Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[C:10](=O)[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O=P(Cl)(Cl)[Cl:33].C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:33][C:10]1[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=2)[N:11]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(=O)[nH]2)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(Cl)n2)cc1

Procedure:
0.32 g (0.8 mmol) of 3-octyl-6-(4-octyloxyphenyl)-1H-2-pyridone are heated together with 15 ml of phosphorus oxytrichloride in a sealed tube at 200° C. for 3 hours. The reaction mixture is poured onto ice water, and the resulting mixture is made basic with sodium carbonate. Extraction of the aqueous phase with methylene chloride, washing of the organic phase with sodium chloride solution, drying over sodium sulfate, filtration, removal of the solvent by distillation and chromatography (silica gel, 8:2 hexane/ethyl acetate) give 0.22 g of 2-chloro-3-octyl-6-(4-octyloxyphenyl)pyridine. ##STR15##
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Cl)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][O:3][CH2:2][CH2:1][OH:4])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OCCO
Reactant: CC(C)N(C(=O)CCCCl)C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)N(C(=O)CCCOCCO)C1CCN(Cc2ccccc2)CC1
Yield: 50.4 %

Procedure:
A mixture of ethylene glycol (15 mL, 268 mmol) and N-(1-benzylpiperdin-4-yl)-N-isopropyl 4-chlorobutyramide (5.0 g, 14.9 mmol) was heated at 140° C. for 2 h in the presence of a catalytic amount p-toluenesulfonic acid. The reaction mixture was then dissolved in dichloromethane and the solution washed with 1 N sodium hydroxide, aqueous sodium bicarbonate solution and brine; and dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane/methanol/ammonium hydroxide: 90/9/1) to give 2.72 g of the title intermediate as viscous oil (51% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20](O)([CH3:22])[CH3:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1>C1COCC1>[C:20]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:22])=[CH2:21]
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(C)(C)O)c3o2)cc1
Solvent: C1CCOC1
Product: C=C(C)c1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
2-[5-Methoxy-2-(4-methoxy-phenyl)-benzofuran-7-yl]-propan-2-ol 115 (0.4 g, 1.3 mmol) and Burges Reagent (0.4 g, 1.7 mmol) in THF (10 ml) were heated to reflux. After 30 min, the reaction was cooled, concentrated and the product was purified by column chromatography on silica gel (10% Et OAc/Hexane) to give 116 as a solid (0.29 g, 77%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][CH2:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.8 %

Procedure:
40.0 g of 2- hydroxybenzaldehyde, 84 g of 1-chloro-2-tosyloxyethane and 50 g of potassium carbonate are added to 270 ml of dimethylformamide, and the mixture is stirred at room temperature for 3 days. After the reaction, half of the solvent is distilled off under reduced pressure. About 600 ml of water are added to the residue, and the mixture is extracted with ether. The extract is washed with 10% sodium hydroxide solution and water, dried and then distilled to remove the solvent. The residue is distilled at 116°-118° C./0.2-0.3 mmHg to give 2-(2-chloroethyloxy)benzaldehyde (51.9 g, yield: 86%) as a coloress oil. The properties of this compound are the same as those disclosed in J.O.C., 18, 1380-1402 (1953).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO.O>[C:7]1([C:6]2[NH:2][NH:3][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5]=2[CH3:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=Cc1ccccc1)C(=O)c1ccccc1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC1=C(c2ccccc2)NNC1c1ccccc1
Temperature: 68 °C
Yield: 88.9 %

Procedure:
Isolated α-methylchalcone, 1.5 g (85% pure product by gas liquid chromatography) (0.00578 mole) is reacted with 0.55 g (0.008 mole) of 75% hydrazine hydrate in 7.5 ml of methanol and 1 ml of water under N2 at reflux (68° C) for 1 hour. Gas liquid chromatography shows the α-methylchalcone had reacted to form 3,5-diphenyl-4-methylpyrazoline.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH:22]1([CH:21]=[C:20]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=[C:13]3[CH:12]=2)[C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)cc2c1
Yield: 84.1 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine (390 mg, 0.75 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 15 mL, 15 mmol) was stirred for 12 h at room temperature. The mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-methyl-1H-pyrrolo[2,3-b]pyridine (240 mg, 84%) as a solid which was used in the next step without purification: LC/MS m/e calcd for C22H24N2O2S [M+H]+ 381.51, observed 380.9.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][C@@:4]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl.[NH2:30][OH:31].CCN(CC)CC>CO>[OH:31][NH:30][C:17](=[NH:18])[C:16]1[CH:19]=[CH:20][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:27])[CH3:28])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C[C@@H](c1ccc(C#N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](c1ccc(C(=N)NO)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C

Procedure:
A mixture of 4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-benzonitrile (0.50 g), hydroxylamine hydrochloride (0.18 g), and NEt3 (0.43 mL), and methanol (10 mL) was stirred at reflux temperature for 5 h. After cooling to room temperature, the solvent was evaporated, mixture was concentrated, ethyl acetate was added to the residue, and the resulting mixture was washed with water and brine. The organic solution was dried Na2SO4) and concentrated and the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->93:7) to afford the title compound as a foam-like solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:13][C:12]([CH3:14])=[N:11][CH:10]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=C[C:31]=2[N:36](C)C)CCCCC1>CN(C=O)C.O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:13][C:12]([CH3:14])=[N:11][CH:10]=2)[C:4]([O:15][CH3:16])=[CH:3][C:2]=1[C:31]#[N:36]
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COc1cc(Cl)c(F)cc1-c1cnc(C)o1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C#N)c(F)cc1-c1cnc(C)o1
Temperature: 130 °C
Reaction time: 8 h
Yield: 839.9 %

Procedure:
To a mixture of 5-(4-chloro-5-fluoro-2-methoxyphenyl)-2-methyl-1,3-oxazole (1.12 g) and zinc(II) cyanide (0.327 g) in DMF (10 mL) were added tris(dibenzylideneacetone)dipalladium(0) (212 mg) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (182 mg) at room temperature, and the mixture was stirred overnight under a nitrogen atmosphere at 130° C. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (902 mg).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[CH2:27][O:28][C:24]=2[CH:23]=1>C1COCC1>[CH2:14]([O:13][C:11](=[O:12])[NH:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=[O:29])[CH2:27][O:28][C:24]=2[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2c(c1)OCC2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)OCC2=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
54.7 ml (314 mmol) of diisopropylethylamine and 28.3 ml (188 mmol) of benzyl chloroformate are added to a solution of 23.42 g (157 mmol) of 6-amino-1-benzofuran-3(2H)-one in 400 ml of THF at 0° C. and the mixture is stirred at room temperature for 3 hours. Then a further 4.7 ml (31 mmol) of benzyl chloroformate are added, and the mixture is stirred overnight. The mixture is added to ice-water and extracted twice with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/ethyl acetate 5:1) affords 30.80 g (64% of theory) of the product as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.Cl.C[O:10][C:11](=[O:15])[C@H:12]([CH3:14])[NH2:13]>>[CH:1]1([CH2:4][C:5]([NH:13][C@H:12]([C:11]([OH:15])=[O:10])[CH3:14])=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: C[C@H](NC(=O)CC1CC1)C(=O)O

Procedure:
Following General Procedure A above using cyclopropylacetic acid (Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.15 in 25% ethyl acetate/hexanes) and purification was by flash column chromatography using 25% ethyl acetate/hexanes as the eluant.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16](Br)[C:15]=2[CH3:24])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:25]([O:29][C:30](=[O:48])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)([CH3:28])([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([O:32][CH2:31][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:48])[CH:38]=3)[C:15]=2[CH3:24])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Reactant: CC(C)(C)OC(=O)COc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1cc(C(=O)c2c(C)c(-c3cccc(OCC(=O)OC(C)(C)C)c3)c3ccccn23)ccc1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
The mixture of 2.78 g (7.18 mmol) of methyl 2-amino-5-[(1-bromo-2-methylindolizin-3-yl)carbonyl]benzoate (described in Patent Application WO2005028476), 3.6 g (10.8 mmol) of tert-butyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (CAS 769968-18-5; described in Patent Application WO2004084813), 0.73 g (1.0 mmol) of PdCl2(dppf) in 22 ml of a molar solution of potassium phosphate and 100 ml of 1,2-dimethoxyethane is heated at 100° C. under argon. After 2 hours and 4 hours, a further 100 mg of PdCl2(dppf) are added. After 6 hours at 100° C. under argon, the reaction medium is allowed to return to ambient temperature and is then filtered. The organic solution is washed with water and with a saturated solution of sodium chloride, dried over sodium sulphate and concentrated to dryness. The residue obtained is purified by flash chromatography on silica gel (dichloromethane/diisopropyl ether gradient=100/0 to 0/100), to give 2.84 g (77%) of a yellow powder.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1.I[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[NH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]([CH2:16][CH2:17][CH3:18])[C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccc(N)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a suspension of NaH (493 g, 12.3 mmol) in DMF (10 ml) was added a solution of 4-aminophthalimide (2.00 g, 12.3 mmol) in DMF (10 ml) at 0° C. After stirring at room temperature for 1 h, iodopropane (1.20 ml, 12.3 mmol) was added to this mixture at 0° C. and stirred at room temperature for 28 h. The mixture was poured into water and extracted with AcOEt:toluene=2:1 (150 ml×3). The extract was washed with water, brine, dried (Na2SO4), and concentrated to give yellow solid, which was purified by column chromatography (silica gel: 130 g, CH2Cl2 only to CH2Cl2/MeOH=75/1) to give 1.14 g (45%) of yellow solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:12][CH:11]=1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[O:23]=[C:17]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH2:8])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)N2CCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc(CC(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
Dissolve N-(tert-butoxycarbonyl)-4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-benzylamine (267 mg, 0.8 mmol) in DCM (4 mL). Add 4M hydrogen chloride in dioxane (2 mL, 8 mmol) and stir at room temperature for 1 h. Concentrate in vacuo and elute the compound through a SCX column to obtain the title compound (179 mg, 98%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]([CH2:19][CH2:20][F:21])(C(OCC)=O)[C:6]2=[O:13].[OH-].[Na+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:19][CH2:20][F:21])[C:6]2=[O:13]
Reactant: CCOC(=O)C1(CCF)Cc2c(ccc(OC)c2Cl)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1Cl)CC(CCF)C2=O
Reaction time: 3.5 h

Procedure:
To a solution of ethyl 4-chloro-2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate (56.4 g of crude product from the previous reaction) in THF (330 mL) was added methanol (50 mL) followed by a solution of methanol (116 mL)/water (166 mL). To the resulting clear red-orange solution was added SN aqueous NaOH (55.7 mL, 279 mmol) gradually during 9 minutes giving a black solution. After 3.5 hours, the reaction was quenched by addition of 12N aqueous HCl (30 mL, 360 mmol) and most of the THF and methanol were removed by rotary evaporation at reduced pressure. The residue was partitioned between EtOAc and water and the organic phase was washed with saturated aqueous NaHCO3 and brine and dried over MgSO4. Filtration and removal of the solvent under reduced pressure gave crude product. Purification by flash chromatography on silica gel (elution with CH2Cl2) gave the product. Re-purification of mixed fractions gave additional product. The combined yield esd 4-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one which by NMR contained approximately 4% of the undesired 6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one regioisomer.
Reaction SMILES: [Li]C(C)(C)C.CCCCC.[C:11]1([CH:17]([O:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:28][C:29]1[CH:30]=[N:31][C:32]([Cl:35])=[N:33][CH:34]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[Br:28][C:29]1[C:30]([C:20]2[S:19][C:18]([CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][CH:21]=2)=[N:31][C:32]([Cl:35])=[N:33][CH:34]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C[Si](C)(C)OC(c1ccccc1)c1nccs1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: C1CCOC1
Solvent: CCCCC
Product: C[Si](C)(C)OC(c1ccccc1)c1ncc(-c2nc(Cl)ncc2Br)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.7 M solution of tBuLi in pentane (1.8 mL, 3.0 mmol) was added to a stirred solution of 0.80 g (3.0 mmol) of 2-[phenyl(trimethylsilyloxy)methyl]thiazole in 25 mL of THF at −78° C. The solution was stirred for 10 min at −78° C. before 0.59 g (3.0 mmol) of 5-bromo-2-chloropyrimidine was added. The reaction solution was stirred for 30 min at −78° C., then quenched by addition of 1 mL of AcOH in 4 mL of MeOH. Solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.4 g, 6.1 mmol) was added and the reaction solution was warmed to 0° C. and stirred for 10 min. The reaction solution was then poured into 50 mL of a 0.5 M solution of sodium ascorbate, diluted with 100 mL of a 1 M aqueous solution of Na2CO3. The aqueous solution was extracted four times with CHCl3 and the combined organic extracts dried over MgSO4, filtered and concentrated to give the crude product which was purified by flash chromatography eluting with a linear gradient of 30% EtOAc in hexane to neat EtOAc to deliver the title compound. MS (M+H)+ 456.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N+:13]([O-])=O)[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([NH2:13])[CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc([N+](=O)[O-])cc2cc[nH]c12
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1cc(N)cc2cc[nH]c12
Yield: 81.3 %

Procedure:
A solution of 7-acetyl-5-nitroindole (0.2 g, 1.2 mmol) and 10% Pd/C (30 mg) in 20 mL of MeOH was stirred at reflux for 1 h. The reaction mixture was filtered and concentrated in vacuo, yielding oil (0.17 g, >95%) which was characterized by NMR and subjected to the following reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]([CH:10]=[O:11])=[C:8]([CH:12]=[CH2:13])[N:7]=[C:6]1[CH3:14]>O1CCOCC1.[C].[Pd]>[Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]([CH:10]=[O:11])=[C:8]([CH2:12][CH3:13])[N:7]=[C:6]1[CH3:14]
Reactant: C=Cc1nc(C)n(Cc2ccc(OCCCCC)cc2Cl)c1C=O
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCCOc1ccc(Cn2c(C)nc(CC)c2C=O)c(Cl)c1
Reaction time: 1.5 h
Yield: 48.9 %

Procedure:
1-(2-Chloro-4-(1-pentyloxy)benzyl)-4-ethenyl-2-methyl-1H-imidazole-5-carbaldehyde (575 mg) was dissolved in 1,4-dioxane (6 ml) and palladium carbon (50 mg) was added. The mixture was stirred under a hydrogen atmosphere for 1.5 hr. The reaction mixture was filtered through celite. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with chloroform/ethyl acetate=2/1. The objective fraction was concentrated under reduced pressure to give 1-(2-chloro-4-(1-pentyloxy)benzyl)-4-ethyl-2-methyl-1H-imidazole-5-carbaldehyde (283 mg) as a black brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].O>CN(C=O)C>[OH:1][CH2:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)CBr
Reactant: OCCN1CCCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc2c1CCCCN2CCO
Temperature: 25 °C
Yield: 67 %

Procedure:
1-(2-hydroxyethyl)-6-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepine (52 mg) was dissolved in DMF (3 ml), and the resultant solution was stirred at room temperature. Potassium carbonate (122 mg) and methyl bromoacetate (0.035 ml) were added to the solution, and the mixture was stirred at room temperature. After disappearance of the raw materials was confirmed, water (20 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=2/1) to obtain the object compound (47 mg, yield 67%).
Reaction SMILES: [CH3:1][C:2]1O[CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].[CH2:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:12][CH3:13].C>O>[CH2:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH:7]=[CH:6][C:4](=[O:5])[C:3]([OH:9])=[C:2]1[CH3:1])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOCCCN
Reactant: Cc1occc(=O)c1O
Solvent: O
Product: CCCCOCCCn1ccc(=O)c(O)c1C
Reaction time: 0.5 h

Procedure:
1-(3-Butoxypropyl)-3-hydroxy-2-methylpyrid-4-one was prepared by dissolving 10.0 g maltol and 3 equivalents of 3-butoxypropylamine in 200 ml of water. The mixture was refluxed for 72 hours, decolorizing charcoal was added and the mixture was stirred for an additional 0.5 hours. The mixture was filtered through a coarse frit containing 0.5 inches of Celite, and the filtrate was concentrated in vacuo to remove the water and excess amine. The remaining oil was crystallized from ether, yielding crystals of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[O:9]C(=O)[NH:7][C:6]=2[C:13]=1[Cl:14].[CH3:15][NH2:16]>CN(C=O)C.CO>[NH2:7][C:6]1[C:13]([Cl:14])=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:10]([NH:16][CH3:15])=[O:9]
Reactant: CN
Reactant: O=c1[nH]c2c(Cl)c(Cl)ccc2c(=O)o1
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Cl)c(Cl)c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Crude 7,8-dichloro-1H-benzo[d][1,3]oxazine-2,4-dione (12.8 g) was dissolved in 50 mL of DMF and treated with 35 mL of 2 M methylamine in MeOH. The mixture was stirred at room temperature for 16 hours and extracted with methylene chloride. The organic phase was washed with brine, dried over by sodium sulfate, and concentrated. Chromatography on a silica gel column with methylene chloride and methanol (50:1) gave 1.0 g of 2-amino-3,4-dichloro-N-methyl-benzamide: 1H NMR (300 MHz, CDCl3) δ 7.12 (d, 1H), 6.71 (d, 1H), 6.27 (br, 2H), 6.04 (br, 1H), 2.96 (d, 3H); MS (m/e): 219.2 (M+1).