# Copy-Augmented Representation for Structure Invariant Template-Free Retrosynthesis

arXiv: https://arxiv.org/abs/2510.16588 · HTML: https://mlsanity.com/paper/2510.16588/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 14 of its 39 references that are in the map.
- First posted on arXiv 18 Oct 2025.

## Builds on (most cited first, 14 of 14)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Adam: A Method for Stochastic Optimization](https://mlsanity.com/paper/1412.6980/) (2014)
- [Rethinking the Inception Architecture for Computer Vision](https://mlsanity.com/paper/1512.00567/) (2015)
- [Get To The Point: Summarization with Pointer-Generator Networks](https://mlsanity.com/paper/1704.04368/) (2017)
- [Pointer Networks](https://mlsanity.com/paper/1506.03134/) (2015)
- [Molecular Transformer - A Model for Uncertainty-Calibrated Chemical Reaction Prediction](https://mlsanity.com/paper/1811.02633/) (2018)
- [R-Drop: Regularized Dropout for Neural Networks](https://mlsanity.com/paper/2106.14448/) (2021)
- [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 Graph to Graphs Framework for Retrosynthesis Prediction](https://mlsanity.com/paper/2003.12725/) (2020)
- [RetroXpert: Decompose Retrosynthesis Prediction like a Chemist](https://mlsanity.com/paper/2011.02893/) (2020)
- [Permutation invariant graph-to-sequence model for template-free retrosynthesis and reaction prediction](https://mlsanity.com/paper/2110.09681/) (2021)
- [Root-aligned SMILES: A Tight Representation for Chemical Reaction Prediction](https://mlsanity.com/paper/2203.11444/) (2022)
- [Guiding Attention for Self-Supervised Learning with Transformers](https://mlsanity.com/paper/2010.02399/) (2020)

## Abstract (arXiv)

Retrosynthesis prediction is fundamental to drug discovery and chemical synthesis, requiring the identification of reactants that can produce a target molecule. Current template-free methods struggle to capture the structural invariance inherent in chemical reactions, where substantial molecular scaffolds remain unchanged, leading to unnecessarily large search spaces and reduced prediction accuracy. We introduce C-SMILES, a novel molecular representation that decomposes traditional SMILES into element-token pairs with five special tokens, effectively minimizing editing distance between reactants and products. Building upon this representation, we incorporate a copy-augmented mechanism that dynamically determines whether to generate new tokens or preserve unchanged molecular fragments from the product. Our approach integrates SMILES alignment guidance to enhance attention consistency with ground-truth atom mappings, enabling more chemically coherent predictions. Comprehensive evaluation on USPTO-50K and large-scale USPTO-FULL datasets demonstrates significant improvements: 67.2% top-1 accuracy on USPTO-50K and 50.8% on USPTO-FULL, with 99.9% validity in generated molecules. This work establishes a new paradigm for structure-aware molecular generation with direct applications in computational drug discovery.