# Trustworthy Retrosynthesis: Eliminating Hallucinations with a Diverse Ensemble of Reaction Scorers

arXiv: https://arxiv.org/abs/2510.10645 · HTML: https://mlsanity.com/paper/2510.10645/

## Key facts

- Cited by 4 papers in the map (data through 14 Oct 2026).
- Builds on 20 of its 38 references that are in the map.
- First posted on arXiv 12 Oct 2025.

## Builds on (most cited first, 20 of 20)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Graph Attention Networks](https://mlsanity.com/paper/1710.10903/) (2017)
- [BART: Denoising Sequence-to-Sequence Pre-training for Natural Language Generation, Translation, and Comprehension](https://mlsanity.com/paper/1910.13461/) (2019)
- [Competition-Level Code Generation with AlphaCode](https://mlsanity.com/paper/2203.07814/) (2022)
- [LeanDojo: Theorem Proving with Retrieval-Augmented Language Models](https://mlsanity.com/paper/2306.15626/) (2023)
- [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)
- [A Comprehensive Survey of Hallucination in Large Language, Image, Video and Audio Foundation Models](https://mlsanity.com/paper/2405.09589/) (2024)
- [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)
- [Retro*: Learning Retrosynthetic Planning with Neural Guided A* Search](https://mlsanity.com/paper/2006.15820/) (2020)
- [RetroXpert: Decompose Retrosynthesis Prediction like a Chemist](https://mlsanity.com/paper/2011.02893/) (2020)
- [Learning Graph Models for Retrosynthesis Prediction](https://mlsanity.com/paper/2006.07038/) (2020)
- [Root-aligned SMILES: A Tight Representation for Chemical Reaction Prediction](https://mlsanity.com/paper/2203.11444/) (2022)
- [Re-evaluating Retrosynthesis Algorithms with Syntheseus](https://mlsanity.com/paper/2310.19796/) (2023)
- [Retro-fallback: retrosynthetic planning in an uncertain world](https://mlsanity.com/paper/2310.09270/) (2023)
- [Models Matter: The Impact of Single-Step Retrosynthesis on Synthesis Planning](https://mlsanity.com/paper/2308.05522/) (2023)
- [RetroGFN: Diverse and Feasible Retrosynthesis using GFlowNets](https://mlsanity.com/paper/2406.18739/) (2024)

## Built on by (most cited first, 4 of 4)

- [When Single Answer Is Not Enough: Rethinking Single-Step Retrosynthesis Benchmarks for LLMs](https://mlsanity.com/paper/2602.03554/) (2026)
- [URSA: Chemistry-Aware Benchmark for Utilitarian Retrosynthesis Assessment](https://mlsanity.com/paper/2607.04688/) (2026)
- [Reinforced Reasoning for End-to-End Retrosynthetic Planning](https://mlsanity.com/paper/2603.29723/) (2026)
- [FREA: A Multi-Source Expert Benchmark for Reaction Feasibility Verification](https://mlsanity.com/paper/2610.06614/) (2026)

## Abstract (arXiv)

Retrosynthesis is one of the domains transformed by the rise of generative models, and it is one where the problem of nonsensical or erroneous outputs (hallucinations) is particularly insidious: reliable assessment of synthetic plans is time-consuming, with automatic methods lacking. In this work, we present RetroTrim, a retrosynthesis system that successfully avoids nonsensical plans on a set of challenging drug-like targets. Compared to common baselines in the field, our system is not only the sole method that succeeds in filtering out hallucinated reactions, but it also results in the highest number of high-quality paths overall. The key insight behind RetroTrim is the combination of diverse reaction scoring strategies, based on machine learning models and existing chemical databases. We show that our scoring strategies capture different classes of hallucinations by analyzing them on a dataset of labeled retrosynthetic intermediates. This approach formed the basis of our winning solution to the Standard Industries 1 million Retrosynthesis Challenge. To measure the performance of retrosynthesis systems, we propose a novel evaluation protocol for reactions and synthetic paths based on a structured review by expert chemists. Using this protocol, we compare systems on a set of 32 novel targets, curated to reflect recent trends in drug structures. While the insights behind our methodology are broadly applicable to retrosynthesis, our focus is on targets in the drug-like domain. By releasing our benchmark targets and the details of our evaluation protocol, we hope to inspire further research into reliable retrosynthesis.