Training Chemical Plausibility-Aware Large Language Models for Single-Step Retrosynthesis

Single-step retrosynthesis is a central component of computer-aided synthesis planning, yet its intrinsically one-to-many nature is poorly captured by single-answer evaluation and benchmarking protocols. To address this, we introduce Top-K prompting as a robust training and inference paradigm to better capture diverse, plausible reaction predictions. We compile CREED-CCV-2+USPTO-XL, an ultra-large-scale dataset of ~45.6 million verified reactions to train the C3LM (Chemistry Constraint-Consistent Language Model). By integrating fine-tuning with ChemCensor-based and novelty-oriented rewards, our model achieves state-of-the-art performance on the OOD URSA-expert-2026 benchmark. Further analysis of reaction uniqueness shows that LLMs and conventional models explore complementary reaction spaces, motivating ensemble-based retrosynthesis systems. Overall, our results establish Top-K, plausibility-aware training as a practical new direction for robust future LLM-based synthesis planning.

RetroMPA: A Molecular Property-Aware Auxiliary Framework for Enhancing Retrosynthesis Prediction

Retrosynthesis is a cornerstone of drug discovery and organic synthesis. While data-driven deep learning models have shown remarkable progress, they autonomously learn reaction patterns from extensive datasets with limited integration of established chemical knowledge as priors. To address this limitation, we introduce RetroMPA, a molecular property-aware, post-hoc enhancement module that injects chemical knowledge into the retrosynthesis pipeline. Rather than functioning as an independent SMILES sequence generator, RetroMPA is a broadly applicable, model-agnostic chemical filter designed to recalibrate and optimize the predictive pathways of existing algorithms. This plug-and-play framework integrates seamlessly with a range of data-driven retrosynthesis methods, enhancing outputs without modifying model architecture or requiring resource-intensive retraining. By leveraging a property-aware latent embedding space, RetroMPA consistently improves top-1 accuracy across eight representative retrosynthesis models by an average of 5.50% on USPTO-50K. Furthermore, we validate its scalability on the large-scale USPTO-Full dataset, achieving an average improvement of about 2.03% across both template-based and template-free architectures. Wet-lab experiments provide preliminary support for the practical utility of the framework. These syntheses confirmed viable, previously unreported substrate combinations for classic reaction paradigms---specifically, Suzuki-Miyaura coupling, Bucherer reaction, and Friedel-Crafts acylation---suggesting that RetroMPA can operate beyond mere data fitting. The code is open-sourced at https://github.com/MengzhouLu/RetroMPA.

Strategy-first synthesis planning for complex natural products

The total synthesis of a complex molecule is among the most demanding intellectual and experimental feats in chemistry: a chemist must plan many steps ahead for how to assemble simple building blocks into an intricate target, devise backup strategies, and anticipate procedural challenges. It is also a profoundly creative activity. For half a century, efforts to automate the retrosynthetic design of natural products and other complex molecules have drawn on catalogued reactions, and the resulting tools now report near-complete success on benchmarks built from that same source. But these tools were shaped to fit benchmarked chemistry, and they falter on many natural products, the frontier of the field, whose densely functionalized, polycyclic architectures demand precisely the inventive chemistry the record contains least. Whether a machine could reasonably design such syntheses like an expert chemist does has remained unclear. Here, we show that SynthEx, an agentic framework built on large language models, plans routes to complex natural products that lie beyond the reach of conventional design algorithms. SynthEx proposes competing strategies, assembles a sequence of routine and key steps into a cohesive route, and critiques and improves its own design; the chemistry it favours is more convergent than existing tools produce, and spans a region of reaction space that catalogue-based tools cannot match. Most notably, in blinded assessments, expert chemists judged its key steps comparable to those of published human syntheses and engaged with them as genuine synthesis plans, a response algorithmic route prediction has not previously accomplished. We release routes to more than a thousand natural products as SynthAtlas, an open, interactive database, and anticipate it will become a shared resource for a collection of complex target molecules that lack existing literature routes.

Variational-Ising-Attention (VIA):TailoredAttentionMattersfor Science

Attention enables context modeling via query-key scoring with softmax normalization. Driven by industrial long-context demands, mainstream research has converged toward sparsity and efficiency--yet softmax's independence assumption persists. For scientific tasks unburdened by long-token constraints, however, richer structured coupling may often be essential, making tailored attention both viable and more appropriate. To this end, we propose Variational-Ising-Attention (VIA), which augments softmax normalization with an interacting Ising model; attention patterns emerge from learnable pairwise couplings via variational mean-field inference, redefining attention from a ranking over isolated items to a collective state over interacting entities. We instantiate VIA on retrosynthesis reaction center prediction, a task inherently governed by cooperative bond-breaking constraints. Comprehensive experiments across model variants, coupled with mechanistic analyses, demonstrate that VIA consistently and substantially outperforms standard softmax attention. More broadly, our findings suggest that for scientific problems, the optimal solution is not general-purpose efficiency, but appropriately tailored attention aligned with intrinsic domain structure. This work provides a theoretically grounded and empirically validated instantiation of this paradigm.

RetroAgent: Harnessing LLMs to Search Over Structured Memory for Agentic Retrosynthesis Planning

Multi-step retrosynthesis planning seeks to decompose a target molecule into commercially available building blocks through a sequence of feasible reactions. The vast combinatorial search space makes this task challenging even for expert chemists. Traditional methods combine tree search with offline-trained value networks that score candidates in isolation, without reasoning about complete multi-step routes. Recent work leverages Large Language Models (LLMs) for this task, but relies on simple interfaces that limit exploration of the full search space. We introduce RetroAgent, an LLM agent that bridges symbolic search and neural reasoning through a harness with structured memory. Through memory and chemistry tools, the agent observes the full search state, including explored routes, available alternatives, and properties of intermediates, enabling informed decisions grounded in both global progress and domain knowledge. Experiments on in-distribution and out-of-distribution benchmarks demonstrate that RetroAgent delivers strong performance and generalization.

URSA: Chemistry-Aware Benchmark for Utilitarian Retrosynthesis Assessment

Synthesis planning aiming to find pathways of reactions for a target molecule is one of the most important and challenging tasks in drug discovery. Recent progress has produced both specialized deep-learning retrosynthesis systems and general-purpose large language models, but objective comparison remains difficult due to the lack of flexible, chemically interpretable benchmarking protocols. In the current study, we are introducing the URSA (Utilitarian RetroSynthesis Assessment) evaluation framework that provides the opportunity to benchmark the synthetic routes not only from a formal perspective, such as convergence to commercially available starting materials, but also from a chemical plausibility perspective, mimicking the way expert chemists evaluate the reactions and routes. The study covers a comprehensive evaluation of both conventional end-to-end retrosynthesis solutions and LLMs for the synthesis planning task on a set of novel, diverse target molecules with undisclosed synthetic routes, which represent realistic tasks in the daily drug design routine. We find that while LLMs can support high-level strategic planning, they currently underperform specialized retrosynthesis models in reliably solving synthesis planning tasks.

Project Ariadne: Prompt-Conditioned Route Generation for Synthesis Planning

Retrosynthetic planning seeks to connect a target molecule to commercially available starting materials through a multistep route. Classical planners construct such routes by iteratively applying single-step reaction models within a search procedure; constrained variants often require specialized algorithms or architectural changes. Direct route generation reframes retrosynthesis as sequence generation, but existing direct-generation methods still train separate models for different planning specifications. We introduce Ariadne, a decoder-only route generator that represents the target, optional constraints, and route in one prompt-completion sequence. On the RetroCast/PaRoutes mkt-cnv-160 benchmark family, one 24-layer checkpoint follows route-depth and required-starting-material prompts: adding the corresponding prompt fields raises Solv-0 by 13.7 points for depth constraints and 31.2 points for required-leaf constraints. Ariadne also improves over DESP, a bidirectional search planner, on required-leaf Top-10 and Solv-0 in 24 GPU-minutes versus 6.8 GPU-hours. On standard reconstruction, Ariadne is comparable to DMS Explorer XL at about half the reported inference time. Across additional target-only benchmarks, Ariadne's clearest gains are on route-holdout reconstruction, whereas AiZynthFinder MCTS remains stronger on several Solv-0 comparisons. These results extend sequence generation from specialist retrosynthesis models to prompt-conditioned structural route generation. We release the codebase and training scripts to support further work, but do not introduce Tier-1--3 route checkers; those remain the main bottleneck before models of this kind can become useful to experimental chemists.

Augmenting Molecular Language Models with Local $n$-gram Memory

Transformer-based language models for SMILES strings suffer from a locality gap: standard character-level tokenization fragments chemically meaningful motifs, forcing models to repeatedly learn local syntax at the expense of long-range dependencies. To address this without disrupting standard tokenizers, we propose MolGram, which integrates a conditional $n$-gram memory module into molecular language models. MolGram maps local string patterns to learned embeddings via scalable hash lookups and dynamically injects this regional context into hidden states. Evaluations across three tasks, including unconditional molecule generation, forward reaction prediction, and single-step retrosynthesis, show that MolGram consistently improves performance. Crucially, our analyses demonstrate that MolGram outperforms baselines with 3$\times$ more parameters, establishing explicit local pattern memory as a highly efficient inductive bias.

RETROSPECT: RETROsynthesis via Sequential Prediction, and Chemically Transformed-ranking

Single-step retrosynthesis needs both accurate first-ranked suggestions and candidate lists that are rich enough for downstream selection. We study this as a proposal-selection decomposition. Our system, RETROSPECT, combines a single Transformer proposal model, which we call the ChemAlign Transformer, with a LambdaMART reranker over structural, reaction-template, upstream-score, and optional DFT-derived descriptors. The generator is trained with hybrid root-aligned and random SMILES augmentation, Pre-LayerNorm, tied embeddings, exponential moving average weights, and a differentiable atom-balance auxiliary loss. On the full USPTO-50K test set of 5,007 reactions, the generator reaches 55.00% top-1 and 86.18% top-10 exact-match accuracy with 99.86% top-1 validity. On the merged candidate-pool benchmark used for reranking, which contains 5,007 test products and about 111 candidates per product, a LambdaMART model trained on the structural feature set reaches 59.4% top-1 with 0.7171 mean reciprocal rank. Feature ablations show that upstream proposal score and template-frequency statistics provide most of the reranking signal, while DFT and reaction-center DFT features provide smaller and less consistent gains. These results support a modular view of retrosynthesis: stronger single-model proposal and learned candidate selection are complementary, and the proposal model can serve as a drop-in component for ensemble systems such as RetroChimera (Maziarz et al., 2024)