Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:15])[CH:5]([OH:14])[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:14][CH:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH:4]([CH3:15])[CH3:3])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)C(O)C(=O)N1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC(C(=O)N2CCOCC2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Under ice-cooling, to a solution of 60% sodium hydride (136 mg, 3.41 mmol) in tetrahydrofuran (5 mL) is added dropwise a solution of 3-methyl-1-morpholin-4-yl-1-oxobutan-2-ol (426 mg, 2.27 mmol) in tetrahydrofuran (15 mL), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added p-toluene-sulfonyl chloride (651 mg, 3.42 mmol), and the mixture is stirred at room temperature for 2 hours. After the reaction is completed, water is added to the mixture, and the mixture is extracted with ethyl acetate. This organic layer is washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by distillation, and the obtained residue is purified by silica gel column chromatography (chloroform) to give the title compound (701 mg, yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 74.1 %

Procedure:
4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (800 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (716 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg), HBTU (952 mg), and DIEA (700 uL) in DMF (5 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][CH2:25][CH2:26][OH:27])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:14][CH:15]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:28][S:29]([O:27][CH2:26][CH2:25][CH2:24][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][CH:15]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:31])=[O:30]
Reactant: COc1cc(CCCO)ccc1OCc1coc(/C=C/c2ccccc2)n1
Reactant: CS(=O)(=O)Cl
Product: COc1cc(CCCOS(C)(=O)=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 99 %

Procedure:
In substantially the same manner as in Reference Example 12, 3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol was allowed to react with methanesulfonyl chloride to give 3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate. The yield was 99%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 130-131° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[C:4]=1[NH:5][CH2:6][CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:5]([CH2:6][CH:7]=[O:8])[C:4]1[C:9]([CH2:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(CC)c1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(CC)c1N(CC=O)C(=O)CCl
Temperature: 0 °C

Procedure:
The dimethyl acetal of 2-(2,6-diethylanilino)acetaldehyde (13.0 grams), sodium carbonate (5.8 grams) dissolved in water (50 ml) and benzene (50 ml) were charged into a reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture was cooled to about 0° C. and chloroacetyl chloride (6.2 ml) was incrementally added with stirring. After the addition was complete stirring was continued and the reaction mixture was permitted to warm to room temperature. After this time the mixture was filtered, washed with dilute hydrochloric acid and stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2,6-diethylanilino)acetaldehyde.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])=[CH:21][CH:20]=1.Cl>C(N(CC)CC)C.C(#N)C>[CH2:13]([O:12][C:4](=[O:11])[CH:5]([C:25](=[O:26])[CH:24]([O:23][C:22]1[CH:29]=[CH:30][C:19]([O:18][C:17]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:16]=2[Cl:15])=[CH:20][CH:21]=1)[CH3:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
Into a 500 ml flask equipped with a stirrer and a dropping funnel 9.52 g of anhydrous magnesium chloride and 100 ml of anhydrous acetonitrile are introduced. To the heterogeneous mixture 16.0 g of diethyl malonate are added, the reaction flask is placed into an ice bath whereupon 28 ml of triethyl amine are added. To the solution at 0° C. 35 g of 2-[4'-(2",4"-dichloro-phenoxy)-phenoxy]-propionyl-chloride are added dropwise within 15 minutes. The reaction mixture is stirred at 0° C. for an hour and at room temperature for 12 hours whereupon it is cooled to 0° C. and 60 ml of a 5M hydrochloric acid solution are added. The solution thus obtained is extracted three times with 100 ml of ether each, the united extracts are dried over magnesium sulfate and the solvent and the traces of diethyl malonate are removed. The slightly yellow oil thus obtained slowly solidifies. Thus 41.8 g of the desired compound are obtained, yield 89%, mp.: 46°-50° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:37])[CH2:23][CH2:22]1.C(N(CC)CC)C>CCOCC>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:37])[CH2:23][CH2:22]1
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Reactant: CCCCCCCCCC(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC(=O)Oc1cc2c(cc1OC)CCN(C)C2C1(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Decanoyl chloride (0.45 g) was added to a mixture of (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (1 g, prepared in a similar manner to that described in Example 77), triethylamine (0.7 g) and ether (30 ml). The mixture was stirred at ambient temperature for 24 hours, then washed with water, 10% aqueous sodium hydroxide solution, and brine. The organic layer was dried over magnesium sulphate, filtered and concentrated to yield a gum which was purified by chromatography on a silica gel column using a 1:3 mixture of ether and light petroleum as eluant. The relevant fractions were concentrated in vacuo to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.95 g) as a gum; having specific optical rotation αD of +21.47°.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.CON(C)[C:18](=[O:20])[CH3:19].[Cl-].[NH4+]>CCOCC>[S:6]1[C:10]([C:18](=[O:20])[CH3:19])=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: c1ccc2sccc2c1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)c1cc2ccccc2s1
Temperature: -70 °C
Reaction time: 18 h
Yield: 57 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes; 74.6 ml) was added dropwise under nitrogen at 0° C. to a stirred solution of benzo[b]thiophene (25.0 g) in ether (350 ml), then the mixture cooled to −70° C. and a solution of N-methoxy-N-methylacetamide (19.21 g) in ether (100 ml) was added dropwise. The mixture was stirred at ambient temperature for 18 hours, then it was poured into saturated aqueous ammonium chloride solution (400 ml). The organic phase was separated, washed with water (300 ml) and saturated aqueous sodium chloride solution (300 ml), dried (Na2SO4) and the solvents were removed in vacuo. The residue was triturated with petroleum ether (b.p. 60-80° C.) (50 ml) and the resulting solid was collected by filtration and dried in vacuo to give 1-(benzo[b]thiophen-2-yl]ethan-1-one (18.7 g) as a brown solid, m.p. 78-81° C.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][NH2:11])[CH:5]=1.C(O[CH:16]=[C:17]([C:23]#[N:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[NH2:24][C:23]1[N:10]([C:6]2[CH:5]=[C:4]([O:3][CH:2]([F:1])[F:12])[N:8]([CH3:9])[N:7]=2)[N:11]=[CH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Cn1nc(NN)cc1OC(F)F
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cc(OC(F)F)n(C)n2)c1N

Procedure:
1.70 g (9.55 mmole) 5-Difluoromethoxy-3-hydrazino-1-methylpyrazole and 1.62 g (9.55 mmole) ethyl ethoxymethylenecyanoacetate in 30 ml ethanol was stirred for 1 hour at boiling point. After cooling the precipitated product was filtered off, washed with a little ethanol and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)([O-:3])=[O:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].N1C=CC=CC=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1C1OCCO1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C4OCCO4)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Nitro-5-piperazinylphenyl)-1,3-dioxolane (6.63 g, 24 mmol) was added portionwise over 1 hour to a stirred solution of 3,4-dimethoxybenzoyl chloride (4.76 g, 24 mmol) and pyridine (4.04 g, 48 mmol) in dry dichloromethane (200 mL). The mixture was stirred overnight at room temperature, washed twice with water and concentrated in vacuo to provide 2-[2-nitro-5-[4-(3,4-dimethoxybenzoyl)piperazinyl]phenyl]-1,3-dioxolane used without further purification below.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[CH2:2].Br[C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.O>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1/[CH:1]=[CH:2]/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1ccccc1/C=C/c1ccc2ccccc2c1
Yield: 86.5 %

Procedure:
29.7 g (0.13 mol) of 2-vinylnaphthalene, 25 g (0.16 mol) of ethyl 2-bromobenzoate, 22.5 ml (0.16 mol) of triethylamine, 0.54 g of palladium diacetate and 1.44 g of triphenylphosphine in 200 ml of acetonitrile were heated to 100° C. for 20 h. The reaction mixture was then poured into water and the mixture was extracted repeatedly with ethyl acetate. The organic phase was concentrated under reduced pressure and the residue was purified chromatographically on silica gel. 34 g (71%) of the product were obtained.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)CCC.O1CCOCC1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:20][C:21]#[N:22])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCCCO
Product: N#CCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A suspension of 4,4-diphenylpiperidine (4.00 g, 16.9 mmol, 1.00 equiv), chloroacetonitrile (1.40 mL, 21.9 mmol, 1.30 equiv, Aldrich), potassium carbonate (4.67 g, 33.8 mmol, 2.00 equiv), and potassium iodide (561 mg, 3.38 mmol, 0.20 equiv) in n-butanol (20 mL) and 1,4-dioxane (20 mL) was stirred at reflux under argon for 48 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to afford 4.01 g (86%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.[CH3:41][NH:42][CH3:43]>>[CH3:41][N:42]([CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1)[CH3:43]
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CNC
Product: CN(C)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1

Procedure:
The title compound was prepared from 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56, Step B, and dimethylamine (2.0 M solution in methanol) in the manner of Example 42, m.p. 95-104° C.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]3[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:36])/[CH:26]=[CH:27]/[C:28]3[CH:29]=[CH:30][C:31]([CH2:34][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9][OH:10])=[CH:32][CH:33]=3)=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: OCCNC1CCCCC1
Reactant: O=C(/C=C/c1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(CN(CCO)C2CCCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
0.24 g (1.7 mmol) of 2-cyclohexylaminoethanol are added to a suspension of 130 mg (0.34 mmol) of (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide in 10 mL of DMF and the mixture is stirred for 48 hours at 80° C. Then the reaction mixture is poured onto water and the precipitate formed is suction filtered and washed with water. The solid is dried in the circulating air dryer at 50° C. Yield: 20 mg (10% of theory); C30H33ClN2O2 (M=489.05); melting point: 178° C.-179° C.; calc.: molecular ion peak (M+H)+: 489/491 (Cl); found: molecular ion peak (M+H)+: 489/491 (Cl).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:11][C:12]([C:14]1[C:19]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[N:18][CH:17]=[C:16]([CH:27]2[CH2:29][CH2:28]2)[N:15]=1)=[O:13])C.[OH-].[Na+].Cl>C(O)C>[CH:27]1([C:16]2[N:15]=[C:14]([C:12]([NH:11][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:30])=[O:3])=[O:13])[C:19]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[N:23][CH:22]=3)=[N:18][CH:17]=2)[CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid ethyl ester (972 mg, 2.4 mmol) at rt in ethanol (15 ml) under an argon atmosphere was added 1 N NaOH (3 ml, 3.0 mmol). The suspension was stirred at rt for overnight. After the addition of 1 N HCl (3 ml) stirring was continued for 1 hr. The solid was collected by filtration, washed with H2O, then EtOH and dried.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: BrBr
Reactant: O=C(Cc1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
In chloroform (200 ml) is dissolved 2-phenylacetophenone (25.5 g) and thereto is added a solution of bromine (22 g) in chloroform (100 ml) and the mixture is stirred at room temperature for 5 hours and then allowed to stand overnight. After distilling off chloroform, to the resulting residue is added methanol. The precipitates are filtered off and the filtrate is subjected to a silica gel chromatography and eluted with chloroform. The eluates are collected and distilled to remove chloroform to give 2-bromo-2-phenylacetophenone (26 g) as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:20]>>[NH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[NH:12][C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[S:11]
Reactant: Nc1cccc(O)c1N
Reactant: S=C=Nc1c(Cl)cccc1Cl
Product: Nc1cccc(O)c1NC(=S)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 61 %

Procedure:
1.0 equivalent of 2,6-dichlorophenyl isothiocyanate was treated with 1.0 equivalent of 2,3-diaminophenol and heated to reflux for 1 h. After cooling to RT, the precipitate was filtered off with suction, washed with ether, and dried. The desired thiourea was obtained in a yield of 61%. M.p.: 202-204° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[ClH:26].CO>>[ClH:26].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Br)c23)CC1
Agent: Cl
Solvent: CO
Product: Brc1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 71 (123 mg) and 10% hydrogen chloride/methanol solution (6 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (52 mg) as light yellow powdery solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:19]=[C:15]([C:16](Cl)=[O:17])[C:14]([OH:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1>>[OH:20][C:14]1[CH:13]=[CH:12][C:11]([N:10]=[N:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:19][C:15]=1[C:16]([NH:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][CH:23]=1)=[O:17]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: COc1ccc(N=Nc2ccc(O)c(C(=O)Cl)c2)cc1
Product: COc1ccc(N=Nc2ccc(O)c(C(=O)Nc3ccc4cn[nH]c4c3)c2)cc1

Procedure:
5-(4-Methoxyphenylazo)salicoyl chloride and 6-aminoindazole were reacted together as described in Preparation 7. The product was crystallized in aqueous pyridine, m.p. 279°, λmax (methanol) = 350 nm.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.CN(C=O)C>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])=[O:12])=[CH:8][N:7]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1ccc(Cl)nc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
0.51 ml (6.98 mMol) Thionylchloride and 10 □l DMF were added to a suspension of 1.0 g (6.34 mMol) 6-chloronicotinic acid in 5 ml tetrahydrofuran. The reaction mixture was stirred at 65° C. for 1.5 hours, cooled to 0° C. and 1.98 ml (19.0 mMol) diethylamine were added over 40 minutes. The resulting suspension was stirred 4 hours at room temperature and 1 hour at 60° C. After cooling to room temperature, 5.0 ml aqueous NaOH 2N were added and stirring pursued for 30 minutes. The system was diluted with 25 ml deionized water and 20 ml ethyl acetate. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The combined organic extracts were washed with aqueous NaOH 1N and half-saturated aqueous NaCl, dried (Na2SO4) and evaporated to yield 0.68 g (50%) 6-chloro- N,N-diethyl-nicotinamide as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:7](=[O:8])[NH:6][NH:5][C:4]1=[O:9])[CH3:2].[C:19]([O:25][CH3:26])(=[O:24])[CH:20]=[CH:21][CH:22]=[CH2:23]>>[CH2:1]([C:3]1([CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:4](=[O:9])[N:5]2[CH2:23][CH:22]=[CH:21][CH:20]([C:19]([O:25][CH3:26])=[O:24])[N:6]2[C:7]1=[O:8])[CH3:2]
Reactant: C=CC=CC(=O)OC
Reactant: CCC1(CCOC2CCCCO2)C(=O)NNC1=O
Product: CCC1(CCOC2CCCCO2)C(=O)N2CC=CC(C(=O)OC)N2C1=O
Yield: 58.6 %

Procedure:
In a manner analogous to that described in Example 7(B) (b), from 7.75 g of 4-ethyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione and 3.7 g of methyl penta-2,4-dienoate there were obtained 6.49 g (59%) of methyl 2-ethyl-2,3,5,8-tetrahydro-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 96°-97° C. (from diethyl ether).