Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:14]3[C:19](=[O:20])[C:18]([CH3:21])=[CH:17][C:16]([CH3:22])=[N:15]3)[C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:35]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1)([CH3:37])[CH3:36].N12CCCN=C1CCCCC2>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([N:14]3[C:19](=[O:20])[C:18]([CH3:21])=[CH:17][C:16]([CH3:22])=[N:15]3)[C:11]([NH:47][S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH:35]([CH3:37])[CH3:36])=[CH:39][CH:40]=3)(=[O:45])=[O:46])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(C)c(=O)n(C(C(=O)O)c2ccc3c(c2)OCO3)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)c(=O)n(C(C(=O)NS(=O)(=O)c2ccc(C(C)C)cc2)c2ccc3c(c2)OCO3)n1
Reaction time: 1 h

Procedure:
A solution of 0.8 g of 2-(1,3-benzodioxol-5-yl)-2-(4, 6-dimethyl-2,3-dihydropyridazin-3-on-2-yl)acetic acid and 0.64 g of carbonyldiimidazole in 50 ml of THF is heated at 60° for 2 hours. 0.79 g of 4-isopropylbenzenesulfonamide and 0.59 g of 1, 8-diazabicyclo[5.4.0]undec-7-ene are then added and the mixture is stirred at this temperature for a further 1 hour. After customary working up, 2-(1,3-benzodioxol-5-yl)-2-(4,6-dimethyl-2,3-dihydropyridazin-3-on-2-yl) N-(4-isopropylphenylsulfonyl)acetamide is obtained, m.p. 105°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([NH:29][CH3:30])[CH2:25][CH2:24]2)[CH:22]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([C@H:23]4[CH2:28][CH2:27][C@H:26]([NH:29][CH3:30])[CH2:25][CH2:24]4)[CH:22]=2)=[CH:3][C:2]([C:36]2[CH:37]=[C:32]([Cl:31])[C:33]([OH:48])=[C:34]([Cl:47])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Product: CN[C@H]1CC[C@H](n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1

Procedure:
Following general procedure F, {6-bromo-4-[1-(trans-4-(methylamino)cyclohexyl)-1H-pyrazol-4-ylamino]quinolin-3-yl}(cyclopropyl)methanone (60 mg, 0.128 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.192 mmol) to afford the desired product (17 mg, 24%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6+TFA-d) δ 8.95-8.65 (br s, 1H), 8.63-8.51 (m, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 8.02-7.97 (m, 1H), 7.54 (s, 1H), 4.26 (m, 1H), 3.11-3.02 (m, 1H), 2.60 (s, 3H), 2.20-2.08 (m, 4H), 1.88-1.76 (m, 2H), 1.58-1.46 (m, 2H), 1.00-0.76 (m, 4H); ESI MS m/z 550 [C29H29Cl2N5O2+H]+; HPLC 98.4% (AUC), tR=11.56 min.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].[CH3:32][Mg]Br.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([CH3:32])([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2]
Reactant: C[Mg]Br
Reactant: CCCCCC(=O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(C)(O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O

Procedure:
A solution of 1.72 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -10° C. with 9.7 ml. of 3 M methyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.26 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.45, 5.80 (shoulder), 5.85, 6.45, 7.25, 10.30 μ. NMR: δ 1.32 (S, 15-methyl), 4.01 (S, 4, ketal), 4.40 (M, 2, CH2NO2), 5.22 (M, 2, 5 and 6--H), 5.63 (M, 2, 13 and 14--H) ppm. Mass spectrum: M+ at m/e 453), (theory 453), M+--H2O at m/e 435.2571 (theory 435.2620).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]([O:15][CH3:16])=[O:14]>>[CH3:16][O:15][C:13](=[O:14])[CH2:12][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(O)cccc1Br
Reactant: COC(=O)CBr
Product: COC(=O)COc1cccc(Br)c1OC

Procedure:
The compound of Formula XVIII wherein s is zero can also be prepared by treating 3-bromo-2-methoxyphenol with methyl bromoacetate to give 3-bromo-2-methoxyphenoxyacetic acid methyl ester which is reduced to the alcohol using, e.g., diisobutylaluminum hydride with subsequent protection of the alcohol with an R12 protecting group as generally described hereinbefore.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)c(F)c1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Aluminum chloride 30.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition at 5-10° C. of 3-fluoroanisole (63.6 g, 0.5 mol). The mixture was stirred at 0-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL) The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94° C.; 1H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19](=[O:21])[CH3:20])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-isopropoxy-phenol (800 mg, 5.26 mmol, 1.0 eq.) and triethylamine (1.47 mL, 10.5 mmol, 2.0 eq.) in DCM (22 mL), acetyl chloride (0.45 mL, 6.36 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred at r.t. for 4 days. Sat. aq. NaHCO3 soln. was added and the layers were separated. The org. phase was dried over MgSO4, filtered, and concentrated in vacuo to give acetic acid 4-isopropoxy-phenyl ester as a yellow oil. The product was used without further purification.
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)CCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COc1cccc(CCl)c1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCO
Product: COc1cccc(CS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A dimethoxyethane (10 ml) suspension of sodium 4-chlorobenzenesulfinate (210 mg, 1.06 mmol) and 3-methoxybenzyl chloride (154 μl, 1.06 mmol) was stirred at 70° C. for 16 hours. After cooling to room temperature, butanol (2 ml) and tetrabutylammonium bromide (45 mg) were added and the resulting mixture was stirred further at 70° C. for 16 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate (=5:1) eluate was concentrated under reduced pressure, whereby the title compound (216 mg, 69%) was obtained as a white solid.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][CH:10]=N1.[N:13]1([CH2:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH-:27])=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>C(OCC)(=O)C>[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH:10]=[CH:11][CH:12]=[N:8]3)=[CH:28][CH:29]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: [NH-]CCCOc1ccc(Cn2cccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cnn(CCCOc2ccc(Cn3cccn3)cc2)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (5 ml) and sodium hydride (60% oil dispersion) (62 mg) was added pyrazole (100 mg), and the mixture was stirred for 30 minutes. An anhydrous N,N-dimethylformamide solution (5 ml) of 3-[4-(1-pyrazolyl)methylphenoxy]propylamide (produced in Reference Production Example 1 described below) (434 mg) was then added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then diluted with ethyl acetate (50 ml), which was washed twice with saturated aqueous ammonium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was subjected to silica gel column chromatography, which afforded 340 mg of 1-{3-[4-(1-pyrazolyl)methylphenoxy]propyl}pyrazole (compound 31) in colorless oil. Yield, 82%.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].[H][H]>[Rh].CO>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: [H][H]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Agent: [Rh]
Solvent: CO
Product: COc1cccc(C(O)C2CCNCC2)c1OC
Temperature: 40 °C
Yield: 89.7 %

Procedure:
A 1-L Parr reactor was charged with 12.43 g (0.051 mol) of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10), 5.74 g of a 5% Rhodium on Carbon catalyst, and 237 g of methanol. The solution was warmed to 40° C. and treated with 100 psi of hydrogen for 5.5 h. When the reaction was complete, the solution was filtered and the catalyst washed with 108 g of methanol which was added to the filtrate. The weight of the filtered solution was 310.45 g. The methanol solution was assayed for the title compound using high pressure liquid chromatography. The methanol solution was found to contain 3.7% title compound by weight. This corresponds to 11.5 g (90% yield) of title compound.
Reaction SMILES: [CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:27]([C:31]([O:33]CC)=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[CH:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc2nc(C(C)C)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A mixture of ethyl 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (1.2 g) in methanol (5 ml) and 2N NaOH (5 ml) was heated for 4 hours under reflux. The reaction mixture was concentrated to dryness and then dissolved in water, followed by neutralization with 1N-HCl to give crystals. Recrystallization from DMF-50% EtOH afforded colorless prisms (0.8 g, 71%), m.p. 265°-267° C. (decomp.).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F>O1CCCC1>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A solution of 4-hydroxy-1-methylpiperidine (0.30 g, 2.65 mmol) in anhydrous tetrahydrofuran (6 ml) was added dropwise to a suspension of 60% sodium hydride (0.054 g, 2.27 mmol) in anhydrous tetrahydrofuran (6 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 3,4-Difluoronitrobenzene (0.30 g, 1.89 mmol) was added to the reaction mixture under ice cooling, and the mixture was refluxed for 3 hours. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.18 g, 38%) as a yellow crystal.
Reaction SMILES: CC1C=CC(S(O[C@H:12]([CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:13][CH3:14])(=O)=O)=CC=1.[CH2:22]([O:24][C:25](=[O:41])[CH2:26][N:27]=[C:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[C:29]1([C:28](=[N:27][CH:26]([C@H:12]([CH2:13][CH3:14])[CH2:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[C:25]([O:24][CH2:22][CH3:23])=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=CCCC(C)C[C@H](CC)OS(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCCC(C)C[C@@H](CC)C(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 110 °C
Yield: 35.7 %

Procedure:
To a solution of (S)-5-methylnon-8-en-3-yl 4-methylbenzenesulfonate (15 g, 48.3 mmole) and N-(diphenylmethylene)glycinate ethyl ester (15.5 g, 58.0 mmole) in toluene (150 mL) was added LiHMDS (72.5 mL, 72.5 mmole, 1 M solution in THF) at 0° C. The reaction mass was allowed to come to room temperature heated at 110° C. for 2 h. The reaction mass was cooled to room temperature, quenched with water and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound (7.0 g, 35.7%). The crude compound was taken to the next step without further purification. MS: MS m/z 406.4 (M++1).
Reaction SMILES: [C:1]1([C:7](=[N:14]C2C=CC(C3CCCC(CC(OCC)=O)C3)=CC=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:34]1[CH:39]=[CH:38][C:37]([C@@H:40]2[CH2:44][CH2:43][C:42](=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]2)=[CH:36][CH:35]=1>>[C:1]1([C:7](=[N:14][C:34]2[CH:39]=[CH:38][C:37]([C@@H:40]3[CH2:44][CH2:43][C:42](=[CH:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:41]3)=[CH:36][CH:35]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=C1CC[C@@H](c2ccc(Br)cc2)C1
Reactant: CCOC(=O)CC1CCCC(c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1
Product: CCOC(=O)C=C1CC[C@@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2)C1

Procedure:
Following the procedure described for ethyl (3-{4-[(diphenylmethylene)amino]phenyl}cyclohexyl)acetate (Intermediate 89(iii)), replacing ethyl [3-(4-{[(trifluoromethyl)sulphonyl]oxy}phenyl)cyclohexyl]acetate with ethyl [(3R)-3-(4-bromophenyl)cyclopentylidene]acetate, the title compound was obtained; MS m/e MH+ 410.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30](=[O:33])[CH2:31]Br)=[CH:28][CH:27]=1)#[N:25]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:31]=1[C:30](=[O:33])[C:29]1[CH:34]=[CH:35][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(C#N)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-cyanophenacyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][C:3]=1[NH:16][CH2:17][CH3:18].[CH:19](O)=O>>[CH2:17]([N:16]1[C:3]2[CH:4]=[C:5]([CH:6]=[C:7]3[S:11][C:10](=[O:12])[NH:9][C:8]3=[O:13])[CH:14]=[CH:15][C:2]=2[N:1]=[CH:19]1)[CH3:18]
Reactant: O=CO
Reactant: CCNc1cc(C=C2SC(=O)NC2=O)ccc1N
Product: CCn1cnc2ccc(C=C3SC(=O)NC3=O)cc21
Temperature: 100 °C
Yield: 63 %

Procedure:
5(4-Amino-3-ethylamino-benzylidene)-thiazolidine-2,4-dione (50 mg, 0.19 mmol) (intermediate 36) was dissolved in formic acid (5 mL) and the solution stirred at 100° C. over night. Formic acid was then removed in vacuo. The crude residue was then purified by silica gel column to give the title compound (35 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12].[O-]CC.[Na+]>O>[N:10]([CH:13]([CH:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[OH:9])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N+:11]=[N-:12]
Reactant: O=Cc1cccnc1Cl
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(N=[N+]=[N-])C(O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of 2.0 g of 2-chloro-3-formylpyridine (prepared as described in Preparation 75), 7.5 g of ethyl azidoacetate and 87 ml of a 65 mM ethanolic solution of sodium ethoxide was stirred at 0° C. for 2 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, in that order, and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.83 g of the title compound having Rf=0.61 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[CH3:41][C:42]1[N:47]=[C:46]([CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][N:53]([C:10](=[O:12])[C:9]3[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=3)[CH2:52][CH2:51]2)[CH:45]=[CH:44][CH:43]=1
Reactant: Cc1cccc(CCN2CCNCC2)n1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(CCN2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 72.7 %

Procedure:
4-(Methylsulfonylamino) benzoic acid (2.16 g, 10.05 mmol) was added to a stirring solution of 1-hydroxybenzotriazole hydrate (1.36 g, 10.05 mmol) and dicyclohexylcarbodiimide (2.08 g 10.05 mmol) in DMF (30 mL) at 25° C. under nitrogen. After 45 minutes, 1-[2-(6-methyl-2-pyridyl)ethyl]piperazine (2.27 g, 11.05 mmol) was added as a suspension in DMF (15 mL). The resulting mixture was stirred at room temperature overnight. The work-up was performed as disclosed in Example 5 to give 2.94 g (73%) of the title compound which was treated with ethanolic HCl to afford 2.15 g of product as a dihydrochloride: mp 165°-167° C.; 1H NMR (DMSO-d6): δ 10.14 (s, 1H), 8.19 (m, 1H), 7.63 (m, 2H), 7.45 (d, J=8.72 Hz, 2H), 7.25 (d, J=8.71 Hz, 2H), 3.85-3.20 (m, 12H), 3.06 (s, 3H), 2.67 (s, 3H); IR (KBr): 3420, 3000, 2560, 1640 cm-1 ; MS (m/z) 403 (MH+, 25%) 217 (30), 91 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2.C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:3]3[CH:4]=[C:5]([F:9])[C:6]([OH:8])=[CH:7][C:2]=3[F:1])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(-c3cc(F)c(O)cc3F)ccc2c1
Solvent: C1CCOC1
Product: Oc1cc(F)c(-c2ccc3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 6-(2,5-difluoro-4-hydroxyphenyl)-2-naphthol (500 mg, 1.84 mmol) and NCS (295 mg, 2.21 mmol) in THF (37 mL) according to method C to yield 370 mg (66%) of yellowish solid: mp 203-204° C.; 1H NMR (DMSO-d6): δ 6.90 (1H, dd, J=11.90 Hz, J=7.50 Hz), 7.32 (1H, d, J=8.88 Hz), 7.49 (1H, dd, J=11.87 Hz, J=7.60 Hz), 7.72-7.76 (1H, m), 7.84 (1H, d, J=8.97 Hz), 8.03 (1H, s), 8.06 (1H, d, 8.87 Hz), 10.58 (2H, s); MS (ESI) m/z3051307 (M−H)−; HRMS calcd for C16H9ClF2O2 306.02591, observed 305.01863 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[CH2:18][CH2:19][NH:20][CH2:21][C:10]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCOCC1>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[CH2:18][CH2:19][N:20]([C:30](=[O:31])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=3)[CH2:21][C:10]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1c2c(c3ccccc31)CCNC2
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1COCCO1
Product: Cc1cccc(NC(=O)N2CCc3c(n(CC(=O)OC(C)(C)C)c4ccccc34)C2)c1

Procedure:
A solution of 9-tert-butyloxycarbonylmethyl-1,2,3,4-tetrahydro-9H-pyrido [3,4-b]indole (3.56 g, 12.0 mmol) and 3-methylphenylisocyanate (1.60 ml, 12.4 mmol) was stirred in dioxan (40 ml) at room temperature for 4 hours. Evaporation of the solvent and chromatography on silica gel with ethyl acetate-hexane (1:3) as eluant gave the product. (3.29 g, 65%).