Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1)[NH2:3].[CH3:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=O.C(O)C.CO>C(O)C.O>[CH3:18][C:19](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:20]=[N:3][NH:2][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1
Reactant: COc1cc2c(cc1OC)C(NN)=NCC2
Reactant: CC(C=O)=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CO
Product: COc1cc2c(cc1OC)C(NN=CC(C)=Cc1ccccc1)=NCC2

Procedure:
In a manner similar to that of Example 18 condensation of 1-hydrazino-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (9 g.) and α-methylcinnamaldehyde (5.62 g.) and recrystallization of the resulting product first from ethanol-methanol and then from ethanol-water afforded 1-[2-(2-methyl-3-phenylallylidene)hydrazino]-6,7-dimethoxy-3,4-dihydroisoquinoline (I: X= C6H5CH=C(CH3), X' = Y = Y' = H, Z = Z' = CH3O) hydrochloride monohydrate (10.2 g., m.p. 215°-217° C.).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][S:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:22][CH:23]=1)(=[O:30])=[O:31]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccc(-c2nccs2)cc1)Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of (3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 hours. The solvent was removed by evaporation azeotroping with CH2Cl2 to afford the title compound (40 mg). 1H NMR (400 MHz, CDCl3) δ9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431 (M−1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][NH:11]1>C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH3:9][C:4]1[N:3]=[C:2]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Cl)nc(C)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCc3ccccc3C2)nc(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
A mixture of 4-chloro-2,6-dimethylpyrimidine (Chem. Ber. 1902, 35, 1575; 1.24 g, 8.70 mmol) and 1,2,3,4-tetrahydroisoquinoline (3.47 g, 26.1 mmol) was stirred at room temperature for 3 h. The solid formed was then dissolved in toluene (15 ml) and 1 M aqueous potassium phosphate buffer (pH 6.85, 15 ml). The organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Recrystallization in hexane (150 ml) yielded 2-(2,6-dimethyl-pyrimidin-4-yl)-1,2,3,4-tetrahydro-isoquinoline (1.71 g, 82%) as a crystalline light yellow solid. EI mass spectrum, m/e: 239.1 (M calculated for C15H17N3: 239).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O[C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O>C(OC(=O)C)(=O)C.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13](=[O:15])[O:14][C:21]3[C:18]([CH:19]=2)=[CH:17][CH:24]=[C:23]([OH:25])[CH:22]=3)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CCCCOc1ccc(CC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCCCOc1ccc(-c2cc3ccc(O)cc3oc2=O)cc1
Temperature: 0 °C

Procedure:
89.5 g (0.43 mol) of 4-butoxyphenylacetic acid (prepared by the method of McElvain, Carney; J. Am. Chem. Soc. 1946 (68), 2592-2599) and 30.0 g (0.22 mol) of 2,4-dihydroxybenzaldehyde are heated at 120° C. for 5 h in 100 ml of acetic anhydride and 120 ml of triethylamine. The still-hot solution is subsequently added to 3 l of ice-water, and the precipitated product is filtered off with suction and suspended in 1 l of water and 1.4 l of ethanol. After dropwise addition of 190 ml of conc. sulfuric acid, the batch is heated under reflux for 4 h and added to 3 l of water, and the precipitated product is filtered off with suction. The crude product is filtered through silica gel with hot toluene/ethyl acetate (1:1), the solvent is evaporated in vacuo, and the residue is recrystallised from toluene, giving 3-(4-butoxyphenyl)-7-hydroxychromen-2-one as colourless crystals.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.B(F)(F)F.[CH3:10][CH2:11][O:12][CH2:13][CH3:14].O.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:21]1[C:20]2[C:14]3[CH:2]=[CH:3][CH:4]=[CH:5][C:13]=3[O:12][C:11]=2[CH:10]=[CH:22][C:16]=1[C:17]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:18][CH3:19]
Reactant: CCOCC
Reactant: C1CCNC1
Reactant: Cc1ccccc1
Agent: FB(F)F
Solvent: O
Product: CC=C(c1ccc2oc3ccccc3c2c1)N1CCCC1
Yield: 34 %

Procedure:
In 100 ml of toluene, 2 g of the starting ketone, 2.12 g of pyrrolidine and 0.14 g of boron trifluoride etherate were dissolved. The mixture was refluxed for 47 hours under argon atmosphere using a Cope water separator and molecular sieve 4A as the dehydrating agent. After having distilled out the solvent, the residue was subjected to a distillation under a reduced pressure to obtain 0.95 g of the desired enamine (yield: 34%).
Reaction SMILES: C([O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[N:11]=2)=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[N:11]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)Oc1ccc(Cc2nc(-c3c(F)cccc3Cl)nn2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of 0.7 g of 5-(4-acetoxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of ethyl alcohol under ice-cooling, was added a solution of 0.62 g of potassium carbonate in 5 ml of water, and the reaction mixture was stirred at room temperature for 30 minutes, and then concentrated under reduced pressure. The residue was adjusted to pH 4 with diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.6 g of 5-(4-hydroxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc2oc(Cl)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-chloro-5-methoxybenzoxazole (1 eq), 4-bromoaniline (2 eq) and diisopropylethylamine was refluxed in dimethylformamide. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave (4-bromo-phenyl)(5-methoxybenzoxazol-2-yl)amine. MS: MH+=318
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:12]1([NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Cc1cccc(O)c1)Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Cc1cccc(OCc2ccccc2)c1)Nc1cccc2ccccc12
Yield: 47.9 %

Procedure:
A mixture of 2-(3-hydroxyphenyl)-N-naphthylacetamide (5.00 g, 18.03 mmol), benzyl bromide (3.76 g, 22.0 mmol), and potassium carbonate (4.14 g, 30.0 mmol) in acetone (50 mL) was heated to reflux overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered, and concentrated to provide the title compound (3.176 g, 48% yield): 1H NMR (DMSO-d6) 10.13 (br, 1H), 8.06 (m, 1H), 7.94 (m, 1H), 7.77 (d, 1H), 7.67 (d, 1H), 7.26-7.56 (m, 9H), 6.92-7.11 (m, 3H), 5.11 (s, 2H), 3.79 (s, 2H); ES-MS (m/z) 368 [M+H]+.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=1)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([C:17]1[CH:16]=[C:15]([CH:13]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH3:14])[CH:20]=[CH:19][CH:18]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)Cc1cccc(C(C)Br)c1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(C)c2cccc(CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (939 mg), 1-(1-bromoethyl)-3-isobutylbenzene (1.49 g) and potassium carbonate (1.71 g) in N,N-dimethylformamide (20 ml) was stirred at 25° C. overnight. The mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (30 g) eluting with a mixture of ethyl acetate and hexane (1:10) to give methyl 3-[1-(3-isobutylphenyl)ethyl]benzoate (1.45 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]1([C:13]2[NH:17][N:16]=[C:15]([NH2:18])[CH:14]=2)[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:15]2[CH:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[NH:17][N:16]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Temperature: 60 °C
Yield: 50.1 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyrimidine (30.0 g, 184 mmol), 5-cyclopropyl-1H-pyrazol-3-ylamine (22.6 g, 184 mmol) and diisopropylethylamine (46 mL, 278 mmol) in 1-butanol (50 mL) was heated to 60° C. for 65 h. The reaction was cooled to room temperature and diluted with ethyl acetate. The mixture was washed with 2 N sodium hydroxide, water and brine, then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was treated with a small amount of acetonitrile, sonicated and then triturated with ether until a solid was formed. The solid was collected by filtration to give the desired product (23.0 g, 50%) as a yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10](N(CC)CC)C.[CH2:17]=[C:18]1[O:22][C:20](=[O:21])C1>C1(C)C=CC=CC=1>[C:4]([O:6][C@@H:7]([CH3:10])[CH2:8][C:20]([O:22][CH2:18][CH3:17])=[O:21])(=[O:5])[CH2:3][C:2]([CH3:9])=[O:1]
Reactant: C=C1CC(=O)O1
Reactant: CCOC(=O)C[C@H](C)O
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H](C)OC(=O)CC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.7 g (43.2 mmol) Ethyl(3S)-3-hydroxybutanoate and 44 mg (0.43 mmol) triethylamine are dissolved in 40 ml toluene. At 90° C., 4.7 g (56.1 mmol) diketene are added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling down to room temperature, the mixture is poured into ice-water. The phases are separated and the aqueous phase is extracted two times with toluene. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [C:1](Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:6][CH:7]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][Cl:9].[CH2:19](Cl)Cl>>[C:1]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[CH:11]=[CH:10][C:7]([CH3:6])=[C:8]([Cl:9])[CH:19]=2)=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(CCl)CCCc1ccccc1
Reactant: CC(C)(C)Cl
Product: Cc1ccc(-c2ccc(C(C)(C)C)cc2)cc1Cl
Temperature: 50 °C
Reaction time: 12 h

Procedure:
27 g of tert.-butyl chloride are added dropwise to an ice-cooled mixture of 52 g of 2-methyl-5-phenylpentyl chloride and 4.9 g of FeCl3. The mixture is stirred for 7 hours at 50° C. and for 12 hours at room temperature, and taken up in methylene chloride, the solution is washed with water, dried over Na2SO4 and evaporated down, and the residue is distilled to give 40 g of 5-p-tert.-butylphenyl-2-methylphenyl chloride of boiling point 114°-118° C./0.2 mbar.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:28])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:28])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: [Pb+4]
Reactant: OB(O)c1cc(Br)ccc1Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc(Br)cc1[Pb+3]
Temperature: 40 °C
Yield: 91.8 %

Procedure:
To a mixture of lead tetraacetate (26.83 g, 61 mmol) and mercuric diacetate (0.77 g, 2.4 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (50 ml) and the reaction mixture is stirred and heated to 40° C. 5-Bromo-2-chlorophenylboronic acid (11.39 g, 48 mmol) is added in one portion, and the reaction mixture is stirred at 40° C. for 4 hours. After cooling to room temperature potassium carbonate (3.34 g) is added, the mixture stirred vigorously for 5 minutes and then filtered. The filtrate is concentrated in vacuo to give 5-bromo-2-chlorophenyllead triacetate (25.33 g), used without further purification in the next step.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[C:11]([F:12])[C:6]=2[S:5][CH:4]=1.[N:14]([O-])=O.[Na+].O.O.[Cl:20][Sn]Cl.C(O)(C)C>O.Cl>[ClH:20].[CH3:2][C:3]1[C:7]2[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[C:11]([F:12])[C:6]=2[S:5][CH:4]=1
Reactant: Cc1csc2c(F)cc(N)cc12
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1csc2c(F)cc(NN)cc12
Temperature: 25 °C

Procedure:
0.1 mole of 3-methyl-7-fluoro-5-aminobenzothiophene hydrochloride is suspended in 100 ml of water and 100 ml of concentrated hydrochloric acid, and a solution of 0.11 mole of sodium nitrite in 50 ml of water is added dropwise at between -5° C. and 0° C. The diazonium salt solution is added dropwise to a mixture, cooled to 0° C., of 0.21 mole of SnCl2.2H2O and 200 ml of concentrated hydrochloric acid. After the mixture has been warmed to room temperature, 60 ml of isopropanol are added and the crystal mass is filtered off with suction and recrystallised from isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:31][CH:30]2[CH3:43])=[O:28])=[C:6]([NH:8][S:9]([CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:11])=[O:10])[CH:7]=1.O.NN>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[CH2:31][C@H:30]2[CH3:43])=[O:28])=[C:6]([NH:8][S:9]([CH2:12][CH2:13][NH2:14])(=[O:11])=[O:10])[CH:7]=1
Reactant: CC1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NS(=O)(=O)CCN
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide (0.030 g, 0.048 mmol) in EtOH (1 mL) at ambient temperature was added hydrazine hydrate (0.025 mL). The reaction was stirred overnight at ambient temperature then diluted with water and extracted with methylene chloride (2×). The combined organics were washed with saturated aqueous brine and dried over sodium sulfate, filtered and concentrated in vacuo. Purification via radial chromatography (2 mm plate) gave the title compound (0.014 g).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([Cl:15])=[CH:12][C:13]=1[NH2:14])(=[O:8])=[O:7])(C)(C)C>Cl>[ClH:15].[NH2:14][C:13]1[CH:12]=[C:11]([Cl:15])[S:10][C:9]=1[S:6]([NH2:5])(=[O:7])=[O:8]
Reactant: CC(C)(C)NS(=O)(=O)c1sc(Cl)cc1N
Agent: Cl
Product: Nc1cc(Cl)sc1S(N)(=O)=O
Yield: 95.1 %

Procedure:
3-Amino-5-chlorothiophene-2-sulfonic acid tert-butylamide (40.4 g) was heated with stirring at 50° C. to 60° C. in 200 ml of conc. hydrochloric acid for 2.5 h. The crude product was isolated from the cooled mixture by filtration, dried and purified by trituration with 60 ml of ether to afford 17.8 g (48%) of the title compound. 1H-NMR (DMSO-d6): δ 6.64 (s, 1H), 6.84 (very br., 5H).
Reaction SMILES: C[N:2]1[CH2:11][C:10](C)(C)[C:9]2[C:4](=[CH:5][C:6]([NH2:14])=[CH:7][CH:8]=2)[CH2:3]1.Cl[C:16]1[N:21]=[C:20]([C:22]2[C:23]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:47])[C:39]4[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=4[F:46])[CH:34]=[CH:35][CH:36]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)[CH:19]=[CH:18][N:17]=1>>[NH2:2][CH:11]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([NH:14][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:31]5[CH:32]=[C:33]([NH:37][C:38](=[O:47])[C:39]6[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=6[F:45])[CH:34]=[CH:35][CH:36]=5)=[N:24][N:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=45)[CH:19]=[CH:18][N:17]=3)[CH:5]=2)[CH2:10]1
Reactant: CN1Cc2cc(N)ccc2C(C)(C)C1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: NC1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1

Procedure:
The title compound was prepared following a procedure similar to the Example 177, Step C, from 2,4,4-trimethyl-1,2,3,4-tetrahydro-7-isoquinolinamine (50 mg, 0.26 mmol) (synthesized as described in patent WO 0009486, p. 18) and N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (101 mg, 0.22 mmol, prepared according to a procedure similar to that described in Example 27, Step C). ESIMS (M+H)+=616.32.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[CH:4][C:3]=1[Cl:18].[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[Cl:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[NH:1][C:26]([C:23]1[C:22](=[O:29])[N:21]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:20]([CH3:19])[C:24]=1[CH3:25])=[O:27])[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Oc2ccc(N)c(Cl)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 46 °C
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a suspension of 4-(4-amino-3-chlorophenoxy)picolinamide (191 mg, 0.72 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (168 mg, 0.72 mmol) in DCM (10 mL) was added EDCI (166 mg, 0.86 mmol) and HOAT (20 mg, 0.14 mmol). The reaction was stirred at 46° C. for 6 hours, followed by the addition of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.14 mmol) and EDCI (27 mg, 0.14 mmol). The mixture was further stirred at 46° C. for 13 hours, then cooled to rt and diluted with water (10 mL). The resulted mixture was extracted with ethyl acetate (10 mL×3), and the combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as a pale yellow solid (160 mg, 46.5%).
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[N:22][N:23]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[O:20]1[CH:21]=[N:22][N:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Brc1ccc(-c2nnco2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2ccc(-c3nnco3)cc2)CN2CCC1CC2
Temperature: 65 °C
Yield: 39.2 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (1.06 g), 2-(4-bromopbenyl)-1,3,4-oxadiazole (1.58 g), bis(triphenylphosphine)palladium (II) chloride (245 mg), copper (I) iodide (123 mg), triethylamine (7 ml) and dimethylformamide (14 ml) were heated at 65° C. under an atmosphere of argon for 4 hours. The triethylamine and DHF were removed by evaporation. An aqueous solution of sodium hydroxide (2M, 20 ml) was added to the residue and the mixture extracted with dichloromethane (3×30 ml). The organic extracts were combined, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in dichloromethane containing 1% ammonia (density 0.88 g/cm3) to give 3-[2-(4-[1,3,4-oxadiazol-2-yl]phenyl)ethynyl]-3-hydroxyquinuclidine (811 mg) as a solid, m.p. 229-230%; microanalysis, found: C, 67.9; H, 5.8; N, 14.2%; C17H17N3O3. 0.4 H2O requires: C, 67.5; H, 5.9; N, 13.9; NMR: 1.20-1.44(1H,m), 1.50-1.71(1H,m), 1.77-2.04(3H,m), 2.69(4H,t), 2.79-2.94(1H,d), 3.04-3.20(1H,d), 5.69(1H,s), 7.63(2H,d), 8.03(2H,d), 9.35(1H,s); m/z 296(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1.[OH:26]O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:26])[CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: OO
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)c[n+]([O-])cc2Cl)cc1OC1CCCC1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A stirred suspension of N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0 g; that is prepared as described in Example 6) in glacial acetic acid (8 mL) is treated with an aqueous solution of hydrogen peroxide (6 mL; 27.5%). The mixture is stirred for 3 hours at 70-80° C. and then it is treated with a further portion of hydrogen peroxide solution (4 mL), and the solution is stirred for a further 12 hours. The solution is then cooled, basified by treatment with concentrated aqueous sodium hydroxide solution, and extracted with dichloromethane (2×30 mL). The organic extract is washed with brine (30 mL), dried over magnesium sulfate and evaporated. The resulting residue recrystallized from ethyl acetate, to give 3,5-dichloro-4-(3-cyclopentyloxy-4-methoxybenzamido)pyridine-N-oxide (0.73 g), m.p. 118-120° C. [Elemental analysis: C,53.0; H,4.4; N,6.8%; calculated for C18H18O4N2Cl2 :0.5H2O: C,53.2; H 4.7; N 6.9%].