Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].[H-].[Na+].[Br:22][CH2:23][CH2:24]Br>CN(C)C=O>[Br:22][CH2:23][CH2:24][N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7](=[O:13])[C:8]1=[O:12]
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(CCBr)C(=O)C2=O)c(OC)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 100 ml of N,N-dimethylformamide was suspended 10 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, and 1.67 g of sodium hydride (60%, oil) was added to the suspension, followed by stirring at 50° C. for 1 hour. Then, the reaction mixture was cooled to room temperature, after which 16.5 ml of 1,2-dibromoethane was added thereto and the resulting mixture was stirred at the same temperature for 4 hours. After the solvent was distilled off under reduced pressure, a mixed solvent of 100 ml of ethyl acetate and 60 ml of water was added to the residue and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layer was washed with 20 ml of water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform: methanol=30:1) to obtain 6.1 g of 1-(2-bromoethyl)-4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18].C([BH3-])#N.[Na+].O>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH2:18][CH2:17][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1cccc2ccccc12
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCOCC
Solvent: O
Product: c1ccc(C(CCNCCc2cccc3ccccc23)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
An equal molar mixture of 3,3-diphenylpropylamine (2.11 g, 10 mmol), 1′-acetonaphthone (1.70 g, 10 mmol) and 1.25 equivalents of titanium(IV) isopropoxide (3.55 g, 12.5 mmol) were stirred 4 hr at rt. The reaction mixture was then treated with a 1 M solution of ethanolic sodium cyanoborohydride (12.5 ml, 12.5 mmol) and stirred 16 hr at rt. The reaction was diluted with diethyl ether (50 ml) and treated with water (0.72 ml, 40 mmol). After mixing thoroughly the mixture was centrifuged and the ether layer decanted and concentrated to a milky oil. The oil was suspended in diethyl ether and filtered through a 0.45 μM CR PTFE Acrodisc. The diethyl ether filtrate was concentrated to afford N-(3,3-diphenylpropyl)-(1-naphthyl)ethylamine, 3U, as a clear, colorless oil; m/z (rel. int.) 365 (M+, 17), 350 (19),181 (23),155 (100), 141 (25), 115 (11), 91 (13), 77 (6).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>>[F:30][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COC(=O)c1cc(N)ccc1F
Agent: [Na+]
Product: COC(=O)c1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 83.6 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 466 mg of methyl 5-amino-2-fluorobenzoate in place of the 2,4-difluoroaniline. 625 mg of methyl 2-fluoro-5-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:27][NH2:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH:29](OCC)(OCC)OCC>>[CH2:1]([C:5]1[N:6]2[CH:29]=[N:28][N:27]=[C:7]2[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(OCC)OCC
Reactant: CCCCc1nc(NN)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nncn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A mixture of 4′-[(4-butyl-2-hydrazino-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.6 g) and triethyl orthoformate (30 mL) was stirred at 100° C. for 16 hr. The reaction mixture was concentrated, and ethyl acetate and water were added to the obtained residue. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.46 g, 17%).
Reaction SMILES: Br[CH:2]([C:4]1([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)OCCO1)C.[C:21]([O-:24])(=[O:23])C.[K+]>C(N)=O>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:4]([CH3:2])[C:21]([OH:24])=[O:23])[CH:18]=[CH:17]2
Reactant: CC(=O)[O-]
Reactant: COc1ccc2cc(C3(C(C)Br)OCCO3)ccc2c1
Agent: [K+]
Solvent: NC=O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Temperature: 170 °C
Reaction time: 2.5 h
Yield: 52 %

Procedure:
A mixture of 2-(1-bromoethyl)-2-(6-methoxy-2-naphthyl)-1,3-dioxolane (3.37 g; 10 mmol), potassium acetate (1.2 g; 12 mmol) and formamide (50 ml) is heated under stirring at 170° C. for 2.5 h. The reaction mixture is worked up as described in example 1a to provide 2-(6-methoxy-2-naphthyl)-propionic acid (yield 52%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:20])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([CH2:16][C:17]([OH:19])=[O:18])[CH:7]=[CH:6][C:5]1=2.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:3][C:4]1([CH3:20])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([CH2:16][C:17]([O:19][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:18])[CH:7]=[CH:6][C:5]1=2
Reactant: BrCc1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)OCc3ccccc3)ccc21

Procedure:
730 mg (0.024 mol) of sodium hydride (80 and 100 ml of DMF were introduced into a three-necked flank under a nitrogen stream. A solution of 5 g (0.02 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid in 40 ml of DMF was added dropwise and the mixture was stirred until the gaseous emission ceased. 2.9 ml (0.024 mol) of benzyl bromide were then added and the mixture was stirred at room temperature for 4 hours. The reaction medium was poured into water, and extracted with ethyl acetate. The organic phase was decanted off, dried over magnesium sulfate and evaporated. 6.7 g (100%) of the expected ester were recovered in the form of a slightly yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[CH:36][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:25]=[CH:24][C:23]5[CH2:22][NH:21][CH2:20][CH2:19][C:18]=5[N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:33]=[CH:34][N:35]=[CH:36][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2c3cnc(Nc4ccc5c(n4)CCNC5)nc3n(C3CCCC3)c2cn1
Yield: 80.5 %

Procedure:
A solution of tert-butyl 2((9-cyclopentyl-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (217 mg, 0.477 mmol) in TFA/DCM (1:1, 2 mL) was stirred at room temperature for 30 minutes and then concentrated. The residue was purified by flash chromatography on silica gel eluting with 25% to 75% solvent A (DCM:MeOH:NH4OH, 100:10:1) in DCM to give the title compound as a yellow solid (148 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ 1.87-1.90 (2H, m), 2.14-2.21 (4H, m), 2.43-2.47 (2H, m), 2.89 (2H, t, J=5.0 Hz), 3.26 (2H, t, J=5.0 Hz), 4.02 (2H, s), 5.36 (1H, m), 7.41 (1H, d, J=10.0 Hz), 7.85 (1H, d, J=5.0 Hz), 8.19 (1H, br. s), 8.31 (1H, d, J=10.0 Hz), 8.52 (1H, d, J=5.0 Hz), 8.91 (1H, s), 9.11 (1H, s) ppm; LCMS m/z: 386 (M+1).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:14])[CH:8]([NH2:13])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:5])([CH3:4])[CH3:3].[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=O.C(N(CC)CC)C>ClCCl>[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[CH:20]=[N:13][CH:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:14]
Reactant: O=Cc1nccs1
Reactant: CC(C)CC(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(N=Cc1nccs1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-methyl-pentanoic acid tert-butyl ester, hydrochloride (5.00 g, 22.34 mmol), 1,3-thiazole-2-carboxaldehyde (2.53 g, 22.34 mmol) and triethylamine (3.1 mL, 22.3 mmol) in dichloromethane (60 mL) was heated under reflux under nitrogen for 19 hours. The reaction mixture was allowed to cool to room temperature, washed twice with water, dried over Na2SO4 and evaporated to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)[CH:3]=1.[F:21][C:22]([F:28])([F:27])[S:23]([OH:26])(=[O:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:28])([F:27])[S:23]([OH:26])(=[O:25])=[O:24].[NH2:13][CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CSc1nc(N)cc(NCCNC(=O)OC(C)(C)C)n1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc(N)cc(NCCN)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-Butyl N-[2-[(6-amino-2-methylsulfanyl-pyrimidin-4-yl)amino]ethyl]carbamate (105 mg, 0.35 mmol) was dissolved in a mixture of DCM (20 ml) and trifluoromethanesulfonic acid (5 ml) and stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure, the residue was taken up in THF and evaporated again to yield 182 mg of a residue that was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[O:11][CH:12]1[CH2:16][CH2:15][O:14][CH2:13]1.Cl[C:18]1[C:19]2[S:26][CH:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1.[OH-].[NH4+].O>CC(O)C>[O:14]1[CH2:15][CH2:16][CH:12]([O:11][C:3]2[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=2[NH:1][C:18]2[C:19]3[S:26][CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[C:6]([NH2:8])=[O:7])[CH2:13]1
Reactant: NC(=O)c1ccc(N)c(OC2CCOC2)c1
Reactant: Clc1ncnc2ccsc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1ccc(Nc2ncnc3ccsc23)c(OC2CCOC2)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 324.8 %

Procedure:
The reaction was carried out in 4 batches using ACE pressure tubes. The 4-amino-3-(tetrahydrofuran-3-yloxy)-benzamide (0.52 g, 1.0 eq, 2.34 mmol) was added to a solution of 4-chlorothieno[3,2-d]pyrimidine (0.40 g, 1.0 eq, 2.34 mmol) in IPA (4 ml). The reaction mixtures were then stirred at 120° C. for 18 hours before being allowed to cool. 28% w/w Ammonium hydroxide solution (4 ml) followed by water (8 ml) were added and the reactions combined. The precipitate was isolated by filtration, washed with water (4×50 ml), dried on the sinter, washed with cyclohexane (8×50 ml), and then dried in vacuo to give the title compound as an off-white solid (2.71 g, 7.6 mmol, 81%). LCMS: [M+H]+=357; Rt=1.27 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8](=[O:27])[CH:9]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:33].[Na+].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8](=[O:27])[CH:9]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=1)[S:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:33]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1cccc(CN(C)C(=O)C(Sc2ccccc2)c2cc(OC)cc(OC)c2)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(CN(C)C(=O)C(c2cc(OC)cc(OC)c2)S(=O)c2ccccc2)c1

Procedure:
A mixture of the acetamide derivative from step 3 above (4.1 g), sodium metaperiodate (3.3 g), methanol (50 ml) and water (30 ml) was heated under reflux for 1.5 hours. The reaction mixture was filtered and the filtrate concentrated to dryness. The residue was purified by chromatography on silica gel using ethyl acetate as eluent, giving N-(3-methoxybenzyl)-N-methyl-2-(3,5-dimetoxyphenyl)-2-(phenylsulfinyl)acetamide (2.7 g) as a viscous oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:23]=1[C:24](O)=[O:25].N12CCCN=C1CCCCC2.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:24](=[O:25])[C:23]3[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:22]=3[Cl:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3Cl)CC2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
A mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.255 mmol), 2,5-dichlorobenzoic acid (0.31 mmol), 1,8-diazabicylco[5.4.0]undec-7-ene (0.51 mmol) and 1-hydroxybenozotriazole hydrate (0.31 mmol) in DMF (2 mL) was stirred at ambient temperature for 15 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.31 mmol) was then added. The mixture was stirred at ambient temperature overnight, and then diluted with EtOAc (50 mL) and washed with aqueous saturated NaHCO3 (2×20 mL) and brine (2×20 mL). The organic extract was dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography to give the title compound as a white solid (102 mg, 89% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 7.85, 7.32-7.40, 7.01, 4.01-4.08, 3.77-3.93, 3.35-3.55, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 450 (M).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1(/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]1(/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]([C:17]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(/C=C/c2ccccc2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(/C=C/c2ccccc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.269 g (1.2 mmol) of (E)-4-stilbenecarboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate/dichloromethane=4/1/1), after which it was recrystallized from hexane to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[C:34]([CH3:43])=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[C:34]=4[CH3:43])(=[O:40])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(Cl)c4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-2-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=610.1)=80%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:20](O)[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:10])=[O:9].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc3c(c2)OCO3)sc2ncccc12
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc3c(c2)OCO3)sc2ncccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2 -(α-hydroxy-3,4-(methylenedioxy) benzyl]-thieno [2,3-b]pyridine-3-sulfonamide (0.10 g, 0.18 mmoles)[see Example 4(B)] and triethylsilane (0.29 ml, 1.8 mmoles) in CH2Cl2 (2 ml) was added boron trifluoride etherate (0.10 ml, 0.81 mmoles). The orange-brown solution was stirred 2 hours at ambient temperature then diluted with EtOAc (50 ml) and washed with H2O (75 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect an orange oil. Flash chromatography (40% EtOAc/hexanes) provided 66 mg (66%) of the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:3]=1[C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([O:23][CH3:24])[CH:8]=1.[OH-:31].[Na+].OO.Cl>CO>[OH:31][C:5]1[C:4](=[O:25])[C:3]2[C:2](=[CH:29][C:28]([I:30])=[CH:27][CH:26]=2)[O:1][C:6]=1[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([O:23][CH3:24])[CH:8]=1
Reactant: COc1cc(C=CC(=O)c2ccc(I)cc2O)cc(OC)c1OCc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2oc3cc(I)ccc3c(=O)c2O)cc(OC)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a stirring solution of 33 (0.85 g, 1.6 mmol) in methanol (17 ml) and 16% aqueous sodium hydroxide solution (2.2 ml, 8.8 mmol, 5.3 equ) at 0° C. was added 15% aqueous hydrogen peroxide (2.2 ml, 9.7 mmol, 5.9 equ) dropwise. The solution was stirred at 0° C. for ten minutes then sealed and placed in a refrigerator for 24 hours. The reaction was then acidified (1N HCl) and extracted with dichloromethane (2×). The organic layer was then dried (MgSO4) and concentrated to give a dark yellow foam. This was triturated with ethanol to give 3-hydroxy-7-iodo-(4-benzyloxy-3,5-dimethoxyphenyl)-chromen-4-one (0.84 g, 96%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([NH:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNCCCC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Product: CCCCN(CCCC)c1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with dibutylamine to obtain 4-(dibutylamino)-7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 426.4.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1cccc(F)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1cccc(F)c1F

Procedure:
To a suspension of 2,3-difluoro-cinnamic acid (2.94 g, 16 mmol) in ethanol (100 mL) is added Pd (10% on carbon, 50 mg) and the mixture is treated with hydrogen (7.5 bar) for 15 h. The suspension is filtered through celite and the solvent evaporated to provide the title compound.
Reaction SMILES: [Cl:1]C1C(Cl)=CC=CC=1OC.C(Cl)(=O)CC.[Cl-].[Al+3].[Cl-].[Cl-].Cl.Cl[C:22]1[C:27]([Cl:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][C:23]=1[C:31](=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[Cl:28][C:27]1([Cl:1])[C:26]([O:29][CH3:30])=[CH:25][CH:24]=[C:23]([C:31](=[O:34])[CH2:32][CH3:33])[CH2:22]1
Reactant: COc1cccc(Cl)c1Cl
Reactant: CCC(=O)c1ccc(OC)c(Cl)c1Cl
Agent: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: CCC(=O)C1=CC=C(OC)C(Cl)(Cl)C1
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (177.0 g., 1.0 mole) and propionyl chloride (101.8 g., 1.1 mole) in methylene chloride (600 ml.) is cooled to 5° C. and treated with aluminum chloride (146.7 g., 1.1 mole) during a 11/2 hour period. The reaction is allowed to warm to 25° C. and after 16 hours is poured into ice-water (2 l.) and concentrated hydrochloric acid (200 ml.). The organic phase is washed with 10% sodium hydroxide solution and saturated salt solution, and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane to give 124.5 g. (53%) of 2',3'-dichloro-4'-methoxypropionphenone which melts at 51°-54° C.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.COC1C=C2C(=CC=1)C(C)(O)CCC2>>[CH3:14][O:13][CH:12]1[CH2:11][CH:10]2[C:5]([CH:6]=[CH:7][CH2:8][CH2:9]2)=[CH:4][C:3]1=[O:2]
Reactant: COc1cc2ccccc2cc1OC
Agent: COc1ccc2c(c1)CCCC2(C)O
Product: COC1CC2CCC=CC2=CC1=O

Procedure:
This material is prepared according to the procedure for Preparation 9 wherein 2,3-dimethoxynaphthalene is substituted for 1,2,3,4-tetrahydro-6-methoxy-1-methyl-1-naphthalenol.