Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:6]2[C:2]([CH3:21])([CH3:1])[C:3](=[O:20])[N:4]([C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)=[O:9])[C:5]2=[O:7])=[CH:27][CH:26]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-chlorobenzyl bromide (26 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 20 mg of white crystals.
Reaction SMILES: [H][H].C([O:10][CH2:11][C@@H:12]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14][C@H:13]1[OH:21])C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].C(O)(=O)C>[CH2:17]([C@H:16]1[CH2:15][CH2:14][C@@H:13]([OH:21])[C@@H:12]1[CH2:11][OH:10])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[C@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCC[C@H]1CC[C@@H](O)[C@@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
In an atmosphere of hydrogen, a mixture of 4.29 g of (1R,2S,3S)-2-benzyloxymethyl-3-butylcyclopentan-1-ol (prepared in Reference Example 7), 500 ml of 10% palladium-carbon, 20 ml of ethyl acetate and 10 ml of acetic acid was stirred for 16 hrs at room temperature. After stirring the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:3) as eluent to give 2.59 g of the title compound having the following physical characteristics in a 91.8% yield.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[CH:13]=[C:14]([NH:21][C:22]([C:24]2([CH3:27])[CH2:26][O:25]2)=[O:23])[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:14]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:12]([CH3:11])[CH:13]=2)=[O:23])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(O)cc1F
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(C#N)c(F)c2)ccc1[N+](=O)[O-]

Procedure:
3-(4-Cyano-3-fluorophenoxy)-2-hydroxy-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide was prepared as described in Example 1 starting from 2-fluoro-4-hydroxybenzonitrile and 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide. 1H NMR (DMSO-d6): 1.46 (3H, s), 2.53 (3H, s), 4.11 (1H, d, J=10.1 Hz), 4.371 (1H, d, J=10.1 Hz), 6.33 (1H, bs), 6.96 (1H, m), 7.18 (1H, m), 7.80 (1H, m), 7.88 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.91 (1H, d, J=2.1 Hz), 8.03 (1H, d, J=9.0 Hz), 10.21 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([NH:9][C:10]1[S:18][C:13]2[CH2:14][O:15][CH2:16][CH2:17][C:12]=2[C:11]=1[C:19]([O:21]CC)=O)=[O:8].[CH2:25]([NH2:27])[CH3:26]>>[CH2:25]([NH:27][C:19]([C:11]1[C:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]=2[S:18][C:10]=1[NH:9][C:7]([CH:3]1[C:4]([CH3:5])([CH3:6])[C:2]1([CH3:1])[CH3:24])=[O:8])=[O:21])[CH3:26]
Reactant: CCOC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCOC2
Reactant: CCN
Product: CCNC(=O)c1c(NC(=O)C2C(C)(C)C2(C)C)sc2c1CCOC2

Procedure:
The product of Example 10B and ethylamine were processed as in Examples 29A and Example 29B to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.18 (s, 1H), 1.21 (s, 6H), 1.26 (t, J=7.3 Hz, 3H), 1.32 (s, 6H), 2.77-2.83 (m, 2H), 3.41-3.55 (m, 2H), 3.98 (t, J=5.3 Hz, 2H), 4.71 (t, J=1.7 Hz, 2H), 5.70-5.82 (m, 1H), 12.02 (s, 1H); MS (DCI/NH3) m/z 352 (M+H)+; anal. calculated for C18H26N2O3S: C, 61.69; H, 7.48; N, 7.99. Found: C, 61.58; H, 7.39; N, 7.94.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14].O.[C:17]([OH:21])(=[O:20])[CH:18]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])/[CH:14]=[CH:18]/[C:17]([OH:21])=[O:20]
Reactant: O=CC(=O)O
Reactant: COc1ccc(/C=C/C(C)=O)c(OC)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)c(OC)c1

Procedure:
A solution of 19 g (92 mmol) of (E)-4-(2,4-dimethoxyphenyl)but-3-en-2-one and 8.4 g (92 mmol) of glyoxylic acid monohydrate in 24 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether/hexane yielded (E,E)-6-(2,4-dimethoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 195°-200°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]=[C:15]3[C:11]([N:12]([CH3:17])[CH:13]=[N:14]3)=[C:10](OC)[N:9]=2)=[C:4]([F:20])[C:3]=1[O:21][CH3:22].Cl.[OH-].[Na+].CN(C=O)C.S(Cl)([Cl:33])=O>O.C(OCC)(=O)C>[Cl:33][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:21][CH3:22])[C:4]=2[F:20])[N:16]=[C:15]2[C:11]=1[N:12]([CH3:17])[CH:13]=[N:14]2
Reactant: COc1c(Cl)ccc(-c2nc(OC)c3c(ncn3C)n2)c1F
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(Cl)ccc(-c2nc(Cl)c3c(ncn3C)n2)c1F
Temperature: 0 °C
Yield: 49.3 %

Procedure:
2-(4-Chloro-2-fluoro-3-methoxyphenyl)-6-methoxy-7-methyl-7H-purine (1.0 g, 3.1 mmol) was combined with 10 mL 6M HCl and heated at reflux for 2 h. After cooling, the mixture was diluted with 15 mL water and the pH was adjusted to 2 by addition of 2M aqueous sodium hydroxide. The precipitated material was collected by filtration, washed with water and dried under vacuum at 80° C. A 500 mg sample of the crude intermediate was slurried in chloroform (10 mL), treated with DMF (0.62 mL, 580 mg, 8.0 mmol) and then with thionyl chloride (0.58 mL, 950 mg, 8.0 mmol). The mixture was heated at reflux for 3 h, cooled and poured into 20 mL of ice-water. The pH was adjusted to 10 by addition of 1M sodium hydroxide. The precipitated product was taken up in ethyl acetate, washed twice with water, once with brine, dried and evaporated to give the title compound (500 mg, 49% yield over two steps): mp 184-186° C.: 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 7.8 (dd, 1H), 7.46 (dd, 1H), 4.11 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:3][C:2]=1[O:1][C:18]1[CH:23]=[N:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1O
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
A mixture of tert-butyl (3-hydroxy-4-methylphenyl)carbamate (3.14 g, 14.1 mmol), 5-bromo-2-nitropyridine (2.38 g, 11.7 mmol), cesium carbonate (5.72 g, 17.6 mmol) and N,N-dimethylformamide (25 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=80/20→0/100) to give the title compound (1.86 g, 44%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[C:28]([Cl:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[ClH:30].[ClH:30].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)=[O:29])[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCCNC(=O)c2cc3ccccc3o2)CC1
Product: Cl
Reaction time: 8 h

Procedure:
To a stirred solution of [4-(2-methoxyphenyl)piperazino]propylamine (1.0 g, 0.04 mol) in 50 mL of methylene dichloride, benzofurane-2-carboxylic acid chloride (1.01 g, 0.0056 mol) and triethylamine (1 g, 0.01 mol) were added. Stirring was continued at room temperature overnight. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The remaining residue was subjected to preparative HPLC using silica gel column and ethyl acetate as the eluent. The title compound was separated and converted to the dihydrochloride salt with ethanolic HCl (0.9 g), m.p. 228°-232° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:21])[C:16]([CH:19]=O)=[CH:17][N:18]=3)[S:13][C:6]=12.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:21])[C:16]([CH2:19][NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1c(C=O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a suspension of 43 (1.3 g, 3.26 mmol) in dry DCM (50 mL) at RT was added 2-methoxyethanamine (1.226 g, 16.32 mmol), acetic acid (0.98 g, 16.32 mmol) and sodium triacetoxyborohydride (3.46 g, 16.32 mmol), and the reaction mixture was stirred at RT for 24 hours. It was then diluted with additional DCM and washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to dryness to afford 44 (1.5 g, 100% yield) as an yellow oil which was used crude in the next step with no additional purification. MS (m/z): 458.2 (M+H).
Reaction SMILES: [C:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)#[N:2].[CH3:20][Mg+].[Br-].CO.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(OCCCC)CCC>[NH2:2][CH:1]([C:3]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(c2ccccn2)C1
Reactant: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(N)C1(c2ccccn2)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl 3-cyano-3-pyridin-2-ylazetidine-1-carboxylate (I-2, 5.0 g, 19.3 mmol) in toluene (100 mL) at room temperature was treated with MeMgBr (55 mL of a 1.0 M solution in dibutyl ether) dropwise over 15 min. After 18 h, the reaction was cooled to 0° C. and treated with MeOH (30 mL) and NaBH4 (1.3 g, 33.2 mmol). After 10 min, the reaction was quenched with the slow addition of saturated aqueous NH4Cl (75 mL), diluted with H2O (75 mL), and extracted with EtOAc (3×150 mL). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl 3-(1-aminoethyl)-3-pyridin-2-ylazetidine-1-carboxylate (I-3). This material was fully resolved into 1R and 1S isomers (>99% ee) using a ChiralPak AD column. NOE analysis of Mosher's amides confirmed the absolute stereochemistry of each isomer. Analytical LCMS: single peak (214 nm), 2.689 min.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:26]=[CH:25][C:9]([C:10]([C:12]2[C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=[CH:14][N:13]=2)=O)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:20]([C:19]1[O:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]=1[C:9]1[CH:25]=[CH:26][C:6]([F:5])=[CH:7][CH:8]=1)([OH:22])=[O:21]
Reactant: CCOC(=O)COc1cccnc1C(=O)c1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1oc2cccnc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.9 %

Procedure:
Sodium ethoxide (1.51 g. 22.6 mmol) was suspended in toluene (25 ml) and ethyl 2-[2-(4-fluorobenzoyl)pyridin-3-yloxy]acetate (3.5 g, 11.5 mmol) was added. The reaction was heated at reflux under an argon atmosphere. After 12 h, the reaction mixture was cooled to room temperature and the product was extracted into water. The aqueous layer was acidified with hydrochloric acid to give 2-carboxy-3-(4-fluorophenyl)-furo[3,2-b]pyridine as a solid (1.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccncc2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 4-hydroxypyridine (0.57 g, 6.0 mmol) to give the titled compound as pale yellow solid substance (1.05 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[C:24]([CH:29]=O)=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:10][CH2:11]2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cccc(-c2ccccc2C=O)c1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1cccc(-c2ccccc2CN2CCN(c3ccccc3OC)CC2)c1

Procedure:
176 mg of the target compound (0.45 mmol, 96.4%) was obtained using 1-(2-methoxyphenyl)piperazine (181 mg, 0.94 mmol), 3′-methoxybiphenyl-2-carbaldehyde (100 mg, 0.47 mmol) and NaBH(OAc)3 (303 mg, 1.41 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[C:10](=[O:41])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(O)(=O)C.C1COCC1.[OH-].[Na+]>O>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:10](=[O:41])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1c(CC2CCc3c(c4ccccc4n3C)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 77.7 %

Procedure:
A solution of 1,2,3,9-tetrahydro-9-methyl-3-[[5-methyl(triphenylmethyl)-1H-imidazol-4-yl]methyl]carbazol-4-one (268 mg) in a mixture of glacial acetic acid (5 ml), THF (5 ml) and water (5 ml) was heated at 100°-110° for 8 h. After cooling, 2N sodium hydroxide solution (50 ml) was added and the resulting suspension was extracted with dichloromethane (2×50 ml). The combined, dried organic extracts were concentrated to give a foam which was purified by FCC eluting with System A (100:8:1) to give the title compound (114 mg) as a solid. The 1H-n.m.r. and t.l.c. of this material were consistent with those obtained for the product of Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH2:26])=[CH:21][CH:20]=[CH:19]2.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([NH:26][S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34])=[CH:21][CH:20]=[CH:19]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Solvent: c1ccncc1
Product: COc1cc2nccc(Oc3ccc4c(NS(=O)(=O)c5ccccc5)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-(6,7-Dimethoxyquinolin-4-yloxy)naphthalen-1-amine (50 mg, 0.144 mmol) and benzenesulfonylchloride (25 mg, 0.144 mmol) were dissolved in pyridine (0.6 mL) then stirred at RT for 3 days. The reaction mixture was concentrated under vacuum. The crude material was purified by silica gel chromatography (2% to 4% MeOH in DCM) to give N-(6-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-1-naphthalenyl)benzenesulfonamide as a tan solid. MS (ESI pos. ion) m/z: 487.1 (M+H). Calc'd for C27H22N2O5S-486.55.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([O:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[Br:26])[CH:13]=[CH2:14].[C:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[N:28].N1CCCCC1>C(O)C.O>[CH2:33]([O:32][C:30]([C:29]1[CH:20]([C:19]2[CH:22]=[C:23]([O:24][CH3:25])[C:16]([O:15][CH2:12][CH:13]=[CH2:14])=[C:17]([Br:26])[CH:18]=2)[C:3]2[C:2](=[CH:1][C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[CH:4]=2)[O:11][C:27]=1[NH2:28])=[O:31])[CH3:34]
Reactant: C=CCOc1c(Br)cc(C=O)cc1OC
Reactant: Oc1ccc2ccccc2c1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: C=CCOc1c(Br)cc(C2C(C(=O)OCC)=C(N)Oc3cc4ccccc4cc32)cc1OC
Temperature: 80 °C

Procedure:
2-Naphthol (170 g, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 g, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (386 mg, 0.76 mmol, 76%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[S:13][C:12]([NH2:14])=[N:11][C:10]=1[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[O:8].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>C1COCC1.O>[Cl:27][CH2:28][C:29]([NH:14][C:12]1[S:13][C:9]([C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:8])=[C:10]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1)=[O:30]
Reactant: Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)Nc1nc(-c2ccco2)c(C(=O)c2ccccn2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Compound 186 (0.900 g, 2.42 mmol) was dissolved in THF (10 mL), and N,N-dimethylaminopyridine (29.6 mg, 0.242 mmol), triethylamine (0.740 mL, 5.32 mmol) and chloroacetyl chloride (0.390 mL, 4.84 mmol) were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. Further, triethylamine (0.740 mL, 5.32 mmol) and chloroacetyl chloride (0.390 mL, 4.84 mmol) were added to the reaction mixture under ice-cooling, followed by stirring for 1 hour at room temperature. Water and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=2:1) to afford the entitled Compound 262 (0.810 g, 96%) as pale yellow crystals.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH2:15])=[O:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.CCN(C(C)C)C(C)C.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.[SH:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][OH:88]>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].O1CCOCC1>[OH:88][CH2:87][CH2:86][CH2:85][CH2:84][CH2:83][CH2:82][CH2:81][CH2:80][CH2:79][CH2:78][CH2:77][S:76][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([C:13]([NH2:15])=[O:14])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(I)cc23)c1
Reactant: OCCCCCCCCCCCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(SCCCCCCCCCCCO)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described in Org. Lett. 2004, 6(24), 4587-4590. To a round bottom flask were added 6-iodo-4-((3-methoxyphenyl)amino)-8-methylquinoline-3-carboxamide (1.0 g, 2.31 mmol), dry dioxane (23 mL) and i-Pr2NEt (0.81 mL, 4.62 mmol). Catalytic Pd2(dba)3 (63 mg, 0.07 mmol), Xantphos (80 mg, 0.14 mmol) and 11-mercapto-1-undecanol (494 mg, 2.42 mmol) were then added. The mixture was evacuated and backfilled with nitrogen (3 cycles). The mixture was heated to reflux for 2 h (HPLC confirmed the completion of the reaction). The reaction mixture was then allowed to reach ambient temperature followed by filtration and concentration. The crude product was used without further purification for the next step. ES/MS calcd. for C29H40N3O3S+ 510.3. Found m/z=510.4 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.[C:15]([C:19]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:29](N(C)C)[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[C:20]=1[OH:41])([CH3:18])([CH3:17])[CH3:16]>O>[C:15]([C:19]1[C:20](=[O:41])[C:21](=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)([CH3:16])([CH3:17])[CH3:18]
Reactant: Cc1ccc(C(c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)N(C)C)cc1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C=C2C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)cc1C
Temperature: 110 °C
Yield: 81.7 %

Procedure:
60 ml of dry toluene and 2.9 g (25.5 mmol) of trifluoroacetic acid are added, under argon, to 6.24 g (17 mmol) of 2,4-di-tert-butyl-6-[dimethylamino-(3,4-dimethyl-phenyl)-methyl]-phenol(compound (201). Table 2), prepared according to Example 1a. The reaction mixture is then maintained at 110° C. for 6 hours. After colling to room temperature, the mixture is poured into 50 ml of water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from isopropanol yields 4.48 g (82%) of a mixture of 2,4-di-tert-butyl-6-(3,4-dimethyl-benzylidene)-cyclohexa-2,4-dienone (compound (301), Table 3) and the corresponding dimer (compound (401), Table 4), m.p. 214-217°C.