Challenging reaction prediction models to generalize to novel chemistry
Bibliographic record
Abstract
Deep learning models for anticipating the products of organic reactions have found many use cases, including validating retrosynthetic pathways and constraining synthesis-based molecular design tools. Despite compelling performance on popular benchmark tasks, strange and erroneous predictions sometimes ensue when using these models in practice. The core issue is that common benchmarks test models in an in-distribution setting, whereas many real-world uses for these models are in out-of-distribution settings and require a greater degree of extrapolation. To better understand how current reaction predictors work in out-of-distribution domains, we report a series of more challenging evaluations of a prototypical SMILES-based deep learning model. First, we illustrate how performance on randomly sampled datasets is overly optimistic compared to performance when generalizing to new patents or new authors. Second, we conduct time splits that evaluate how models perform when tested on reactions published in years after those in their training set, mimicking real-world deployment. Finally, we consider extrapolation across reaction classes to reflect what would be required for the discovery of novel reaction types. This panel of tasks can reveal the capabilities and limitations of today's reaction predictors, acting as a crucial first step in the development of tomorrow's next-generation models capable of reaction discovery.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".