Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:28])([O:4][C:5]([NH:7][C:8]([CH3:27])([CH3:26])[C:9]([NH:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])=[O:6])[CH3:3].Cl.[NH:30]1[CH2:35][CH2:34][C:33]2([CH2:40][C:39](=[O:41])[C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[O:36]2)[CH2:32][CH2:31]1>>[O:41]=[C:39]1[C:38]2[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=2[O:36][C:33]2([CH2:34][CH2:35][N:30]([C:13]([C@H:12]([NH:11][C:9](=[O:10])[C:8]([NH:7][C:5]([O:4][C:2]([CH3:28])([CH3:1])[CH3:3])=[O:6])([CH3:27])[CH3:26])[CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)=[O:15])[CH2:31][CH2:32]2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C1CC2(CCNCC2)Oc2ccccc21
Agent: Cl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2

Procedure:
This intermediate was prepared from α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid (903 mg, 2.3 mmol) and spiro[2H-1-benzopyran-2,4'-piperidin]-4(3H)-one, hydrochloride (535 mg, 2.11 mmol) (Elliott, J., et al, J. Med. Chem. 1992, 35, 3973-3976) by the procedure described in Example 25, Step A (1.25 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([O-:13])=[O:12].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in toluene (4 mL) and ethanol (2 mL) was added (4-nitrophenyl)boronic acid (160 mg, 1 mmol), 2M Na2CO3 (1.4 mL), and Pd(PPh3)4 (6 mg, 0.005 mmol), the reaction was purged with argon, and then heated at 80° C. for about 6 h. The reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanone as off white solid (105 mg, 86% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 8.40-8.34 (m, 3H), 8.08 (dd, 3H), 2.67 (s, 3H), LC-MS m/z calcd for [M+H]+ 243.07. found 243.2.
Reaction SMILES: [CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>ClCCl.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[CH3:1][C@H:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCCCCC[C@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCCC[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h

Procedure:
After (S)-2-octanol (300 mg, 2.30 mmol), triphenylphosphine (726 mg, 2.76 mmol), 4-nitrobenzoic acid (462 mg, 2.76 mmol), and dichloromethane (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (648 mg, 2.76 mmol) dissolved in dichloromethane (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 1.5 hours. Water (10 mL) was added, and separation was carried out. Then, the aqueous layer was extracted using dichloromethane (10 mL,×1). The resulting organic layer was collectively washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-2-(4-nitrobenzoyloxy)octane as a pale yellow liquid substance (572 mg, yield: 89%/(S)-2-octanol).
Reaction SMILES: [CH2:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2OC2[C:3]1=CC=CC=2.C=C1C2C=CC=CC=2SC2C1=CC=CC=2.C=C1C2C=CC=CC=2[NH:39]C2C1=CC=CC=2>>[C:3]([C:2]([C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:1])#[N:39]
Reactant: C=C1c2ccccc2Oc2ccccc21
Reactant: C=C1c2ccccc2Nc2ccccc21
Agent: C=C1c2ccccc2Sc2ccccc21
Product: C=C(C#N)c1ccccc1

Procedure:
1-alkoxycarbonyl-1-phenylethylene; 1,1-dialkoxycarbonyl-2-ethylethylene; 1,1-dialkoxycarbonyl-2-phenylethylene, 1,1-dialkoxycarbonyl-2,2-dimethylethylene; 1,1-dialkoxycarbonylmethylethylene; 9-methylenexanthene; 9-methylenethioxanthene, 9-methylene-10-H-acridine and mixtures of two or more thereof.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][NH:12][CH2:13]4)[CH2:9][CH2:8]3.C=O.[BH3-][C:22]#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([CH3:22])[CH2:13]4)[CH2:9][CH2:8]3
Reactant: COc1ccc2c(c1)CCC13CNCC1CCC23
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCC13CN(C)CC1CCC23
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
2-Methoxy-5,6,6a,7,8,9,10,11-octahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrole (Example 1A, compound 1A-a) (220.0 mg, 0.90 mmol) and paraformaldehyde (810 mg, 2.7 mmol) were stirred in methanol (10 mL) at rt for 30 min. NaBH3CN was added and stirring was continued for 30 min. The mixture was quenched with 1N NaOH (10 mL), extracted with CH2Cl2 (20 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo providing 230.1 mg (98.9%) of the title compound 1B as a white solid.
Reaction SMILES: [NH2:1][N:2]1[C:6]([CH2:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([CH3:30])=O)=[CH:23][CH:22]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:7]([C:6]1[N:2]2[N:1]=[C:28]([CH3:30])[C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=3)[C:3]2=[CH:4][CH:5]=1)[CH3:8]
Reactant: COc1ccc(CC(C)=O)cc1
Reactant: CCc1ccc(C(=O)c2ccc(C#N)cc2)n1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccc2c(-c3ccc(C#N)cc3)c(-c3ccc(OC)cc3)c(C)nn12
Temperature: 80 °C
Yield: 20.2 %

Procedure:
To a solution of 4-[(1-amino-5-ethyl-1H-pyrrol-2-yl)carbonyl]benzonitrile (100 mg) in toluene (1 mL) were added 1-(4-methoxyphenyl)acetone (103 mg) and p-toluene-sulfonic acid monohydrate (16 mg) at ambient temperature. The reaction mixture was heated at 80° C. for 3 hours. The mixture was evaporated in vacuo. The residue was purified by flash silica gel column chromatography eluting with hexane-ethyl acetate 20-1 and 15-1 to give 4-[7-ethyl-3-(4-methoxyphenyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (31 mg, 20.2%) as an yellow solid.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][O:15][CH3:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:17])[NH:7]2.[CH2:18](C([Sn])=C(CCCC)CCCC)[CH2:19]CC>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:16][O:15][CH2:14][O:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:2]([CH:18]=[CH2:19])=[C:3]2[C:8]=1[NH:7][C:6](=[O:17])[CH:5]=[CH:4]2
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COCOc1cc(C)c(Br)c2ccc(=O)[nH]c12
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc(OCOC)c2[nH]c(=O)ccc12
Temperature: 90 °C

Procedure:
Bis-(triphenylphosphine)palladium (II) chloride (98 mg) is added to a solution of 5-bromo-8-methoxymethoxy-6-methyl-1H-quinolin-2-one (410 mg) and tributylvinyltin (603 μL) in dimethylformamide (14 mL) at room temperature. The reaction mixture is heated for 24 hours at 90° C., evaporated and purified by flash column chromatography on silica gel, eluting with 2% methanol in dichloromethane.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:20][C:14]4[NH:15][C:16](=O)[N:17]=[CH:18][C:13]=4[C:12]=3[C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:16]1[N:17]=[CH:18][C:13]2[C:12]([C:21]3[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=3)=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)[O:20][C:14]=2[N:15]=1
Reactant: COc1cc(-c2c(-c3ccc4c(ccn4C)c3)oc3[nH]c(=O)ncc23)cc(OC)c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(-c2c(-c3ccc4c(ccn4C)c3)oc3nc(Cl)ncc23)cc(OC)c1OC

Procedure:
The product of example 4 (200 mg, 0.46 mmol) was heated in freshly distilled P(O)Cl3 (10 ml) to 90° C. for 3 hours and then solvents were removed under vacuum. The residue was dissolved in CH2Cl2 and washed with aqueous NaHCO3 and evaporated. The residue was purified by silica gel column chromatography using increasing gradient of CH2Cl2 in hexane to pure CH2Cl2. Yield (40%); 1H NMR (300 MHz, CDCl3) δ: 3.77 (s, 6H, 2×OMe), 3.79 (s, 3H, OMe), 3.94 (s, 3H, OMe), 6.49 (d, J=3.0 Hz, 1H), 6.71 (s, 2H), 7.08 (d, J=3.0 Hz, 1H), 7.27 (d, J=9.0 Hz, 1H), 7.53 (dd, J=9.0, 1.2 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H), 8.72 (bs, 1H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[C:6]([NH:13][CH2:14][C:15](O)=[O:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[C:9]([O:8][C:6](=[O:7])[NH:13][CH2:14][C:15](=[O:16])[N:3]1[CH2:4][CH2:5][S:1][CH2:2]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCSC1

Procedure:
Thiazolidine (85 mmol) and Boc-glycine (57 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 60 hour reaction time) and the product used without purification. Yield 12.7g, 90%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(-c3cccc(Cl)c3)c2c2ccccc12
Yield: 13.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 153 using Compound 83 (50 mg, 0.22 mmol) and 3-chloro-phenylboronic acid (44 mg, 0.33 mmol) to provide 155 (9 mg, 14% yield) as a white solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C(C)=CC=CC=1C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>O1CCCC1>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)=[O:26]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: Cc1nc2cc(NC(=O)c3ccco3)ccc2o1
Temperature: 3 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
5-Amino-2-methylbenzoxazole (14 8 g, 0.100 mol) and 2,6-lutidine (12.0 g, 0.111 mol) were combined with 100 mL of tetrahydrofuran (THF) and the solution was cooled to 3° C. in an ice-bath under nitrogen. 2-Furoyl chloride (13.7 g, 0.105 mol) in 20 mL of THF was added dropwise so as to keep the temperature below 10° C. After addition the ice-bath was removed and after stirring for 1 hour the mixture was poured into 300 mL of water. The solid was collected and washed with water and dried. This afforded 21.1 g (87% yield) of product; m.p. 156°-158° C.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22].C(#N)C.[OH-].[Na+]>O>[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][C:15](=[O:17])[C@H:10]([CH2:11][C:12](=[O:13])[OH:14])[NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1.19 g (5.0 mmol) of N-benzoyl-L-aspartic acid and 1.79 g (10.0 mmol) of L-phenylalanine methyl ester were added to a flask which contained 50 ml of 50% acetonitrile in water containing 5 mM CaCl2. The pH of the solution was adjusted to 6.0 with 10M NaOH. The solution was admixed with 4 g of suction filtered immobilized enzyme prepared above. Thereafter, the reaction were carried out with stirring for 4 hours at 40° C. After completion of the reaction, the immobilized enzyme was separated by filtration. The pH of the filtrate was then adjusted to 3.7 by 10 molar hydrochloric acid. Resulting slurry was filtered and washed with water to give N-benzoyl-L-aspartyl-L-phenylalanine methyl ester.