Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:5])=[CH2:4].[OH:6][CH2:7][CH:8](CO)[CH2:9][OH:10]>CN(C)C=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:4][C:3]1([CH3:5])[O:6][CH2:7][CH:8]([CH2:9][OH:10])[CH2:1][O:2]1
Reactant: C=C(C)OC
Reactant: OCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CC1(C)OCC(CO)CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
A solution of 2-methoxypropene (1 g) in N,N-dimethylformamide (150 ml) was added to 2-(hydroxymethyl)-1,3-propanediol (500 mg). p-Toluenesulfonic acid (10 mg) was added thereto, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with n-butanol. The n-butanol layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give (2,2-dimethyl[1,3]dioxan-5-yl)-methanol (378 mg, yield 55%).
Reaction SMILES: [CH3:1][N:2]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[OH-].[K+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:23]([N:7]1[C:8]2[C:4](=[C:3]([N:2]([CH3:1])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=2)[CH:5]=[CH:6]1)[CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)c1cc(N(C)S(C)(=O)=O)c2cc[nH]c2c1
Reactant: CCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a mixture of methyl 4-[methyl(methylsulfonyl)amino]-1H-indole-6-carboxylate (0.437 g) in DMF(15 mL) was added potassium hydroxide (0.087 g) and iodobutane (0.34 mL). The mixture was heated to 70° C. for 6 h. then stirred at room temperature for 72 h. The mixture was partitioned between water and ethyl acetate, the layers were separated and the organic layer washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in methanol (5 mL) to which was added 1N NaOH (2 mL) and the mixture heated to 50° C. for 1 h. The mixture was cooled to room temperature and poured into water and washed with ether. The aqueous layer was acidified to pH 4 with 1N HCl and the product extracted into ethyl acetate which was dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give 0.377 g of the title compound: 1H NMR (CDCl3) δ 0.973, 1.38, 1.87, 3.01, 3.45, 4.21, 6.71, 7.36, 7.82, 8.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN1CCOCC1.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([O:41][CH2:42][CH3:43])[C:37]=1[O:38][CH2:39][CH3:40])[C:32](Cl)=[O:33])[CH3:27].C(=O)=O.CC(C)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][N:13]([C:32](=[O:33])[C:31]3[CH:30]=[C:29]([O:28][CH2:26][CH3:27])[C:37]([O:38][CH2:39][CH3:40])=[C:36]([O:41][CH2:42][CH3:43])[CH:35]=3)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Reactant: CCOc1cc(C(=O)Cl)cc(OCC)c1OCC
Agent: O=C=O
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)N2CCC(CCO)(c3ccc(OC)c(OC)c3)C2)cc(OCC)c1OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[3-(3,4-Dimethoxy-phenyl)-pyrrolidin-3-yl]-ethanol (405 mg, 1.61 mmol) and dichloromethane (20 mL) were combined. 4-Methylmorpholine (350 L, 3.22 mmol, 2 eq.) was added. The mixture was cooled in a dry-ice/acetone bath and a solution of 3,4,5-triethoxy-benzoyl chloride (461 mg, 1.69 mmol) in dichloromethane (10 mL) was added dropwise. After the addition was complete, the dry-ice/acetone bath was changed to an ice bath and the mixture was stirred for 1 h. Allowed to warm to ambient temperature and maintained overnight. The solution was extracted with 1N HCl (2×50 mL), saturated NaHCO3 (50 mL), and H2O (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel eluting with ethyl acetate/methanol (20:1) to obtain a residue. The residue was dissolved in dichloromethane (50 mL), extracted with water (2×50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain a residue. Heated at 70° C./0.5 Torr for 16 h to obtain the title compound: Rf =0.31 (silica gel, 20:1 ethyl acetate/methanol), mp=139°°141° C.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]([C:13](O)=[O:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH2:8][O:7][C:6]=2[C:5]([CH3:20])=[CH:4][CH:3]=1.[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[C:24]=1[NH2:25])[CH3:22]>>[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[C:24]=1[NH:25][C:13]([CH:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH2:8][O:7][C:6]2[C:5]([CH3:20])=[CH:4][CH:3]=[C:2]([CH3:1])[C:12]1=2)=[O:14])[CH3:22]
Reactant: Cc1ccc(C)c2c1OCc1ccccc1C2C(=O)O
Reactant: CCc1cccc(CC)c1N
Product: CCc1cccc(CC)c1NC(=O)C1c2ccccc2COc2c(C)ccc(C)c21
Yield: 41 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 6, 11-dihydro-1,4-dimethyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 64 (Compound AC) in place of Compound A and 0.62 g of 2,6-diethylaniline in place of aniline to obtain 0.61 g of Compound 50.
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[C@H:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16]>C(O)C>[F:13][C:14]([F:21])([F:20])[C:15]([NH:12][C@@H:2]([CH3:1])[C@H:3]([OH:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Solvent: CCO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of (−)-4-hydroxynorephedrine (90 g) and ethyl trifluoroacetate (96 mL) in ethanol (543 mL) was stirred at room temperature for 4 hrs. The reaction mixture was concentrated in vacuo, and then ethyl acetate and water were added to the residue. The organic layer was separated, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (128 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH2:22]([NH:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:29]([CH3:30])[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CNCc1ccccc1
Product: CCC(=O)[O-]
Product: CN(Cc1ccccc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 34.5 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 71 μL (0.55 mmol) of benzyl-methylamine. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in methanol, 35 mg (17%) of 8-(benzyl-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14](/[CH:18]=N/NS(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.[CH2:32](B(CC)CC)[CH3:33].[OH-].[Na+].O>C1COCC1>[F:31][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:32][CH3:33])[CH:13]=2)=[CH:8][CH:9]=1
Reactant: CCB(CC)CC
Reactant: Cc1ccc(S(=O)(=O)N/N=C/c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 88.7 %

Procedure:
A mixture of N′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide (0.67 mg, 1.52 mmol) in THF was treated with triethyl borane (1.0 M in THF, 1.52 mL, 1.52 mmol), stirred for 2 minutes, treated with NaOH (2.5 N, 0.61 mL, 1.52 mmol), refluxed for 2 hours, cooled to room temperature, poured into water and extracted with EtOAc. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (ISCO) using hexanes/EtOAc (50/1) as the eluting solvents to give 1-{[4-(difluoromethoxy)phenyl]ethynyl}-3-propylbenzene as a clear oil (386 mg, 89% yield), MS m/e (M+H)+ 286; 1H NMR (400 MHz, DMSO-d6) 0.85 (t, J=7.32 Hz, 3H), 1.57 (m, 2H), 2.6 (t, J=7.32 Hz, 2H), 7.2 (m, 3H), 7.35-7.45 (m, 4H), 7.58 (d, J=8.79 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].[NH2:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(OCC)C.C(Cl)(Cl)Cl>[C:1]([NH:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:32])=[CH:17][CH:18]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCC(=O)Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)N[C@@H](Cc1ccc(OC(=O)OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A solution of 6.0 g (50 m-mol) of pentanoyl chloride in ethyl ether (50 ml) and an aqueous solution (26 ml) of 2N-sodium hydroxide were added dropwise at the same time over the period of 30 minutes to an aqueous 2N-sodium hydroxide solution (38.5 ml) of 7.00 g (38.6 m-mol) of tyrosine under agitation at 5° C., while maintaining the pH value between 9 and 11. The mixture was stirred for an additional 2 hours at room temperature and, after addition of 2N-sodium hydroxide (5 ml) thereto, was warmed at 70° C. for 10 minutes. After cooling the reaction liquid at -10° C., 9.87 g (58m-mol) of benzyloxycarbonyl chloride and an aqueous 2N-sodium hydroxide solution (20.5 ml) were added dropwise at the same time to the reaction liquid under vigorous agitation. After completion of the reaction, 3N-hydrochloric acid was added to the reaction mixture to adjust the pH value to 3. A white precipitate formed was collected by filtration and recrystallized from chloroform whereby 12.80 g (yield: 82.9%) of N-pentanoyl-O-benzyloxycarbonyltyrosin was obtained.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:3]1.[CH2:17](Br)[CH:18]=[CH2:19].C(N(CC)CC)C>CN(C)C=O>[CH2:19]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH2:3][CH:2]1[CH3:1])[CH:18]=[CH2:17]
Reactant: CC1CN(c2ccc([N+](=O)[O-])cn2)CCN1
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
630 mg (2.72 mmol) of 3-methyl-1-(5-nitropyridin-2-yl)piperazine from Example 13.1 and 267 μl (3.09 mmol) of allyl bromide were dissolved in 10 ml of dimethylformamide. 1.2 ml (8.4 mmol) of triethylamine were then added dropwise to the solution. After the mixture had been stirred at room temperature for 1 hour, a further 65 μl (0.75 mmol) of allyl bromide were added dropwise to the reaction mixture, which was then stirred for a further hour. After that, a further 65 μl (0.75 mmol) of allyl bromide and 0.5 ml (3.6 mmol) of triethylamine were added drop-wise. The mixture was then stirred overnight at room temperature. After the solvent had been evaporated down to dryness, the resulting residue was taken up in water and this solution was made alkaline using a 1N aqueous solution of sodium hydroxide. After that, the aqueous reaction mixture was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate, filtered and evaporated down to dryness, with 707 mg (90% of theory) of the title compound being obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na].[OH-].[Na+].S(OC)(O[CH3:23])(=O)=O>O.C(O)C>[CH3:23][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=S(=O)(O)c1ccc2ccc(O)cc2c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(S(=O)(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 7-hydroxynaphthalene-2-sulfonic acid, sodium salt (15 g, 60.9 mmol) in 150 mL of 2:1 H2O/ethanol is added solid NaOH (2.68 g, 67 mmol) at room temperature. The mixture is stirred until a homogenous solution forms, and dimethyl sulfate (6.34 mL, 67 mmol) is then added. A precipitate eventually forms and the mixture is stirred over a period of 16 hours. The crude mixture is concentrated in vacuo and the residue is stirred in 100 mL of absolute EtOH as a slurry for 2 hours. The precipitate is filtered and dried. The solid is heated at reflux in 100 mL of 95% EtOH for 2 hours, allowed to cool to room temperature, filtered and dried to give 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid, sodium salt. A mixture of the sulfonic acid, sodium salt (12.6 g, 48.6 mmol) in 20 mL of phosphorous oxychloride and phosphorous pentachloride (13.2 g, 63.2 mmol) is heated slowly to 60° C. until a homogenous solution forms and then is heated at 120° C. for 4 hours. The resulting mixture is cooled in an ice bath and a mixture of ice/ice water is added slowly with stirring. The mixture is diluted with water and extracted with CHCl3 (2×100 mL). The combined organic layers are washed successively with water, saturated NaHCO3 solution and saturated NaCl. The organic phase is dried over anhydrous MgSO4, filtered and concentrated to give 10 g of a crude oil. The crude product is purified by column chromatography in a gradient of 5% EtOAc/hexanes to 30% EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a white crystalline solid.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][S:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36](O)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][S:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:37])=[CH:25][C:24]=3[CH:39]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccsc2)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccsc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (250 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (187 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (131 mg) and triethylamine (638 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienylmethyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 58) (233 mg) as yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:2].[CH:19]([O-])([O-])[O:20]C.F[C:25](F)(C(F)F)COC1C=CC(C(NCCOC2C=CC(CC(OC3C=CC(C(C)C)=CC=3)C(O)=O)=CC=2)=O)=CN=1>>[CH3:25][O:2][CH:1]([O:20][CH3:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2cccc(C=O)c2)cc1
Reactant: COC([O-])[O-]
Reactant: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(OCC(F)(F)C(F)F)nc3)cc2)C(=O)O)cc1
Product: COC(=O)c1ccc(-c2cccc(C(OC)OC)c2)cc1

Procedure:
In a similar manner to that described in Example 11(a), a reaction was carried out using methyl 3′-formylbiphenyl-4-carboxylate (1.60 g), which is the product of Reference example 14(a), methyl orthoformate (3.64 ml) and amberlyst 15 (160 mg) and the reaction mixture was treated to afford the desired compound (1.91 g) as a syrup.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].[CH3:19][O-:20].[Na+]>CN(C=O)C.[Cu]Br>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:18])=[C:2]([O:20][CH3:19])[C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2cc3c(Br)c(O)ccc3o2)cc1
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(O)ccc2oc(-c3ccc(O)cc3)cc12
Temperature: 150 °C
Yield: 36.6 %

Procedure:
A solution of 4-bromo-2-(4-Hydroxyphenyl)-benzofuran-5-ol 130 (0.100 g, 0.32 mmol) and copper (I) bromide (0.047 g, 0.32 mmol) in DMF (4 mL) was treated with sodium methoxide (0.73 mL, 3.2 mmol, 25% by weight in MeOH) and heated at 150° C. for three hours under a nitrogen atmosphere. The reaction was quenched at room temperature with 1 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed once with a saturated sodium bicarbonate solution, then dried over magnesium sulfate and filtered. Then the material was purified by column chromatography using 30% ethyl acetate in hexane as the eluent to yield 132 (0.030 g, 36.6%) as a brown solid: Mp. 165-168° C.; 1H NMR (DMSO-d6) δ 7.72 (d, 2 H, J=8.6 Hz), 7.23 (s, 1 H), 7.1 (d, 1 H, J=8.7 Hz), 6.86 (d, 2 H, J=8.6 Hz), 6.76 (d, 1 H, J=8.6 Hz), 3.94 (s, 3 H); MS 257 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])#[N:2]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C#N)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of 5-cyanoindole (10 g) and freshly prepared silver carbonate on diatomaceous earth (40.66 g) was stirred and heated under reflux in toluene (100 ml) for 18 h, under an atmosphere of nitrogen. The mixture was cooled to room temperature, methyl 4-bromomethyl-3-methoxybenzoate (22.7 g) added, and stirring continued for 4 h. Ethyl acetate (200 ml) was added, the mixture filtered through diatomaceous earth, the filter pad washed with ethyl acetate and the filtrate evaporated. The dark oil obtained was purified by flash chromatography, eluting with 45:45:10 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from toluene to give methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.8 g, 53%) as white crystals; mp 148°-149°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.08(s, 2H, ArCH2Ar'), 8.00(s, 1H, H4 -indole), 11.49(br s, 1H, H1 -indole).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([NH2:6])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[F:13][B-:14]([F:17])([F:16])[F:15].[H+].[N:19](OC(C)(C)C)=O>C(O)C>[F:13][B-:14]([F:17])([F:16])[F:15].[Br:1][C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[C:5]([N+:6]#[N:19])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)cc(CC)c1N
Reactant: CC(C)(C)ON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Product: CCc1cc(Br)cc(CC)c1[N+]#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
At 0° C., to a stirred solution of commercial 4-bromo-2,6-diethylaniline (10.0 g, 43.9 mmol) in absolute ethanol (219 mL) was added 48% aq. tetrafluoroboric acid (17.2 mL), followed by tert-butyl nitrite (5.7 mL, 48.0 mmol). After 0.5 h, the reaction was poured into ice cold ether (877 mL). The resulting precipitate was washed with cold ether and dried to give 9.39 g (66%) of the title compound. 1HNR: consistent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:10]2=[N:11][CH:12]=[C:13]([C:16]#[N:17])[C:14](Cl)=[C:9]2[CH:8]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25].Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]1[S:18][C:10]2=[N:11][CH:12]=[C:13]([C:16]#[N:17])[C:14]([NH:25][C:24]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:22]([O:21][CH3:20])[CH:23]=3)=[C:9]2[CH:8]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COC(=O)CCCc1cc2c(Cl)c(C#N)cnc2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COC(=O)CCCc1cc2c(Nc3cc(OC)c(OC)c(OC)c3)c(C#N)cnc2s1
Yield: 70.2 %

Procedure:
A mixture of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl ester (60 mg, 0.20 mmol), 3,4,5-trimethoxyaniline (92 mg, 0.50 mmol), and pyridine hydrochloride (10 mg, 0.09 mmol) in 10 mL of 2-ethoxyethanol is heated at reflux for 24 hours. The solution is cooled and the solvent is evaporated. The residue is purified by flash column chromatography eluting with 1:1 ethyl acetate:hexane to provide 62 mg of 4-[5-cyano-4-(3,4,5-trimethoxy-phenylamino)-thieno[2,3-b]pyridin-2-yl]-butyric acid methyl ester as a tan solid, mp 101–103° C.; 1H NMR (DMSO-d6) δ 1.94 (quintet, J=7 Hz, 2H), 2.41 (t, J=7 Hz, 2H), 2.88 (t, J=7 Hz, 2H), 3.60 (s, 3H), 3.67 (s, 3H), 3.75 (s, 6H), 6.60 (s, 2H), 7.28 (s, 1H), 8.40 (s, 1H), 9.62 (s, 1H); MS 442.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Li+].CC([N-]C(C)C)C.[C:19](=[O:21])=[O:20]>C1COCC1.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: COc1cncc(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cncc(OC)c1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A solution of 3,5-dimethoxypyridine (600 mg, 4.3 mmol) (prepared according to the method of Testaferri, L. et al Tetrahedron, 1985, 41, 1373) in THF (2.6 ml) was added to a solution of LDA [generated from n-BuLi (1.9 ml, 2.5 M in hexane, 4.73 mmol) and diisopropylamine (0.6 ml, 5.16 mmol)] in THF (2.6 ml) at −78° C. under nitrogen. The reaction mixture was stirred for 30 minutes at −78° C., transferred via cannula to a suspension of crushed solid CO2 (30 g) in toluene (100 ml) under vigorous stirring and warmed to room temperature. The reaction is quenched by addition of water (20 ml) to and 1M NaOH (10 ml) and the aqueous layer separated, acidified to pH 4 with glacial acetic acid and extracted with 10% MeOH in dichloromethane (3×50 ml). The combined organic layers were dried (MgSO4) and the solvent removed under vacuum to give the title compound (502 mg, 63%) as a white solid.