in the map (data through 14 Oct 2026).
- Builds on 23 of its 67 references that are in the map.
- First posted on arXiv 8 Jul 2024.

## Builds on (most cited first, 23 of 23)

- [Hindsight Experience Replay](https://mlsanity.com/paper/1707.01495/) (2017)
- [Molecular Transformer - A Model for Uncertainty-Calibrated Chemical Reaction Prediction](https://mlsanity.com/paper/1811.02633/) (2018)
- [Learning to Plan Chemical Syntheses](https://mlsanity.com/paper/1708.04202/) (2017)
- [Retrosynthesis Prediction with Conditional Graph Logic Network](https://mlsanity.com/paper/2001.01408/) (2020)
- [Molecule Edit Graph Attention Network: Modeling Chemical Reactions as Sequences of Graph Edits](https://mlsanity.com/paper/2006.15426/) (2020)
- [Retrosynthetic reaction prediction using neural sequence-to-sequence models](https://mlsanity.com/paper/1706.01643/) (2017)
- [ChemBO: Bayesian Optimization of Small Organic Molecules with Synthesizable Recommendations](https://mlsanity.com/paper/1908.01425/) (2019)
- [Retro*: Learning Retrosynthetic Planning with Neural Guided A* Search](https://mlsanity.com/paper/2006.15820/) (2020)
- [Learning To Navigate The Synthetically Accessible Chemical Space Using Reinforcement Learning](https://mlsanity.com/paper/2004.12485/) (2020)
- [Amortized Tree Generation for Bottom-up Synthesis Planning and Synthesizable Molecular Design](https://mlsanity.com/paper/2110.06389/) (2021)
- [A Model to Search for Synthesizable Molecules](https://mlsanity.com/paper/1906.05221/) (2019)
- [Barking up the right tree: an approach to search over molecule synthesis DAGs](https://mlsanity.com/paper/2012.11522/) (2020)
- [Re-evaluating Retrosynthesis Algorithms with Syntheseus](https://mlsanity.com/paper/2310.19796/) (2023)
- [RetroGraph: Retrosynthetic Planning with Graph Search](https://mlsanity.com/paper/2206.11477/) (2022)
- [Self-Improved Retrosynthetic Planning](https://mlsanity.com/paper/2106.04880/) (2021)
- [Neural-guided, Bidirectional Program Search for Abstraction and Reasoning](https://mlsanity.com/paper/2110.11536/) (2021)
- [Retrosynthetic Planning with Dual Value Networks](https://mlsanity.com/paper/2301.13755/) (2023)
- [Projecting Molecules into Synthesizable Chemical Spaces](https://mlsanity.com/paper/2406.04628/) (2024)
- [Retro-fallback: retrosynthetic planning in an uncertain world](https://mlsanity.com/paper/2310.09270/) (2023)
- [Retrosynthetic Planning with Experience-Guided Monte Carlo Tree Search](https://mlsanity.com/paper/2112.06028/) (2021)
- [Models Matter: The Impact of Single-Step Retrosynthesis on Synthesis Planning](https://mlsanity.com/paper/2308.05522/) (2023)
- [FusionRetro: Molecule Representation Fusion via In-Context Learning for Retrosynthetic Planning](https://mlsanity.com/paper/2209.15315/) (2022)
- [Fast and Precise: Adjusting Planning Horizon with Adaptive Subgoal Search](https://mlsanity.com/paper/2206.00702/) (2022)

## Built on by (most cited first, 24 of 24)

- [Chemical reasoning in LLMs unlocks strategy-aware synthesis planning and reaction mechanism elucidation](https://mlsanity.com/paper/2503.08537/) (2025)
- [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)
- [Synthelite: Chemist-aligned and feasibility-aware synthesis planning with LLMs](https://mlsanity.com/paper/2512.16424/) (2025)
- [LARC: Towards Human-level Constrained Retrosynthesis Planning through an Agentic Framework](https://mlsanity.com/paper/2508.11860/) (2025)
- [Tango*: Constrained synthesis planning using chemically informed value functions](https://mlsanity.com/paper/2412.03424/) (2024)
- [Exploring Synthesizable Chemical Space with Iterative Pathway Refinements](https://mlsanity.com/paper/2509.16084/) (2025)
- [Procrustean Bed for AI-Driven Retrosynthesis: A Unified Framework for Reproducible Evaluation](https://mlsanity.com/paper/2512.07079/) (2025)
- [SynthStrategy: Extracting and Formalizing Latent Strategic Insights from LLMs in Organic Chemistry](https://mlsanity.com/paper/2512.01507/) (2025)
- [BioMedGPT-Mol: Multi-task Learning for Molecular Understanding and Generation](https://mlsanity.com/paper/2512.04629/) (2025)
- [RetroAgent: Harnessing LLMs to Search Over Structured Memory for Agentic Retrosynthesis Planning](https://mlsanity.com/paper/2607.14512/) (2026)
- [From Feasible to Practical: Pareto-Optimal Synthesis Planning](https://mlsanity.com/paper/2605.07521/) (2026)
- [ChemHGNN: A Hierarchical Hypergraph Neural Network for Reaction Virtual Screening and Discovery](https://mlsanity.com/paper/2506.11041/) (2025)
- [MMORF: A Multi-agent Framework for Designing Multi-objective Retrosynthesis Planning Systems](https://mlsanity.com/paper/2604.05075/) (2026)
- [Project Ariadne: Prompt-Conditioned Route Generation for Synthesis Planning](https://mlsanity.com/paper/2606.24184/) (2026)
- [It Takes Two to Tango: Directly Optimizing for Constrained Synthesizability in Generative Molecular Design](https://mlsanity.com/paper/2410.11527/) (2024)
- [A User-Tunable Machine Learning Framework for Step-Wise Synthesis Planning](https://mlsanity.com/paper/2504.02191/) (2025)
- [FragmentRetro: A Quadratic Retrosynthetic Method Based on Fragmentation Algorithms](https://mlsanity.com/paper/2509.15409/) (2025)
- [Fuzzy Categorical Planning: Autonomous Goal Satisfaction with Graded Semantic Constraints](https://mlsanity.com/paper/2601.20021/) (2026)
- [Reinforced Reasoning for End-to-End Retrosynthetic Planning](https://mlsanity.com/paper/2603.29723/) (2026)
- [Margin-calibrated Classifier Guidance for Property-driven Synthesis Planning](https://mlsanity.com/paper/2605.13101/) (2026)
- [SynLaD: Latent Diffusion for Generating Synthesizable Molecules Conditioned on 3D Pharmacophore Profiles](https://mlsanity.com/paper/2607.01105/) (2026)
- [Strategy-first synthesis planning for complex natural products](https://mlsanity.com/paper/2608.07454/) (2026)
- [Coverage Before Control: Route-Instruction Grounding and Steering for Controllable Retrosynthesis](https://mlsanity.com/paper/2609.39955/) (2026)

## Abstract (arXiv)

Computer-aided synthesis planning (CASP) algorithms have demonstrated expert-level abilities in planning retrosynthetic routes to molecules of low to moderate complexity. However, current search methods assume the sufficiency of reaching arbitrary building blocks, failing to address the common real-world constraint where using specific molecules is desired. To this end, we present a formulation of synthesis planning with starting material constraints. Under this formulation, we propose Double-Ended Synthesis Planning (DESP), a novel CASP algorithm under a bidirectional graph search scheme that interleaves expansions from the target and from the goal starting materials to ensure constraint satisfiability. The search algorithm is guided by a goal-conditioned cost network learned offline from a partially observed hypergraph of valid chemical reactions. We demonstrate the utility of DESP in improving solve rates and reducing the number of search expansions by biasing synthesis planning towards expert goals on multiple new benchmarks. DESP can make use of existing one-step retrosynthesis models, and we anticipate its performance to scale as these one-step model capabilities improve.