| # Dataset Notes — Table 1 (Wren Group, SynOpen 2023) |
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| ## Summary |
| - 27 successful reactions (compounds 16–43) |
| - 2 confirmed FAILED reactions (ortho-Cl and ortho-Br anilines) |
| - All reactions: Amine + Diethyl Squarate (DES) → Monosquarate-amide |
| - Solvent: EtOH (except compound 16: MeOH) |
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| ## Key Patterns Learned From Data |
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| ### Substituent Position Effect on Yield |
| | Position | Avg Yield | Notes | |
| |---|---|---| |
| | Para | ~70% | Best position consistently | |
| | Meta | ~48% | Moderate | |
| | Ortho | ~18–38% | Low — steric clash (Cl/Br = FAIL) | |
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| ### Amine Type Effect |
| | Amine | Catalyst needed? | Avg Yield | |
| |---|---|---| |
| | Benzylamine | No | ~57% (up to 99% at reflux) | |
| | Aniline | Usually yes | ~47% | |
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| ### Catalyst Effect (Zn(OTf)₂) |
| - Anilines without catalyst: often no reaction |
| - With 10–20 mol%: reaction initiates |
| - Benzylamines: react without catalyst (more nucleophilic) |
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| ### Temperature Effect |
| - r.t. is standard |
| - Reflux can boost yield dramatically (compound 37: 99%) |
| - But reflux not always transferable between substrates |
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| ### Complete FAIL Conditions |
| - Ortho-Cl aniline → NO REACTION even at reflux + 48h + catalyst |
| - Ortho-Br aniline → NO REACTION even at reflux + 48h + catalyst |
| - Reason: poor nucleophilicity + steric crowding combined |
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| ## Paper 3 — Biological Activity Data (HDAC8 IC₅₀, ChemMedChem 2026) |
| Active compounds (single-digit micromolar): |
| - 9b (para-F aniline monosquarate) → HDAC8 IC₅₀ = 1.20 μM ⭐ BEST |
| - 14b (N-methyl bis-squaramide benzylamine) → 1.3 μM |
| - 13b (bis-squaramide benzylamine) → 1.8 μM |
| - 13c (bis-squaramide para-Br aniline) → 2.0 μM |
| - All aliphatic/heterocyclic compounds → >35 μM (inactive) |
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| Key SAR: para > meta > ortho for both yield AND HDAC8 activity |
| Benzylamine > aniline in both synthesis and biology |
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| ## Missing Data (Need From Lecturer) |
| - Exact substituent identities for compounds 30, 31, 32 (tolyl position unclear) |
| - Any unpublished reaction attempts |
| - Reactions with different DES:amine ratios (all 1:1 in this paper) |
| - Squaric acid (not DES) as starting material results |
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