# Retro-fallback: retrosynthetic planning in an uncertain world

arXiv: https://arxiv.org/abs/2310.09270 · HTML: https://mlsanity.com/paper/2310.09270/

## Key facts

- Cited by 16 papers in the map (data through 14 Oct 2026).
- Builds on 15 of its 60 references that are in the map.
- First posted on arXiv 13 Oct 2023.

## Builds on (most cited first, 15 of 15)

- [PyTorch: An Imperative Style, High-Performance Deep Learning Library](https://mlsanity.com/paper/1912.01703/) (2019)
- [GuacaMol: Benchmarking Models for De Novo Molecular Design](https://mlsanity.com/paper/1811.09621/) (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)
- [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)
- [Root-aligned SMILES: A Tight Representation for Chemical Reaction Prediction](https://mlsanity.com/paper/2203.11444/) (2022)
- [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)
- [RetroGraph: Retrosynthetic Planning with Graph Search](https://mlsanity.com/paper/2206.11477/) (2022)
- [Self-Improved Retrosynthetic Planning](https://mlsanity.com/paper/2106.04880/) (2021)
- [Retrosynthetic Planning with Dual Value Networks](https://mlsanity.com/paper/2301.13755/) (2023)
- [Modern Hopfield Networks for Few- and Zero-Shot Reaction Template Prediction](https://mlsanity.com/paper/2104.03279/) (2021)

## Built on by (most cited first, 16 of 16)

- [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)
- [AOT*: Efficient Synthesis Planning via LLM-Empowered AND-OR Tree Search](https://mlsanity.com/paper/2509.20988/) (2025)
- [RetroGFN: Diverse and Feasible Retrosynthesis using GFlowNets](https://mlsanity.com/paper/2406.18739/) (2024)
- [Chemist-aligned retrosynthesis by ensembling diverse inductive bias models](https://mlsanity.com/paper/2412.05269/) (2024)
- [Preference Optimization for Molecule Synthesis with Conditional Residual Energy-based Models](https://mlsanity.com/paper/2406.02066/) (2024)
- [Evaluating Molecule Synthesizability via Retrosynthetic Planning and Reaction Prediction](https://mlsanity.com/paper/2411.08306/) (2024)
- [Trustworthy Retrosynthesis: Eliminating Hallucinations with a Diverse Ensemble of Reaction Scorers](https://mlsanity.com/paper/2510.10645/) (2025)
- [Order Matters in Retrosynthesis: Structure-aware Generation via Reaction-Center-Guided Discrete Flow Matching](https://mlsanity.com/paper/2602.13136/) (2026)
- [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)
- [Project Ariadne: Prompt-Conditioned Route Generation for Synthesis Planning](https://mlsanity.com/paper/2606.24184/) (2026)
- [Gradient Propagation in Retrosynthetic Space: An Efficient Framework for Synthesis Plan Generation](https://mlsanity.com/paper/2405.16123/) (2024)
- [A Scientific Reasoning Model for Organic Synthesis Procedure Generation](https://mlsanity.com/paper/2512.13668/) (2025)
- [Margin-calibrated Classifier Guidance for Property-driven Synthesis Planning](https://mlsanity.com/paper/2605.13101/) (2026)
- [Strategy-first synthesis planning for complex natural products](https://mlsanity.com/paper/2608.07454/) (2026)

## Abstract (arXiv)

Retrosynthesis is the task of planning a series of chemical reactions to create a desired molecule from simpler, buyable molecules. While previous works have proposed algorithms to find optimal solutions for a range of metrics (e.g. shortest, lowest-cost), these works generally overlook the fact that we have imperfect knowledge of the space of possible reactions, meaning plans created by algorithms may not work in a laboratory. In this paper we propose a novel formulation of retrosynthesis in terms of stochastic processes to account for this uncertainty. We then propose a novel greedy algorithm called retro-fallback which maximizes the probability that at least one synthesis plan can be executed in the lab. Using in-silico benchmarks we demonstrate that retro-fallback generally produces better sets of synthesis plans than the popular MCTS and retro* algorithms.