Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](C)(C)O[Si](C)(C)C.[N+:22]([O-])([OH:24])=[O:23].O>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 78.9 %

Procedure:
To a stirred solution of 2,3,4-Trifluorobenzoic acid (70 Kg, 398 Mol) in sulphuric acid (96 wt %; 194 L) and hexamethyldisiloxane (6.5 Kg, 40 Mol), at 23° C., was added a 1:1 mixture of sulphuric acid (96 wt %) and nitric acid (98 wt %) (total 70.1 Kg), over 75 min. The temperature of the reaction mixture was maintained between 15 and 25° C. during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg), keeping the temperature of the ice mixture below 0° C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0° C., then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L), and the solid was then suspended in water (280 L) and stirred for 2 hours at 0° C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45° C. for 2 days, to provide 2,3,4-Trifluoro-5-nitro benzoic acid (69.4 Kg, 74.3% yield). 1H NMR (400 MHz, d6 DMSO) δ 8.44 (1H, apparent dt, J 2, 7, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ −153.9, −131.5, −120.9. 13C NMR (100 MHz, d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C—F, dt, J 251, 10), 148 (C—F, dd, J 265, 13), 154 (C—F, dd, J 265, 10), 163 (COOH). IR νmax/cm−1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (−) m/z 220 (M−1) detected.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:39]1([S:49](Cl)(=[O:51])=[O:50])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:49]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)(=[O:51])=[O:50])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cccc5ccccc45)ccc3N2)=C(O)c2ccccc21
Yield: 101.6 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.80 mmol), and 1-naphthalenesulfonyl chloride (45.3 mg, 0.20 mmol) in acetone (1.5 mL) was stirred at rt for 72 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (32.0 mg, quant. yield).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([C:20](O)=[O:21])[CH:14]=2)=[CH:9][CH:8]=1)=[O:5].[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH2:33])[CH3:29].CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH:33][C:20]([C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[CH:17][CH:16]=1)=[O:21])[CH3:29]
Reactant: CCOC(CN)OCC
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CNC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 1 was hydrolyzed by heating it in a solution of LiOH to yield 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid. A mixture of 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (800 mg, 2.2 mmol), 2,2-diethoxy-ethylamine (0.32 mL, 2.2. mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (5 mmol) in dry DMF (5 mL) was stirred at room temperature for 24 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (EtOAc) (2×20 mL). The organic extract was washed with water and dried. The oil obtained on concentration of the organic layer was purified by flash chromatograghed on silica gel to give 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (2,2-diethoxy-ethyl)-amide as colorless oil (0.68 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:12]1[CH:16]=[N:15][N:14]=[C:13]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.O=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[O:12][CH:16]=[N:15][N:14]=3)=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(-c2nnco2)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Yield: 72.1 %

Procedure:
A mixture of 4-methoxybenzeneboronic acid (1.9 g, 12 mmol), 4-(1,3,4)oxadiazol-2-yl-phenol (1.0 g, 6.2 mmol), copper(II)acetate (1.1 g, 6.2 mmol), crushed 4-Angstrom molecular sieves (0.65 g), triethylamine (4.2 mL) and methylene chloride (22.7 mL) was stirred under 1 atm of oxygen gas for 48 hours. The mixture was filtered through a pad of Celite®, concentrated in vacuo and purified by radial chromatography (2:1 hexane-ethyl acetate), affording 1.2 g of 2-[4-(4-Methoxy-phenoxy)-phenyl]-[1,3,4]oxadiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.C1N=CN([C:15]([N:17]2C=N[CH:19]=[CH:18]2)=[O:16])C=1>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:15]([NH:17][C:18]2[CH:19]=[C:4]([CH3:5])[N:3]=[C:2]([CH3:7])[CH:1]=2)=[O:16])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(N)cc(C)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)Nc2cc(C)nc(C)c2)cc(C)n1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
2,6-Dimethyl-pyridin-4-ylamine (1.22 g, 10 mmol) is dissolved in dry dioxane (30 mL) and CDI (891 mg, 5.5 mmol) is added. The mixture is heated at 80° C. for 1 h. Further CDI (160 mg) is added and stirring is continued for 15 h. The mixture is evaporated and purified by FC (SiO2, EtOAc-MeOH) to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([O:24]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2cccs2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A suspension of tert-butyl[6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (1.04 g, 2 mmol) and 5% palladium carbon (1.0 g) in ethanol (10 ml) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-hydroxy-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.82 g, 96.5%) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15].Br[CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH2:17][C:18]#[N:19]
Reactant: N#CCBr
Reactant: Oc1ccc2c(nnn2CC2CC2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CCOc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-ol (25 mg, 0.093 mmol), bromoacetonitrile (34 mg, 0.28 mmol, 3 equiv) and potassium carbonate (64 mg, 0.47 mmol, 5 equiv) were combined in dimethylsulfoxide (1 mL) and placed into a preheated oil bath at 80° C. for 30 minutes. The mixture was cooled to ambient temperature, filtered and purified by preparative HPLC (20 to 95% water containing 0.5% trifluoroacetic acid: acetonitrile containing 0.5% trifluoroacetic acid). The appropriate fractions were poured into sodium bicarbonate (50 mL, aqueous saturated) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound as a light brown solid: 1H-NMR (400 MHz, CDCl3) δ 7.55 (1H, d, J=9.2 Hz), 7.41 (1H, d, J=9.0 Hz), 4.91 (2H, s), 4.53 (2H, d, J=7.1 Hz), 1.45-1.35 (1H, m), 0.71-0.66 (2H, m), 0.52-0.48 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 307.0187 [(M+H)+; calculated for C12H12BrN4O: 307.0189].