Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=[O:7].[CH:22]1([CH2:25][OH:26])[CH2:24][CH2:23]1>O1CCOCC1>[C:16]1([CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:26][CH2:25][CH:22]3[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OCC1CC1
Reactant: O=C(NC1CCN(Cc2ccccc2)CC1)c1ncc[nH]1
Solvent: C1COCCO1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)OCC1CC1

Procedure:
A solution of 4-imidazolylcarbonylamino-1-phenylmethylpiperidine (10 g, 0.035 mol), from Preparation 2, in dioxane (100 mL) was added to cyclopropanemethanol (2.42 g, 0.035 mol), then heated overnight at 80°-100° C. with stirring. The reaction mixture was allowed to return to room temperature and the dioxane evaporated under reduced pressure, and the residue was flash-chromatographed using ethyl acetate/heptane (50:50) as eluent. 9.5 g of cyclopropylmethyl (1-phenylmethyl-4-piperidyl)carbamate, m.p. 70°-72° C., was recovered and used in the next step without further purification.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.P(Br)(Br)[Br:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1C=CC=CC=1>[Br:25][CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CBr)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxymethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.86 g) in tetrahydrofuran (5 ml) was dropwise added to a solution of phosphorus tribromide (0.18 ml) in a mixture of tetrahydrofuran (10 ml) and benzene (5 ml) under ice cooling. After stirring for 4 hours at the same temperature, the reaction mixture was poured into ice-water (50 ml) adjusted to pH 9 with saturated aqueous potassium carbonate and extracted with ethyl acetate (50 ml). The separated organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and acetone (5:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 3-bromomethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.73 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:24]5)=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1.CN([CH:37]=[O:38])C>>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3([C:18]([NH:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])=[C:24]5[CH:37]=[O:38])=[O:19])[CH2:17][CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
POCl3 (12 g, 80 mmol) was added dropwise to DMF (40 mL) held at −20° C. After the addition was complete, the reaction mixture was allowed to warm to 0° C. and was stirred for 1 h. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)cyclopropanecarbox amide (3.0 g, 8.0 mmol) was added and the mixture was warmed to 25° C. After stirring for 30 minutes the reaction mixture was poured over ice and stirred for 2 h. The mixture was then heated at 100° C. for 30 min. The mixture was cooled and the solid precipitate was collected and washed with water. The solid was then dissolved in 200 mL dichloromethane and washed with 200 mL of a saturated aq. NaHCO3. The organics were dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-1H-indol-5-yl)cyclopropane-carboxamide (2.0 g, 61%). ESI-MS m/z calc. 404.5, found 405.5 (M+1)+; retention time 3.30 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 10.39 (5, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.35-7.31 (m, 2H), 7.04-7.03 (m, 1H), 6.97-6.90 (m, 2H), 6.03 (s, 2H), 1.53 (s, 9H), 1.42-1.39 (m, 2H), 1.05-1.03 (m, 2H).
Reaction SMILES: C([O-])=O.C([NH+](CC)CC)C.C(O)=O.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:26][C:25](=[O:33])[CH:24]=1>O>[CH2:23]([C:24]1[C:25](=[O:26])[O:33][C:20]2[C:15]([C:14]=1[OH:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:32]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC[NH+](CC)CC
Agent: O=C[O-]
Solvent: O=CO
Solvent: O
Product: O=c1oc2ccccc2c(O)c1Cc1ccccc1
Temperature: 135 °C

Procedure:
Triethylammonium formate (TEAF) was prepared by adding TEA (20.0 mL) to formic acid (16.5 mL) with ice cooling. To TEAF was added benzaldehyde (3.78 mL) and 4-hydroxy-chromen-2-one (6.0 g) and the resulting mixture was heated to 130-140° C. for 3 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and conc. in vacuo to give a light yellow solid. The crude solid was recrystallized from EtOH to give 3-Benzyl-4-hydroxy-chromen-2-one as a white solid (1.95 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])=[CH:5][CH:4]=1)#[N:2].[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)[O:11][C:10]2=[O:20])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCC1CN(c2ccc(C#N)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reaction time: 25 h

Procedure:
A mixture of 2.96 g of 3-(4-cyanophenyl)-5-methanesulfonyloxymethyl-2-oxazolidinone (m.p. 162°-163°; obtainable by reacting 4-aminobenzonitrile with 2,3-epoxypropanol to give 4-(2,3-dihydroxypropylamino)benzonitrile (oily), reacting with diethyl carbonate/potassium tert-butylate at 110° to give 3-(4-cyanophenyl)-5-hydroxymemthyl-2-oxazolidinone (m.p. 130°-131°) and esterifying with methanesulfonyl chloride), 1.69 g of ethyl piperidine-4-carboxylate, 70 ml of acetonitrile, 1.38 g of potassium carbonate and 1.65 g of potassium iodide is boiled for 25 h. After customary working up, ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-carboxylate ("IA") is obtained, FAB 358.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30]([N:36]3[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCNCCN1
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
1-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one was prepared from (4S,5R)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12d) and [1,4]diazepan-5-one (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 607.3 [(M+H)+]
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C@H:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][C:8]([OH:10])=[O:9].[CH3:21]O>>[NH2:5][C@@H:6]([CH2:7][C:8]([O:10][CH3:21])=[O:9])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: N[C@@H](CC(=O)O)C(=O)OCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 29 h

Procedure:
SOCl2 (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled (ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid (10.04 g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removed and the reaction mixture was stirred at ambient condition for 29 hr. Most of the volatile component was removed in vacuo and the residue was carefully partitioned between EtOAc (150 mL) and saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (150 mL, 2×), and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford (S)-1-benzyl 4-methyl 2-aminosuccinate as a colorless oil (9.706 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 7.40-7.32 (m, 5H), 5.11 (s, 2H), 3.72 (app t, J=6.6, 1H), 3.55 (s, 3H), 2.68 (dd, J=15.9, 6.3, 1H), 2.58 (dd, J=15.9, 6.8, 1H), 1.96 (s, 2H). LC (Cond. 1): RT=0.90 min; LC/MS: Anal. Calcd. for [M+H]+ C12H16NO4: 238.11. found 238.22.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.Cl.O1CCOCC1>C(O)C>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1ncc(CCc2cccnc2)c2ccccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Clc1ccc(Nc2ncc(CCc3cccnc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere, 250 mg (0.93 mmol) of 1-chloro-4-(2-pyridin-3-yl-ethyl)isoquinoline in 2.9 ml of abs. ethanol are mixed with 131 mg (1.02 mmol) of 4-chloro-aniline and 0.23 ml of 4 N HCl/dioxane, and stirred for 8 h at 80° C. The mixture is cooled to RT, filtered and the residue washed with acetonitrile. The residue is dissolved in 4 ml of water, then 0.9 ml of sat. NH3 solution are added, stirring is effected for 10 min, the precipitate is filtered off and washed with water. Recrystallisation from acetonitrile yields 1-(4chloroanilino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline; m.p.157-158° C.
Reaction SMILES: [C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28]>CN(C=O)C.CC(C)=O>[ClH:20].[NH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCOCCO
Agent: Cl
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOCCN
Reaction time: 16 h
Yield: 40 %

Procedure:
Stearoyl chloride (6.4 g; 21 mmol) (commercial product) was added dropwise in 5 min to a solution of 2-(2-aminoethoxy)ethanol hydrochloride (2.9 g; 20 mmol) in DMF (50 mL) at room temperature to afford a suspension. After 16 h, the suspension was diluted with acetone and the precipitated solid filtered and washed with acetone. The crude was crystallized from EtOAc; the solid was filtered, washed with EtOAc and dried under reduced pressure to give the desired compound (3.3 g; 8 mmol). Yield 40%. Acidic titer (0.1 N NaCH): 93%. K.F.: 1.06%. The 1H-NMR, 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([O:21]C)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1nc(-c2ccc(N(C)C)cc2)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of methyl 2-[4-(dimethylamino)phenyl]quinazoline-4-carboxylate (2.02 g, 6.57 mmol, 1.00 equiv) in ethanol (60 mL) and a solution of NaOH (1.32 g, 33.00 mmol, 5.00 equiv) in water (20 mL). The resulting solution was stirred for 6 h at 50° C. in an oil bath. The reaction mixture was cooled to room temperature. The mixture was concentrated under vacuum. The residue was dissolved in 20 mL of water. The pH value of the solution was adjusted to 5-6 with acetic acid. The solids were collected by filtration. This resulted in 800 mg (41%) of 2-[4-(dimethylamino)phenyl]quinazoline-4-carboxylic acid as a red solid. (ESI) m/z 294 ([M+H]+).
Reaction SMILES: [S:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:14][C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.O>[CH2:24]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH2:4][CH2:3][CH:2]([CH2:14][C:15]3[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=3)[S:1][C:6]1=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)COC(CC2CCc3c([nH]c4ccccc34)S2)=N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)COC(CC2CCc3c(n(Cc4ccccc4)c4ccccc34)S2)=N1
Reaction time: 0.5 h

Procedure:
71 mg of 2-(2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)methyl-4,4-dimethyl-2-oxazoline (prepared as described in Example 80) in 1 ml of dimethylformamide was added to a suspension of 11 mg of sodium hydride (55% w/w dispersion in mineral oil) in 1 ml of dimethylformamide, with stirring and ice-cooling. Stirring was continued at this temperature for 30 minutes and then 0.03 ml of benzyl bromide was added to the reaction mixture, with stirring and ice-cooling. Stirring was continued for a further hour. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a mixture of 20% v/v ethyl acetate in hexane as the eluent, to afford 71 mg of the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33]>C1COCC1>[C:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])[CH2:5][CH2:6]2)[CH:15]=[CH:14][CH:13]=1)(=[O:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)c3ccc4ccccc4c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-(3-[1-(2-aminoethyl)-4-piperidinyl]phenyl)-2-methylpropanamide and 2-naphthoyl chloride: ESMS m/e: 444. 2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:31][C:32]([F:47])([F:46])[S:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>O1CCCC1.O>[C:1]1([C:7]2[N:11]([S:42]([C:39]3[CH:38]=[CH:37][C:36]([S:33]([C:32]([F:47])([F:31])[F:46])(=[O:35])=[O:34])=[CH:41][CH:40]=3)(=[O:44])=[O:43])[CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(S(=O)(=O)C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 60 mg) was added, and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (0.30 mL) was added and the mixture was further stirred at the same temperature for 15 min. 4-[(Trifluoromethyl)sulfonyl]benzenesulfonyl chloride (432 mg) was added and the reaction mixture was stirred at room temperature for 30 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give 5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde (191 mg) as an orange solid. The obtained 5-phenyl-1-({4-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-1H-pyrrole-3-carbaldehyde (191 mg) was subjected to a similar operation as in the synthesis of Example 179 to give the title compound as a solid (yield 86 mg, 40%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[C:24]([O:39][CH3:40])=[CH:23][C:4]=1[CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)C(=O)OC(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[C:4]([CH2:5][CH2:6][NH:7][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:23][C:24]([O:39][CH3:40])=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[CH:26]=1
Reactant: COc1cc(CCN(Cc2ccc(F)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(CCNCc2ccc(F)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 10 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
A solution of HCl in 1,4-dioxane (0.05 mL) was added to a solution of tert-butyl 2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxyphenethyl(4-fluorobenzyl)-carbamate (0.03 g, 0.4 mmol) in DCM (5 mL) at 0° C. The solution was allowed to warm to 10° C. and stirred at this temperature for one hour. The solvents were removed under reduced pressure and the residue was washed with methanol (2×5 mL) to give the title compound (0.017 g, 68%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Cl[C:11]1[N:12]=[CH:13][C:14]([C:17]([NH:19][C:20]2[NH:21][N:22]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[CH:24]=2)=[O:18])=[N:15][CH:16]=1>CS(C)=O.CO>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][C:23]2[CH:24]=[C:20]([NH:19][C:17]([C:14]3[CH:13]=[N:12][C:11]([N:6]4[CH2:7][CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]4)=[CH:16][N:15]=3)=[O:18])[NH:21][N:22]=2)[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=1
Reactant: CCN1CCCNCC1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Solvent: CS(C)=O
Solvent: CO
Product: CCN1CCCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
1-ethyl-1,4-diazepane (205 mg, 1.60 mmol) was added to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (310 mg, 0.80 mmol) in DMSO (4.00 ml) at 25° C. The resulting solution was stirred at room temperature for 2 h. The reaction was incomplete so the temperature was increased to 60° C. and the reaction mixture was stirred for a further 15 mins. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford crude product as an orange dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (228 mg, 59%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[N:15]1([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:18]1[CH2:19][CH2:20][N:15]([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:16][CH2:17]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Product: Cc1c(C(O)CN2CCN(CCc3ccc4c(c3)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-(1-Hydroxy-2-{4-[2-(1-oxo-1,3-dihydro-2-benzo furan-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one and 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N1[C:22]([CH3:23])=[CH:21][C:20](C)=[CH:19][C:18]=1[CH3:25].C(Br)C1C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][N:14]([CH2:25][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:13](=[O:16])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)NN2)cc1OC
Reactant: Cc1cc(C)nc(C)c1
Agent: BrCc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C2CC(=O)N(Cc3ccccc3)N2)cc1OC

Procedure:
5 g of 5-(3,4-dimethoxyphenyl)-pyrazolin-3-one, prepared according to Example 1C, were suspended in 100 ml of toluene. First 3 ml of collidine and subsequently 3.6 ml of benzyl bromide were added dropwise to the suspension. After heating for 6 hours under reflux, the reaction mixture was cooled, and the precipitated crystals were filtered out and washed with isopropanol. The crystals obtained were dissolved in dichloromethane and washed with 2M citric acid. The organic phase was dried with magnesium sulfate and concentrated. For purification the residue was recrystallized from isopropanol. 4 g of 5-(3,4-dimethoxyphenyl)-2-benzyl-pyrazolin-3-one were obtained having a melting point of 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]#[N:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].N.[H][H]>[Ni].CO>[NH2:15][CH2:14][CH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1
Reactant: CCOC(=O)c1ccc(CC#N)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)c1ccc(CCN)cc1Cl
Reaction time: 4.5 h
Yield: 77 %

Procedure:
A mixture composed of 1.9 g (8.5 mmol) of ethyl 2-chloro-4-(cyanomethyl)benzoate, 0.5 g of Raney nickel in 70 ml of methanol containing a few ml of liquid ammonia is subjected to a hydrogen pressure of about 60 kg/cm2, at 50° C. for 5 h, and then at 80° C. for 4.5 h. After filtration of the reaction medium, 1.5 g of oil are obtained (Yield=77%).