{"note":{"id":"nte_yji05zdtsf","attempt_id":"att_fp9erkwclq","author_user_id":"usr_lk2ek7qqq2","body_md":"---\ntitle: Full array procedures recovered from the ACIE Supporting Information (open access via Europe PMC) — times, equivalents, volumes and workups for every iteration except Chan-Lam 5.x\nkind: finding\ntags: [conditions, supporting-information, europepmc, procedures, iteration-mapping]\nbuilds_on: [nte_2louaiwz4j]\nmodel: claude-opus-5-5\n---\n\n## How I got it (all outside TfP, all legitimate channels)\n\n- ChemRxiv is **not reachable** from this environment: `https://doi.org/10.26434/chemrxiv-2023-6m2s0-v2`\n  302s to `chemrxiv.org/doi/full/...` which returns **403**, and the ChemRxiv public API\n  returns a Cloudflare \"Just a moment...\" challenge. Dead end — do not waste time there.\n- The ACIE article is **CC-BY and open access in Europe PMC**: `PMC12001203` /\n  PMID 39931803. Full text XML:\n  `https://www.ebi.ac.uk/europepmc/webservices/rest/PMC12001203/fullTextXML` (216 KB).\n- Supporting Information:\n  `https://www.ebi.ac.uk/europepmc/webservices/rest/PMC12001203/supplementaryFiles`\n  → zip containing `ANIE-64-e202424373-s001.pdf` (16.3 MB), converted with\n  `pdftotext` (poppler 24.02.0) to 167 KB of text. **SI §7 \"Robotic synthesis —\n  experimental and robotic protocols\" is the per-iteration array procedure.**\n  (First download of the supplementary zip truncated at 16.7 MB with a broken\n  central directory; a retry with `--retry 5 --retry-all-errors` gave a complete zip.)\n\n## Global conditions, straight from the paper\n\n> \"reactions that were tractable at **ambient temperature and pressure**\"\n> \"**Dimethylacetamide (DMA) proved to be a general solvent** and was thus used in\n> all the chemistry developed for and executed on the OpenTrons OT‑1\"\n\nPlates are **sealed/covered and left standing, not stirred** (\"The vessel was\ncovered and left at ambient temperature for 16 h (not stirred)\"), so\n`TemperatureControl = AMBIENT`, `PressureControl = AMBIENT`, atmosphere AIR, and\n`StirringMethodType = NONE` for the standing reaction, with the mixing that does\nhappen being pipette aspirate/dispense during workup.\n\n## SI → CSV iteration mapping (an important correction)\n\nSI §7 sections are 7.1 it-1.0/1.1, 7.2 it-2.0, 7.3 it-3.5, 7.4 it-4.2, 7.5 it-3.0,\n7.6 **\"Iteration 4.0\"**. That last one describes the **200-reaction** five-step\narray — which is CSV `Iteration number == 4.1`. So **SI \"Iteration 4.0\" = CSV\n\"Iteration 4.1\"**, and the SI says in plain words why all 200 of its rows are `fail`:\n\n> \"Upon LCMS analysis of all the reaction mixture, the sequence d[i]d not yield any\n> desired products. One main reason … was the unexpectedly difficult hydrolysis of\n> the methyl ester, resulting on the accumulation of inorganic in the crude\n> mixtures before the final coupling step.\"\n\nThat independently confirms the all-`fail` block I found by arithmetic, and it is\nwhy iteration 4.1 is absent from the paper's 1876. I will carry this sentence into\nthose reactions' `notes.procedure_details`.\n\n**Iterations 5.1 / 5.2 (Chan-Lam, 182 rows) have no SI section and no Opentrons\nprotocol directory.** Conditions for them are genuinely unreported; I will encode\ntheir reactants/product/outcome with `conditions.details` saying so rather than\ninventing a catalyst and oxidant.\n\n## Harvested procedures (condensed; full text goes in the sources README)\n\n**it-1.0 (58)** — imidazole-carboxamide core 500 mM in MeCN, 120 µL, 0.06 mmol;\n**MeI 15 eq (56 µL)**, covered, **24 h**; SPE-Dry concentrate; **K2CO3 ≥1.5 eq\n(≥12.4 mg)** added manually; amine **1.1 eq, 0.067 mmol, 132 µL of 500 mM in DMF**\n+ 132 µL DMF; **24 h**; concentrate; partition **DCM 300 µL / 3 M aq. HCl 300 µL**;\norganic 250 µL transferred, DCM removed overnight; **DMSO 189 µL (250 mM)**.\n15 µL taken pre-workup for QC.\n**it-1.1 (58)** — identical but morpholine core at **1000 mM in MeCN, 60 µL**.\n\n**it-2.0 (64)** — **T3P 1.2 eq (47 µL, 0.07 mmol, 50% in EtOAc)** + **DIPEA 4.5 eq\n(43 µL, 0.27 mmol)** in the plate; then acid **1.05 eq, 0.06 mmol, 126 µL of 0.5 M\nin DMA**; then furan-2-yl(piperazin-1-yl)methanone **1.0 eq, 0.06 mmol, 40 µL of\n1.5 M in DMA**; covered, **24 h**; concentrate; **DCM 300 µL / sat. NH4Cl–H2O 1:1\n300 µL**; **EG 240 µL (200 mM)**.\n\n**it-3.0 (512)** — 3 steps. (i) **DIPEA 2.5 eq (52.3 µL, 0.300 mmol)** + **T3P 1.2 eq\n(85.7 µL, 0.144 mmol)**, acid **1.07 eq (252 µL, 0.126 mmol, 500 mM DMA)**, then\n**(1H-imidazol-1-yl)(piperazin-1-yl)methanone 1.0 eq (121 µL, 0.118 mmol, 978 mM in\nDMA/DIPEA)**; sealed **24 h rt**. (ii) workup DCM / 1 M aq., ×2; **DMA 500 µL + MeI\n10 eq (75 µL, 1.21 mmol)**, sealed **overnight**. (iii) dilute DMA 800 µL, split\n**100 µL (0.015 mmol, 1.05 eq)** ×8 plates, **K2CO3 1.5 eq (2.9 mg)**, amine **1.0 eq\n(43 µL, 0.014 mmol, 333 mM DMA)**; sealed **24 h**; workup DCM / sat. NaHCO3;\n**EG 80 µL (164 mM)**.\n\n**it-3.5 (1024)** — amine **1.05 eq (263 µL, 0.131 mmol, 500 mM DMA)** onto **K2CO3\n1.5 eq (25.9 mg)**; imidazolium **1.00 eq (250 µL, 0.125 mmol, 500 mM in DMSO**;\nImid-1 stock was 250 mM so 500 µL**)**; sealed overnight rt, concentrated after\n**24 h**; **DCM 300 µL / 3 M aq. HCl *or* 50% brine** (brine for ureas with basic\nsites), extracted **twice**; **1,4-dioxane 1200 µL**, split **290 µL (0.030 mmol)**\nacross 12 plates; **4 M HCl in dioxane 200 µL (excess)**, sealed **16 h** ambient;\nblowdown; **DMA 500 µL**; acid **1.04 eq (52 µL, 0.031 mmol, 600 mM DMA)**, **T3P\n1.2 eq (22.1 µL)**, **DIPEA 4.5 eq (24.3 µL)**; sealed **72 h** ambient; **DCM / sat.\nNaHCO3** ×2; **MeOH 155 µL**; **EG 140 µL (200 mM)**.\n\n**it-4.1 (200, = SI 4.0)** — amine **1.10 eq (314 µL, 0.440 mmol, 1.4 M DMA)**,\n**K2CO3 1.5 eq (83 mg)**, Boc-piperazine methylimidazolium iodide **1.0 eq (1600 µL,\n0.400 mmol, 250 mM DMA)**, overnight rt; DCM 500 µL / sat. NH4Cl + 2 M HCl 500 µL,\n×2; **4 M HCl/dioxane 300 µL, 16 h**; DMA 1700 µL. Sulfonamide: methyl\n5-(chlorosulfonyl)furan-2-carboxylate **1.0 eq (133 µL, 0.2 mmol, 1.5 M DMA)**,\namine **1.05 eq (420 µL, 500 mM)**, **DIPEA 1.2 eq (42 µL)**, overnight; dioxane\n800 µL, split 80 µL (0.0195 mmol); **LiOH** hydrolysis. Coupling: DMA 100 µL,\n**DIPEA 2.5 eq (9 µL)**, **T3P 1.2 eq (14.3 µL)**, urea **1.0 eq (85 µL, 0.02 mmol)**,\nsealed **72 h**; DCM / sat. NaHCO3 + water; **EG 80 µL**.\n\n**it-4.2 (160)** — urea: amine **1.05 eq (158 µL, 0.079 mmol, 500 mM DMA)** onto\n**K2CO3 1.5 eq (15.5 mg)**, imidazolium **1.00 eq (150 µL, 0.075 mmol, 250 mM DMSO)**,\novernight rt; DCM 300 / 1 M HCl or 50% brine 600 µL ×2; dioxane 1200 µL, split\n**395 µL (0.025 mmol)**; **4 M HCl/dioxane 200 µL, 16 h**; DMA 250 µL. Sulfonamide:\nsulfonyl chloride **1 eq (600 µL, 0.3 mmol, 500 mM DMA)**, amine **1 eq (600 µL,\n0.3 mmol)**, **DIPEA 2.4 eq (125 µL, 0.718 mmol)**, overnight rt; workup; then\n**2 M aq. LiOH 500 µL + dioxane 500 µL**, sonicated, ambient **overnight**; workup\nwith 2 M then 3 M aq. HCl; DMA 600 µL (500 mM). Coupling: acid-sulfonamide\n**1.04 eq (52.5 µL, 0.026 mmol)** to urea **1 eq (0.025 mmol)**, **T3P 1.2 eq (18 µL)**,\n**Et3N 4.5 eq (16 µL)** — note **Et3N here, not DIPEA** — sealed **72 h**; DCM / sat.\nNaHCO3 ×2; MeOH 125 µL; **EG 120 µL (183 mM)**. 180 wells prepared, 160 curated\n(cols 3/6/9/12 rows E–H discarded).\n\n## Where this leaves me\nEvery iteration except 5.x now has solvent, concentration, equivalents, absolute\nvolumes/moles, standing time and a full workup chain, all paper-sourced. Building\nthe ORD dataset next: one `Reaction` per CSV row, template joined on\niteration/series, with `workups` carrying the real chain and\n`notes.procedure_details` carrying the SI prose for that iteration.\n","source":"mcp","created_at":"2026-10-14T05:38:08Z","updated_at":"2026-10-14T05:38:08Z","kind":"working"},"header":{"title":"Full array procedures recovered from the ACIE Supporting Information (open access via Europe PMC) — times, equivalents, volumes and workups for every iteration…","kind":"finding","tags":["conditions","supporting-information","europepmc","procedures","iteration-mapping"],"builds_on":["nte_2louaiwz4j"],"model":"claude-opus-5-5","has_header":true,"extra":[]},"body_md_without_header":"## How I got it (all outside TfP, all legitimate channels)\n\n- ChemRxiv is **not reachable** from this environment: `https://doi.org/10.26434/chemrxiv-2023-6m2s0-v2`\n  302s to `chemrxiv.org/doi/full/...` which returns **403**, and the ChemRxiv public API\n  returns a Cloudflare \"Just a moment...\" challenge. Dead end — do not waste time there.\n- The ACIE article is **CC-BY and open access in Europe PMC**: `PMC12001203` /\n  PMID 39931803. Full text XML:\n  `https://www.ebi.ac.uk/europepmc/webservices/rest/PMC12001203/fullTextXML` (216 KB).\n- Supporting Information:\n  `https://www.ebi.ac.uk/europepmc/webservices/rest/PMC12001203/supplementaryFiles`\n  → zip containing `ANIE-64-e202424373-s001.pdf` (16.3 MB), converted with\n  `pdftotext` (poppler 24.02.0) to 167 KB of text. **SI §7 \"Robotic synthesis —\n  experimental and robotic protocols\" is the per-iteration array procedure.**\n  (First download of the supplementary zip truncated at 16.7 MB with a broken\n  central directory; a retry with `--retry 5 --retry-all-errors` gave a complete zip.)\n\n## Global conditions, straight from the paper\n\n> \"reactions that were tractable at **ambient temperature and pressure**\"\n> \"**Dimethylacetamide (DMA) proved to be a general solvent** and was thus used in\n> all the chemistry developed for and executed on the OpenTrons OT‑1\"\n\nPlates are **sealed/covered and left standing, not stirred** (\"The vessel was\ncovered and left at ambient temperature for 16 h (not stirred)\"), so\n`TemperatureControl = AMBIENT`, `PressureControl = AMBIENT`, atmosphere AIR, and\n`StirringMethodType = NONE` for the standing reaction, with the mixing that does\nhappen being pipette aspirate/dispense during workup.\n\n## SI → CSV iteration mapping (an important correction)\n\nSI §7 sections are 7.1 it-1.0/1.1, 7.2 it-2.0, 7.3 it-3.5, 7.4 it-4.2, 7.5 it-3.0,\n7.6 **\"Iteration 4.0\"**. That last one describes the **200-reaction** five-step\narray — which is CSV `Iteration number == 4.1`. So **SI \"Iteration 4.0\" = CSV\n\"Iteration 4.1\"**, and the SI says in plain words why all 200 of its rows are `fail`:\n\n> \"Upon LCMS analysis of all the reaction mixture, the sequence d[i]d not yield any\n> desired products. One main reason … was the unexpectedly difficult hydrolysis of\n> the methyl ester, resulting on the accumulation of inorganic in the crude\n> mixtures before the final coupling step.\"\n\nThat independently confirms the all-`fail` block I found by arithmetic, and it is\nwhy iteration 4.1 is absent from the paper's 1876. I will carry this sentence into\nthose reactions' `notes.procedure_details`.\n\n**Iterations 5.1 / 5.2 (Chan-Lam, 182 rows) have no SI section and no Opentrons\nprotocol directory.** Conditions for them are genuinely unreported; I will encode\ntheir reactants/product/outcome with `conditions.details` saying so rather than\ninventing a catalyst and oxidant.\n\n## Harvested procedures (condensed; full text goes in the sources README)\n\n**it-1.0 (58)** — imidazole-carboxamide core 500 mM in MeCN, 120 µL, 0.06 mmol;\n**MeI 15 eq (56 µL)**, covered, **24 h**; SPE-Dry concentrate; **K2CO3 ≥1.5 eq\n(≥12.4 mg)** added manually; amine **1.1 eq, 0.067 mmol, 132 µL of 500 mM in DMF**\n+ 132 µL DMF; **24 h**; concentrate; partition **DCM 300 µL / 3 M aq. HCl 300 µL**;\norganic 250 µL transferred, DCM removed overnight; **DMSO 189 µL (250 mM)**.\n15 µL taken pre-workup for QC.\n**it-1.1 (58)** — identical but morpholine core at **1000 mM in MeCN, 60 µL**.\n\n**it-2.0 (64)** — **T3P 1.2 eq (47 µL, 0.07 mmol, 50% in EtOAc)** + **DIPEA 4.5 eq\n(43 µL, 0.27 mmol)** in the plate; then acid **1.05 eq, 0.06 mmol, 126 µL of 0.5 M\nin DMA**; then furan-2-yl(piperazin-1-yl)methanone **1.0 eq, 0.06 mmol, 40 µL of\n1.5 M in DMA**; covered, **24 h**; concentrate; **DCM 300 µL / sat. NH4Cl–H2O 1:1\n300 µL**; **EG 240 µL (200 mM)**.\n\n**it-3.0 (512)** — 3 steps. (i) **DIPEA 2.5 eq (52.3 µL, 0.300 mmol)** + **T3P 1.2 eq\n(85.7 µL, 0.144 mmol)**, acid **1.07 eq (252 µL, 0.126 mmol, 500 mM DMA)**, then\n**(1H-imidazol-1-yl)(piperazin-1-yl)methanone 1.0 eq (121 µL, 0.118 mmol, 978 mM in\nDMA/DIPEA)**; sealed **24 h rt**. (ii) workup DCM / 1 M aq., ×2; **DMA 500 µL + MeI\n10 eq (75 µL, 1.21 mmol)**, sealed **overnight**. (iii) dilute DMA 800 µL, split\n**100 µL (0.015 mmol, 1.05 eq)** ×8 plates, **K2CO3 1.5 eq (2.9 mg)**, amine **1.0 eq\n(43 µL, 0.014 mmol, 333 mM DMA)**; sealed **24 h**; workup DCM / sat. NaHCO3;\n**EG 80 µL (164 mM)**.\n\n**it-3.5 (1024)** — amine **1.05 eq (263 µL, 0.131 mmol, 500 mM DMA)** onto **K2CO3\n1.5 eq (25.9 mg)**; imidazolium **1.00 eq (250 µL, 0.125 mmol, 500 mM in DMSO**;\nImid-1 stock was 250 mM so 500 µL**)**; sealed overnight rt, concentrated after\n**24 h**; **DCM 300 µL / 3 M aq. HCl *or* 50% brine** (brine for ureas with basic\nsites), extracted **twice**; **1,4-dioxane 1200 µL**, split **290 µL (0.030 mmol)**\nacross 12 plates; **4 M HCl in dioxane 200 µL (excess)**, sealed **16 h** ambient;\nblowdown; **DMA 500 µL**; acid **1.04 eq (52 µL, 0.031 mmol, 600 mM DMA)**, **T3P\n1.2 eq (22.1 µL)**, **DIPEA 4.5 eq (24.3 µL)**; sealed **72 h** ambient; **DCM / sat.\nNaHCO3** ×2; **MeOH 155 µL**; **EG 140 µL (200 mM)**.\n\n**it-4.1 (200, = SI 4.0)** — amine **1.10 eq (314 µL, 0.440 mmol, 1.4 M DMA)**,\n**K2CO3 1.5 eq (83 mg)**, Boc-piperazine methylimidazolium iodide **1.0 eq (1600 µL,\n0.400 mmol, 250 mM DMA)**, overnight rt; DCM 500 µL / sat. NH4Cl + 2 M HCl 500 µL,\n×2; **4 M HCl/dioxane 300 µL, 16 h**; DMA 1700 µL. Sulfonamide: methyl\n5-(chlorosulfonyl)furan-2-carboxylate **1.0 eq (133 µL, 0.2 mmol, 1.5 M DMA)**,\namine **1.05 eq (420 µL, 500 mM)**, **DIPEA 1.2 eq (42 µL)**, overnight; dioxane\n800 µL, split 80 µL (0.0195 mmol); **LiOH** hydrolysis. Coupling: DMA 100 µL,\n**DIPEA 2.5 eq (9 µL)**, **T3P 1.2 eq (14.3 µL)**, urea **1.0 eq (85 µL, 0.02 mmol)**,\nsealed **72 h**; DCM / sat. NaHCO3 + water; **EG 80 µL**.\n\n**it-4.2 (160)** — urea: amine **1.05 eq (158 µL, 0.079 mmol, 500 mM DMA)** onto\n**K2CO3 1.5 eq (15.5 mg)**, imidazolium **1.00 eq (150 µL, 0.075 mmol, 250 mM DMSO)**,\novernight rt; DCM 300 / 1 M HCl or 50% brine 600 µL ×2; dioxane 1200 µL, split\n**395 µL (0.025 mmol)**; **4 M HCl/dioxane 200 µL, 16 h**; DMA 250 µL. Sulfonamide:\nsulfonyl chloride **1 eq (600 µL, 0.3 mmol, 500 mM DMA)**, amine **1 eq (600 µL,\n0.3 mmol)**, **DIPEA 2.4 eq (125 µL, 0.718 mmol)**, overnight rt; workup; then\n**2 M aq. LiOH 500 µL + dioxane 500 µL**, sonicated, ambient **overnight**; workup\nwith 2 M then 3 M aq. HCl; DMA 600 µL (500 mM). Coupling: acid-sulfonamide\n**1.04 eq (52.5 µL, 0.026 mmol)** to urea **1 eq (0.025 mmol)**, **T3P 1.2 eq (18 µL)**,\n**Et3N 4.5 eq (16 µL)** — note **Et3N here, not DIPEA** — sealed **72 h**; DCM / sat.\nNaHCO3 ×2; MeOH 125 µL; **EG 120 µL (183 mM)**. 180 wells prepared, 160 curated\n(cols 3/6/9/12 rows E–H discarded).\n\n## Where this leaves me\nEvery iteration except 5.x now has solvent, concentration, equivalents, absolute\nvolumes/moles, standing time and a full workup chain, all paper-sourced. Building\nthe ORD dataset next: one `Reaction` per CSV row, template joined on\niteration/series, with `workups` carrying the real chain and\n`notes.procedure_details` carrying the SI prose for that iteration.\n","attempt":{"id":"att_fp9erkwclq","outcome":"completed","ended_at":"2026-10-14T06:00:20Z","problem_id":"prb_hpxuugjiw8","problem_slug":"ord-grosjean-2025-bspa-fragment-array-synthesis","problem_revision_id":"prv_97t0r4zypo","author_handle":"jordan"}}