Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)=O.C1([CH2:26][CH2:27][C:28]([NH2:30])=[S:29])C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:27]([C:28]1[S:29][C:3]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([F:19])[CH:14]=2)=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=2)[N:30]=1)[CH3:26]
Reactant: Cc1cccc(C(=O)C(Br)c2ccnc(F)c2)c1
Reactant: NC(=S)CCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(F)c2)s1
Yield: 38.1 %

Procedure:
A solution of 2-bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone hydrobromide (11 g, 29 mmol) and thiopropionamide (2.7 g, 30 mmol) in N,N-dimethylformamide (30 mL) was stirred for 14 hours at room temperature. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The extracts were washed with water, dried, then, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to obtain a title compound (3.3 g, yield 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]4[S:38][CH:39]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[N:41]=4)[CH:30]=3)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([NH:27][C:28](=[O:48])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=[CH:36][C:37]4[S:38][CH:39]=[C:40]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[N:41]=4)[CH:30]=3)[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Yield: 83.7 %

Procedure:
Ethyl 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[2-(4-phenyl-2-thiazolyl)vinyl]benzoylamino]phenoxyacetate (0.30 g, 0.43 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 ml) and methanol (5 ml), 1 N sodium hydroxide aqueous solution (1.0 ml) was added to the solution, and the mixture was subjected to 12 hours of reaction. The reaction solution was acidified by adding ice and 10% citric acid aqueous solution, and the product formed was extracted three times with chloroform. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. By crystallizing the resulting residue from chloroform-acetonitrile, 4-[3-(4-chlorophenylsulfonyl)propyl]-2-[3-[2-(4-phenyl-2-thiazolyl)vinyl]benzoylamino]phenoxyacetic acid (0.24 g, 0.36 mmol, 83%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[N:5]=[C:4](Cl)[N:3]=1.[F:10]C1N=C(Cl)N=C(Cl)N=1>>[N:3]1[C:4]([F:10])=[N:5][C:6]([F:8])=[N:7][C:2]=1[F:1]
Reactant: Fc1nc(F)nc(Cl)n1
Reactant: Fc1nc(Cl)nc(Cl)n1
Product: Fc1nc(F)nc(F)n1

Procedure:
If 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used in place of cyanuric chloride as the starting material, very good yields of pure cyanuric fluoride are possible even with molar ratios of hydrogen fluoride/cyanuric halide which are lower than those mentioned above. For example, when 2,4-difluoro-6-chloro-s-triazine is used the reaction is advantageously carried out with a molar ratio of hydrogen fluoride/2,4-difluoro-6-chloro-s-triazine of 1:1 to 4:1, preferably about 2:1; if 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, advantageous results are obtained with a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 2:1 to 5:1 and preferably the reaction is carried out using a molar ratio of hydrogen fluoride/2-fluoro-4,6-dichloro-s-triazine of 3:1. When 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine is used as the starting material, the reaction is also carried out at temperatures betwen 150° C. and 300° C.; preferably the reaction is carried out at between 180° C. and 220° C., as when cyanuric chloride is used as the starting material. Pure cyanuric fluoride is likewise obtaining in high yield when a mixture of 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine or a mixture of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine and 2-fluoro-4,6-dichloro-s-triazine is employed, in place of cyanuric chloride, 2,4-difluoro-6-chloro-s-triazine or 2-fluoro-4,6-dichloro-s-triazine, as the starting material. In this case the most advantageous molar ratio of hydrogen fluoride/cyanuric halide mixture depends on the mixing ratio of the two or the three cyanuric halide components in the starting mixture. The most advantageous temperature range for the reaction when a mixture of cyanuric halides is used is the same as that when pure cyanuric chloride is employed as the starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1cccc(O)c1
Product: CC(C)c1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 79.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted with 3-isopropyl phenol (18 mg, 0.12 mmol) to give the title compound (42 mg, 83%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: N[C:2]1[CH:7]=CC(OC)=[CH:4][C:3]=1S(N)(=O)=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:16]=1[S:23]([NH2:26])(=[O:25])=[O:24]>>[O:24]=[S:23]1(=[O:25])[C:16]2[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=2[N:14]2[CH2:7][CH2:2][CH2:3][CH:4]2[NH:26]1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Reactant: COc1ccc(S(N)(=O)=O)c(N)c1
Product: O=S1(=O)NC2CCCN2c2cc(O)ccc21

Procedure:
In Step A, 2-amino-5-methoxybenzenesulphonamide is replaced by 2-amino-4-methoxybenzenesulphonamide.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[H][H]>CO.[Pd]>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:2]([NH2:3])=[O:4])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: COc1cccc(-[n+]2ccc(C(N)=O)cc2)c1
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Product: COc1cccc(N2CCC(C(N)=O)CC2)c1
Yield: 82.6 %

Procedure:
A suspension of 4-carbamoyl-1-(3-methoxyphenyl)-pyridinium chloride (26 g) in methanol (300 ml) was hydrogenated at ambient temperature and pressure in the presence of 10% palladium-on-carbon catalyst (2.0 g) until hydrogen uptake ceased (~2 days) The mixture was filtered, excess triethylamine added and the solvent removed in vacuo to give a pink solid. This was partitioned between water and chloroform. The organic phase was dried and the solvent removed in vacuo to give 1-(3-methoxyphenyl)piperidine-4-carboxamide as a pink solid (19 g), m.p. 153°-156° C.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]12.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1.C(N(CC)CC)C>C(#N)C>[Cl:11][C:12]1[N:13]=[C:14]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][CH2:8][CH2:9][CH2:10][CH:2]3[CH2:1]2)[CH:15]=[N:16][CH:17]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C1CCN2CCNCC2C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1cncc(N2CCN3CCCCC3C2)n1

Procedure:
A solution of octahydro-2H-pyrido[1,2-a]pyrazine (4 gm, 0.029 moles), 2,6-dichloropyrazine (4.28 gm, 0.029 moles) and triethylamine (8 ml. 0.06 moles) in 75 ml of acetonitrile is heated under reflux for 4 hours. After cooling, the precipitate is filtered off and washed with a little acetonitrile. The filtrate is concentrated under reduced pressure and the resulting residue is partitioned between water and ether. The aqueous layer is made basic with potassium carbonate and extracted 3 times with 100 ml. portions of ether. The combined ether layer is washed with saline and dried over sodium sulfate. After filtering off the drying agent the clear filtrate is made acidic with dry hydrogen chloride gas. The precipitate is filtered off, washed with ether and dried. After two crystallizations from ethanol there is obtained a 4.5 gm (54 percent) yield of title compound, m.p. 298°-301° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:32])=[C:11]([N:16]4[CH2:21][CH2:20][CH:19]([NH:22]C(OC(C)(C)C)=O)[C:18]([CH3:31])([CH3:30])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:33])[C:6]([C:34]([OH:36])=[O:35])=[CH:5]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].I[CH2:44][CH2:45][CH3:46]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:32])=[C:11]([N:16]4[CH2:21][CH2:20][CH:19]([NH2:22])[C:18]([CH3:30])([CH3:31])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:33])[C:6]([C:34]([O:36][CH:45]([CH3:46])[CH3:44])=[O:35])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(N2CCC(NC(=O)OC(C)(C)C)C(C)(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1c(N2CCC(N)C(C)(C)C2)c(F)cc2c(=O)c(C(=O)OC(C)C)cn(C3CC3)c12
Temperature: 70 °C
Reaction time: 7 h
Yield: 45 %

Procedure:
In a dry dimethylformaide (15 ml) was taken a mixture of 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-7-(4′-t-butoxycarbonylamino-3′,3′-dimethylpiperidin-1-yl)-4-oxo-quinoline-3-carboxylic acid (1 g, 1.98 mmole), K2CO3 (0.275 g, 1.98 mmole) was stirred at 70° C. for 7 hr. Added 1-iodopropane (0.5 g, 2.98 mmole) to reaction mixture and stirred at the same temperature for 16 hr. Solvent was concentrated up to dryness and (15 ml) water was added to it and extracted with chloroform (25 ml×2). Organic layer was separated, dried, concentrated, Which was hydrolysied with trifluoroacetic acid in methylene dichloride and purified on silica column to furnish titled product. Yield 45%, m.p 140–42° C., C24H32FN3O4, m/z 446 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH:33](OC(=O)C)=[O:34]>>[CH:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:34]
Reactant: O=C(N[C@@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)OC=O
Agent: Cl
Product: O=CN1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A142) and acetic formic anhydride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]3=2)[CH:10]=[C:9]1[CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Cs+].[Cs+].BrC[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl.O>[CH3:40][O:39][C:37](=[O:38])[CH2:22][O:21][C:12]1[CH:13]=[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:15]2=[C:16]2[C:11]=1[CH:10]=[C:9]([CH2:23][CH3:24])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc2c(OC)cc3c(c2n1Cc1ccccc1)CCCC3
Reactant: COC(=O)CBr
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: CCc1cc2c(OCC(=O)OC)cc3c(c2n1Cc1ccccc1)CCCC3
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
A solution of 1-benzyl-2-ethyl-4-methoxy-6,7,8,9-tetrahydro-1H-benz[g]indole (660 mg, 2.07 mmol) in methylene chloride (10 mL) was cooled to 0° C. and treated with boron tribromide (0.38 mL, 4.0 mmol). The mixture was stirred for 10 min, poured into ice water, and extracted twice with methylene chloride. The combined methylene chloride layers were washed once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (10 mL) and treated with cesium carbonate (652 mg, 2.00 mmol) and methyl bromoacetate (0.28 mL, 2.0 mmol) at room temperature for 3 h. The mixture was diluted with water and extracted three times with ether. The combined ether extracts were washed once with water, dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, methylene chloride) provided 479 mg (62%) of the title compound as an off-white solid. 1H NMR (CDCl3) δ 7.25 (m, 3H), 6.85 (d, J=7.6 Hz, 2H), 6.52 (s, 1H), 6.16 (s, 1H), 5.57 (s, 2H), 4.79 (s, 2H), 3.86 (s, 3H), 2.97 (m, 2H), 2.84 (m, 2H), 2.59 (q, J=7.3 Hz, 2H), 1.72 (m, 4H), 1.32 (t, J=7.3 Hz, 3H); MS ES+ m/e 378 (p+1); IR (CHCl3, cm1) 2830, 1756, 1732.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:21]([O-])=O)=[C:11]([CH:13]=[C:14]2[NH:18][C:17](=[O:19])[NH:16][C:15]2=O)[CH:12]=1)[CH3:2].CO.II>CN(C)C=O.[Pd]>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[N:21]=[C:15]3[NH:16][C:17](=[O:19])[NH:18][C:14]3=[CH:13][C:11]=2[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Agent: [Pd]
Agent: II
Solvent: CO
Solvent: CN(C)C=O
Product: CCOCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reaction time: 23 h

Procedure:
A solution of 5-[[5-(2-ethoxyethoxy)-2-nitrophenyl]methylene]-2,4-imidazolidinedione (10.60 g, 33 mmol) in dimethylformamide (120 mL) was hydrogenated over 10% palladium on charcoal (1 g) at 50 p.s.i. in a low pressure hydrogenation apparatus. After 23 hours, the mixture was filtered through kieselguhr and the solvent evaporated to leave a solid which was suspended in refluxing methanol (200 mL) and treated with iodine (8.38 g, 33 mmol) added portionwise. After 15 minutes the mixture was concentrated to about 50 mL and diluted with 10% sodium thiosulfate solution and 10% sodium carbonate solution. The mixture was stirred for 15 minutes and the solid filtered off, washed with water and dried in air before being dissolved in a solution of 10% hydrogen chloride in methanol. Addition of diethyl ether precipitated 7-(2-ethoxyethoxy)-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one hydrochloride (4.52 g, 56%), m.p. 290°-293° C. (dec.).
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)=[C:12]1[C:33]([O:35]CC)=[O:34])([O:3]CC)=[O:2].C(COC1C=C(OC)C=CC=1CN1C2C(=CC(O)=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O)(OCC)=O.[H-].[Na+].ICCC>CN(C=O)C>[C:1]([CH2:6][O:7][C:8]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=2)[C:13]([C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)=[C:12]1[C:33]([OH:35])=[O:34])([OH:3])=[O:2]
Reactant: CCCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)OCC)n2Cc1ccc(OC)cc1OCC(=O)OCC
Agent: CCOC(=O)COc1cc(OC)ccc1Cn1c(C(=O)OCC)c(-c2ccc3c(c2)OCO3)c2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCOc1ccc2c(c1)c(-c1ccc3c(c1)OCO3)c(C(=O)O)n2Cc1ccc(OC)cc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethyl 1-(2-Carboethoxymethoxy-4-methoxybenzyl)-3-(3,4-methlenedioxyphenyl)-5-(prop-1-yloxy)indole-2-carboxylate. To a solution of ethyl 1-(2-carboethoxymethoxy-4-methoxybenzyl)-5-hydroxy-3-(3,4-methylenedioxyphenyl)indole-2-carboxylate (175 mg, 0.30 mmol) in DMF stirred at ice bath temperature under an argon atmosphere was added a slurry of NaH (11 mg of 80% oil dispersion, 0.36 mmol, oil removed by pentane wash) in DMF (1 mL). After 15 min at ice bath temperature, 1-iodopropane (0.255 g, 1.5 mmol) was added and the ice bath was removed. The reaction mixture was stirred an additional 30 min at room temperature then partitioned between 3N HCl (25 mL) and EtOAc (75 mL). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo and the resulting solid crystallized from EtOH to afford the title compound (83 mg 47%); m.p. 89°-91° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:27])([CH3:26])[CH2:16][CH:17]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:11]3=[CH:10][C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[C:4]([Cl:35])[CH:3]=1.[NH:36]1[CH:40]=[CH:39][CH:38]=[N:37]1.OC1C=CC=CC=1C=NO.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl.[Cu-]=O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:9]2[CH:10]=[C:11]3[C@H:17]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:16][C:15]([CH3:26])([CH3:27])[O:14][C:12]3=[N:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([N:36]3[CH:40]=[CH:39][CH:38]=[N:37]3)=[CH:3][C:4]=2[Cl:35])=[CH:33][CH:32]=1
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NC1CC(C)(C)Oc2nc(-c3ccc(Br)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(-n4cccn4)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A solution of Example 314(280 mg, 0.48 mmol), pyrazole (65.8 mg, 0.97 mmol), copper(I) oxide (3.5 mg, 0.02 mmol), 2-hydroxybenzaldehyde oxime (33.1 mg, 0.24 mmol), and Cs2CO3 (315 mg, 0.97 mmol) in 10 mL of CH3CN was degassed and stirred at 85° C. for 16 h. The reaction mixture was cooled and diluted with CH2Cl2 (50 mL) and filtered through a cake of Celite. The filtrate was washed with H2O (50 mL) and brine (50 mL). After the phases separated, the organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 3:7 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.46 (s, 3H), 1.50 (s, 9H), 1.55 (s, 3H), 1.18 (m, 1H), 2.29 (m, 1H), 4.76 (br. s, 1H), 5.13 (m, 1H), 6.38 (m, 1H), 6.47 (m, 1H), 7.05 (d, J=8.5, 2H), 7.18 (d, J=8.5, 2H), 7.39-7.72 (m, 5H), 7.90 (m, 1H).
Reaction SMILES: N.[Na].[CH:3]#[CH:4].[CH2:5]([CH2:15][C:16](=[O:18])[CH3:17])/[CH:6]=[C:7](/[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])\[CH3:8].[Cl-].[NH4+]>>[CH3:14][C:12]([CH3:13])=[CH:11][CH2:10][CH2:9]/[C:7](/[CH3:8])=[CH:6]/[CH2:5][CH2:15][C:16]([OH:18])([C:3]#[CH:4])[CH3:17]
Reactant: C#C
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(C)(O)CC/C=C(\C)CCC=C(C)C

Procedure:
A 2 l-capacity, 3-neck, round-bottom flask was charged with 1000 ml of liquid ammonia and 11.5 g of metallic sodium was added thereto. Acetylene gas was blown into the flask, and when the color of the liquid ammonia solution changed from bluish green to white, 97 g of geranyl acetone was added to the solution and the reaction was conducted under reflux for 4 hours. After completion of the reaction, 54 g of ammonium chloride was added to the reaction mixture and liquid ammonia was removed by distillation. Then, 500 ml of ethyl ether and 500 ml of water were added to the residue to cause phase separation. The organic layer was washed with water and distillation of the ether gave 108 g of dehydronerolidol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:6][N:5]=[C:4]2[N:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:3]=12.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]3)=[C:3]3[CH:18]=[CH:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:4]3=[N:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Yield: 29.2 %

Procedure:
4-Chloro-5-(3-methoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri dine (0.400 g, 1.00 mmol), tert-butyl piperazine-1-carboxylate (0.280 g, 1.50 mmol), Pd(OAc)2 (0.0225 g, 0.100 mmol), Xantphos (0.0870 g, 0.150 mmol), and Cs2CO3 (0.490 g, 1.50 mmol) were placed in degassed toluene (4 mL). The mixture was heated to 100° C. for 24 hours. The reaction was cooled to room temperature, filtered through celite, and concentrated. The product was purified (500:5 to 500:7 DCM:MeOH) to yield tert-butyl 4-(5-(3-methoxyphenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazine-1-carboxylate (0.160 g, 29.0% yield).
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[N:17](C(OC(C)(C)C)=O)[CH:18]=[CH:19][CH:20]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[ClH:28]>C(O)C.[Pt]=O>[ClH:28].[CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH:16]1[CH2:20][CH2:19][CH2:18][NH:17]1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1-c1cccn1C(=O)OC(C)(C)C
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(N)cc1C1CCCN1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To platinum oxide (0.16 g) was added 19C (0.4 g, 1.0 mmol) in ethanol (20 mL) and hydrogen chloride (0.15 mL) under nitrogen. The reaction was placed under hydrogen (30 psi) and stirred at rt for 1.5 h. The catalyst was filtered over celite and washed with ethanol and methanol. The filtrate and washings were combined and the solvent was evaporated to give 0.35 g of yellow solid 19D.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][O:22][C:19](=[O:21])[CH3:20])[C:11]=1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCOc1cc[n+]([O-])c(C)c1C
Product: CCCCCCCCOc1ccnc(COC(C)=O)c1C
Yield: 60 %

Procedure:
To 38.7 g (0.1 mol, 1.0 eq.) of 4-octyloxy-2,3-dimethylpyridine-N-oxide, 40.8 g (0.4 mol, 4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 5 hours at 88 to 92° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 17.6 g of 4-octyloxy-2-acetoxymethyl-3-methylpyridine as an oily matter (yield 60.0%).