Matching-while-Decoding: Enhancing Template-Free Retrosynthesis via Explicit Structural Alignment

Single-step retrosynthesis prediction serves as the core operational unit for automated synthesis planning and remains a fundamental computational challenge in pharmaceutical design. While a critical prior in organic chemistry is that chemical reactions typically preserve the majority of the molecular scaffold, current template-free deep learning models struggle to effectively exploit this characteristic. Existing methods attempt to exploit this by minimizing sequence-level edit distance through carefully chosen graph traversal orders. However, this structural correspondence is only indirectly induced and remains highly sensitive to imperfect traversal heuristics, which limits its effectiveness for complex transformations. To address this limitation, we introduce the Matching-while-Decoding paradigm, replacing implicit sequence alignment with direct structural supervision. We operationalize this paradigm within a graph-to-sequence architecture that explicitly maps generated reactant tokens back to the input product graph during decoding. Furthermore, our hierarchical autoregressive formulation utilizes a custom causal attention mask to enable highly efficient, single-pass parallel training. Extensive experiments across the USPTO-50K, USPTO-MIT, and USPTO-FULL benchmarks reveal a critical accuracy and robustness trade-off in existing methodologies, where models either over-rely on augmentation or fail to leverage it. Our approach uniquely resolves this bottleneck by delivering highly competitive canonical accuracy while scaling exceptionally well with test-time augmentation, establishing new state-of-the-art records on USPTO-MIT and augmented USPTO-FULL. By providing this balanced stability across diverse inference protocols, our approach emerges as a highly promising foundation for dependable single-step retrosynthesis prediction.