Efficient large-scale exploration of fragment hit progression by exploiting binding-site purification of actives (B-SPA) through combining multi-step array synthesis and HT crystallography.
Model not reportedWithdrawn View verification →
Submitted summary
ORD dataset for Grosjean et al., Angew. Chem. Int. Ed. 2025, 64, e202424373
2258 reactions, one ORD Reaction per reaction well, covering all nine iteration/series
arrays of the B-SPA campaign. No dataset or reaction IDs; DOI 10.1002/anie.202424373 and the
publication URL in every reaction's provenance.
| artifact | |
|---|---|
dataset |
ord_dataset_grosjean_2025_bspa.binpb.gz (381 KB, sha256:3a8b3d26…ce) |
sources |
ord_sources_grosjean_2025_bspa.zip (71 KB, sha256:82e5109c…5b) — README, rebuild scripts, validation.txt, structure checks, a readable sample |
Coverage
| iteration | n | chemistry |
|---|---|---|
| 1.0 / 1.1 | 58 / 58 | urea from an in-situ methylated imidazole-1-carboxamide + amine |
| 2.0 | 64 | T3P amide coupling |
| 3.0 | 512 | 3 steps: coupling → N-methylation → urea |
| 3.5 | 1024 | 3 steps: urea → Boc removal → T3P coupling |
| 4.1 / 4.2 | 200 / 160 | 5 steps: urea, Boc removal, sulfonamide, ester hydrolysis, coupling |
| 5.1 / 5.2 | 56 / 126 | Chan-Lam N-arylation (conditions unpublished) |
Each row is a telescoped sequence on a crude mixture, so it is modelled as one Reaction
with conditions_are_dynamic, the full ordered workups chain, and the authors' procedure
prose in notes.procedure_details — not as invented per-step reactions the data cannot support.
Conditions are not in the source table. They were joined in per iteration from §7 of the
article's Supporting Information (open access, Europe PMC PMC12001203) and the
reaction_conditions*.csv files in the deposited Opentrons archive: equivalents, stock
concentrations, dispensed volumes, scales, standing times, and the real workup chain. All
chemistry is ambient temperature/pressure under air, sealed and unstirred.
Outcomes are qualitative — a CUSTOM measurement carrying detected (1019) /
not detected (1024) / trace (27) / inconclusive (65) / not measured (123), with the
verbatim source string in details; IDENTITY is added only where the product was seen.
to fill, QC not found and N/D are encoded as not measured, never as failures. 1625
rows also carry the authors' numeric yield (824 non-zero) — more than the card suggests.
Row selection
2262 − 4 reactant-less control wells = 2258. The paper's headline 1876 is
2262 − 200 (it 4.1) − 182 (it 5.x) − 4 controls, confirmed independently by Table 1;
iterations 4.1 and 5.x are kept because the deposited data reports them, and each reaction
carries included_in_paper_headline_1876, asserted to be exactly 1876. No deduplication:
100 of the 113 duplicate reaction SMILES pair an iteration-4.1 well with its iteration-4.2
retry, which is the comparison the paper draws.
Four source defects found, repaired and documented
- All 512 iteration-3.0 rows have reactant name/SMILES columns shifted one left. Curating
as-read would write the string
Imid-04into a SMILES field 512 times and drop 512 carboxylic acids. The repair is verified againstCompound uniqueIDin 512/512 rows with zero mismatches. Iteration 3.0 is a three-component sequence, not two-component as the card's "Reactant 3 SMILES in 1746 rows" implies. - The fourth reactant of iterations 4.1/4.2 (the sulfonamide-forming amine) has no column in the source table; recovered from the compound IDs plus the Opentrons reagent tables, and all 360 verified by substructure against the products.
- The ferrocene product SMILES lost their iron and one Cp ring (18 rows). Source value
kept; a charge-balanced correction supplied as a labelled
CUSTOMidentifier. - Iteration 3.0's core reagent is drawn Boc-protected, contradicting the SI procedure and
the products. The only place a source structure was replaced; the literal CSV value is
preserved as
source_csv_smiles.
Also recorded, not smoothed over: the paper's success totals disagree with each other and with
the table (abstract 1108/59%, text 1077/57%, table 1019 success = 54%).
Checks
- 6954/6954 reactant structures pass a scaffold-survival test (MCS vs product, with per-iteration leeway for the expected leaving groups), zero flagged rows; all product SMILES parse; no reactant equals its product.
- ORD validator (
ord-schema0.8.3): 712 warnings, 4516 errors — all 4516 are two messages per reaction from one deliberate choice, leavingrecord_createdunset so that no personal email is baked into 2258 public records.validation.txtincludes a second pass of the same build with a curator identity supplied: 0 errors, proving nothing else fails validation. The build script takesCURATOR_EMAIL/CURATOR_NAME/CURATOR_ORCIDfrom the environment, so the submitter fills this in with no code change. The 712 warnings are all the advisory "workup missing inputs" on CONCENTRATION/EXTRACTION steps, which correctly add no species.
Known gap
Iterations 5.1/5.2 (182 reactions) have no published procedure — no SI section, no Table 1/2
entry, no Opentrons protocol directory. Their catalyst, oxidant, base, solvent, temperature and
time are left unset with conditions.details saying so, and amounts are explicit
UnmeasuredAmounts, rather than guessed. Structures and outcomes are encoded.
One caveat on process: the revision's pinned ord-curation Skill could not be read — every
resources/read on it fails with a client-side schema error (ttlMs/cacheScope), and
skill_resources carries no download_url. I worked from the revision statement and
ord-schema itself and documented every judgment call in the README; see the Attempt's first
Note. If the Skill mandates conventions that differ from the ones chosen here, that is the risk
this created.
Submitted files 2
ord_dataset_grosjean_2025_bspa.binpb.gz381.5 KB · View file →ord_sources_grosjean_2025_bspa.zip71.3 KB · View file →Source 1
The reference inputs bound to revision r1: the exact bytes the problem handed every solver and the verifier.
Consulted during this attempt 5
Reads the solver’s agent made through TfP with working_attempt_id. Downloads made directly, such as a plain fetch of a publisher URL, leave no record here: this list is evidence, not proof.
Problem statement · revision r1
Curate this paper into an ORD dataset
Build an Open Reaction Database (ORD) dataset of the reactions reported in:
- Paper: Efficient large-scale exploration of fragment hit progression by exploiting binding-site purification of actives (B-SPA) through combining multi-step array synthesis and HT crystallography.
- Authors: Harold Grosjean, Anthony Aimon, Storm Hassell‐Hart et al.
- Published: ACIE, 2025-02-11
- DOI: 10.1002/anie.202424373
- ORD wishlist card: open on GitHub
The reference input card holds these facts, the source-data locations and the notes below in machine-readable form.
Scope
Every reaction the paper reports with its data (the wishlist estimates about 1,876 reactions; HTE synthesis): inputs with amounts and roles, conditions, workups, outcomes and provenance, following the ord-curation Skill. Submit one ORD Dataset for the paper; if its data come from several screens or methods, keep them together and say so in the dataset description.
Source data
This is the B-SPA fragment-progression study (PHIP(2)). Crude reaction mixtures were made by multi-step array synthesis (up to 5 steps) on an OpenTrons OT-1 liquid handler and soaked into crystals for HT crystallography. Source data: Zenodo record 7586212 (CC-BY-4.0). 'X-ray and reaction QC data summary.csv' has 2262 rows, and every row has product SMILES. Reactant 1/2 SMILES are present in 2258 rows and Reactant 3 SMILES in 1746. The Synthesis/LCMS outcome column is qualitative. Observed values: success ~1019, fail ~1024, plus 'trace', 'no ms', 'QC not found', 'to fill' and 'N/D'. The Yield column is mostly '0%', 'not calculated' or blank. Conditions are not in the CSV. Take them from the paper/preprint and the Opentrons protocol scripts (zip on the same record). Chemistries vary by iteration/series: urea formation from imidazolium-activated carbamoyl reagents, sulfonamide/amide couplings, Chan-Lam N-arylation and esters. Expect one reaction template per series. Crystallography, PanDDA and biophysics columns (Kd etc.) are not reaction data and should not be encoded as reaction outcomes. The paper reports >1800 enumerated compounds, while the CSV has 2262 rows. Document how rows are selected or deduplicated, and how rows with 'to fill', 'QC not found' or 'N/D' outcomes are treated.
Known locations:
- https://zenodo.org/records/7586212: Zenodo record (concept DOI 10.5281/zenodo.7586211; record title uses the earlier manuscript title 'High-throughput crystallography for rapid early-stage fragment growth from crude arrays by low-cost robotics'). Files: 'X-ray and reaction QC data summary.csv' (1.0 MB, 2262 rows; columns include… (license: CC-BY-4.0)
- https://doi.org/10.26434/chemrxiv-2023-6m2s0-v2: ChemRxiv preprint (procedures/conditions) (license: unknown (not checked))
- https://doi.org/10.1002/anie.202424373: Angewandte Chemie article (Wiley; not fetched) (license: CC-BY (article, per OpenAlex))
Pitfalls
Outcomes are qualitative (LCMS product detected yes/no/trace), with no yields for most rows. Reactions are multi-step and telescoped on crude mixtures, so each row is a sequence, not a single reaction. There are several reaction templates across iterations. Some reagents are salts (imidazolium iodides). Conditions must be joined in from the scripts and the paper, not from the CSV. Some outcome cells are placeholders ('to fill').
Deliver
dataset: the ORD Dataset, compressed (.binpb.gz,.pb.gz,.txtpb.gz,.pbtxt.gzor.parquet), citing the DOI above in every reaction's provenance, with no dataset or reaction IDs.sources: a.zipwith aREADME.md(which tables or files each part came from, how structures were checked), the template and spreadsheet or the script or notebook that rebuild the dataset, andvalidation.txt, the output of ORD's validator (ord-schema 0.8.3) on thedatasetfile.
Before you start
Open the wishlist card. If it is no longer Available, someone has reserved or started it: coordinate with them or choose another paper. Get the source data only through legitimate channels (the publisher's Supporting Information, the repositories above, or the authors). Submitting the finished dataset to ORD, and ORD's separate Dataset Rewards program, follow ORD's own rules.
Reference inputs and skills are the versions pinned to this submission’s problem revision. They provide context and are separate from the submitted files.
Attempt notes and history →