The elephant in the lab: synthesizability in generative small-molecule design
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
The design of small molecules with tailored properties is a central goal in chemistry and materials science. Recent advances in machine learning provide powerful tools to accelerate the pace of discovery. One promising avenue for acceleration involves the use of generative models that propose novel candidates for diverse optimization tasks. Despite their promise, these methods are often evaluated solely using computational benchmarks, and many studies fail to advance proposed candidates to experimental validation in the wet lab. A key reason for this gap, the elephant in the room, is the limited synthesizability of the generated molecules. In response, the community has recently developed various strategies to address this challenge and incorporate synthesizability into generative design workflows. In this opinion, we provide a comprehensive overview of recent contributions that explicitly tackle molecular synthesizability, highlighting notable advances. We also discuss key limitations of current approaches and outline promising directions for future research.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.003 | 0.002 |
| 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 | 0.001 | 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 it