Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].N1CC[CH:16]([N:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])[CH2:15]C1.C(OC)(C)(C)C>CN(C)C=O>[N:8]1([C:1]([N:3]2[CH2:4][CH2:15][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:6][CH2:7]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C1Nc2ccccc2CCN1C1CCN(C(=O)n2ccnc2)CC1
Temperature: 25 °C

Procedure:
10 g (44.8 mmol) of carbonyldiimidazole (I) are in 40 mL dimethylformamide at 40 to 50° C. dissolved. Then 10.0 g (40.8 mmol) of 1,3,4,5-tetrahydro-3-(4-piperidinyl)-2H-1,3-benzodiazepin-2-one (H) are added batchwise. The suspension formed is liquefied by the addition of 40 mL tert.butyl-methylether and cooled to ambient temperature. After the addition of another 40 mL tert.butyl-methylether the suspension is filtered, the isolated solid is washed with 100 mL tert.butyl-methylether and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:14][CH2:15][C:16](N(OC)C)=[O:17].Cl>C1COCC1>[Cl:14][CH2:15][C:16]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:17]
Reactant: Fc1ccc(Br)nc1
Reactant: CON(C)C(=O)CCl
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(CCl)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Bromo-5-fluoropyridine (50.0 g, 284 mmol) in 200 mL of THF was added dropwise over 25 min to isopropylmagnesium chloride (2 M in THF, 284 mL, 568 mmol) at RT, and the mixture was stirred for 2 hours at room temperature. A solution of 2-chloro-N-methoxy-N-methylacetamide (43.0 g, 313 mmol) in 150 mL of THF was added dropwise over 30 minutes to the reaction mixture at RT. The mixture was stirred at RT overnight. The mixture was then poured into 2000 g of ice with 500 mL of 2 N HCl. The mixture was extracted into ether, washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in 1 L of warm hexane and treated with several grams of silica gel to remove colored impurities. The resulting mixture was then filtered, and the filtrate was concentrated and chilled in an ice bath for 30 minutes. The resulting solid was isolated by filtration to give 2-chloroacetyl-5-fluoropyridine. 1H NMR (500 MHz, CDCl3): δ 8.53 (d, 1H), 8.19 (dd, 1H), 7.60 (td, 1H), 5.09 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)(Cl)=O.[NH3:26]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:26])=[O:21])=[CH:5]2
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: N
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reaction time: 2 h

Procedure:
To a suspension, stirred at 20° C., of 2 g (6.96 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in step 1.1, in 80 mL of dry toluene are added 5.08 mL (69.62 mmol) of thionyl chloride. The reaction mixture is stirred for 2 hours at reflux and then concentrated under reduced pressure. The resulting product is taken up in 10 mL of dichloromethane and this solution is poured, dropwise, into a solution of 9.12 mL (69.62 mmol) of 30% aqueous ammonia in water. The reaction mixture is stirred for 14 hours at 20° C. After this time, a solid is collected by filtration and triturated in 50 mL of diisopropyl ether. After filtering and drying under reduced pressure, 0.58 g of expected product is collected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7][Cl:8])=[O:6].[CH:10](=O)[CH2:11][CH3:12].C(O)(=O)C>ClCCl.N1CCCCC1>[CH3:1][O:2][C:3](=[O:9])[C:4](=[CH:10][CH2:11][CH3:12])[C:5]([CH2:7][Cl:8])=[O:6]
Reactant: CCC=O
Reactant: COC(=O)CC(=O)CCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCC=C(C(=O)CCl)C(=O)OC
Temperature: -27 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 4-chloroacetoacetic acid methyl ester (700 mg: 4.65 mMol.) and propionaldehyde (405 mg: 6.97 mMol.) and acetic acid (28 mg: 0.47 mMol.) in dichloromethane (3 ml) is added a solution of piperidine (24 mg: 0.28 mMol.) in dichloromethane (0.5 ml), and the mixture is stirred at -27° C. for 120 minutes. The reaction mixture is washed with dilute hydrochloric acid and water and concentrated under reduced pressure at lower than 15° C. to give 4-chloro-2-propylideneacetoacetic acid methyl ester (818 mg). Yield: 92%.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=[CH2:27].C1(CNCC2CCCCC2)CCCCC1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2](/[CH:27]=[CH:26]/[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[F:23])[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: C=Cc1ccccc1F
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2F)cc1Nc1ccc(F)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.15 g were added 2-fluorostyrene 0.15 g, N,N-dicyclohexylmethylamine 0.35 mL and palladium acetate 4.6 mg at room temperature, and it was stirred at 130° C. for 4 hours. 2-Fluorostyrene 0.05 g, N,N-dicyclohexylmethylamine 0.087 mL and (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 4.8 mg were added to it, and it was stirred at 130° C. for 2 hours. (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) 9.6 mg and tri-tert-butylphosphine tetrafluoroborate 5.9 mg were added to it, and it was stirred at 130° C. for 8 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(2-fluorophenyl)vinyl)benzoate.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([C:25]2[CH:29]=[C:28]([C:30]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[NH:31])[S:27][C:26]=2[S:40][CH3:41])(=[O:24])=[O:23])[CH:17]=1)C.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:36]([O:35][C:33]([NH:32][C:30](=[NH:31])[C:28]1[S:27][C:26]([S:40][CH3:41])=[C:25]([S:22]([C:18]2[CH:17]=[C:16]([C:10]3[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][O:7][CH2:6][CH2:5][C:4]([OH:42])=[O:3])[CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])[CH:29]=1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CCOC(=O)CCOCc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COCCC(=O)O)c1
Yield: 76.7 %

Procedure:
To a solution of 3-{3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-propionic acid ethyl ester (7.0 mg, 11 μmol) in THF (0.5 mL) and MeOH (0.25 mL) was added a solution of lithium hydroxide monohydrate (0.56 mg, 13 μmol) in H2O (50 mL). The mixture was microwaved at 80° C. for 150 seconds, acidified with 0.25 N HCl to ˜pH 3, extracted with EtOAc/DCM (1:1, 3×). The extracts were combined, washed with H2O, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with MeOH/DCM (2 to 4%) to give the title compound (5.1 mg, 76% yield) as a white solid.