Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[NH:19][CH2:18][CH2:17][C:16]3[C:11]2=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)=[CH:5][C:4]=1[O:24][CH3:25].Cl.I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([S:46][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1)[C:34]#[N:35]>>[CH3:45][O:44][C:38]1[CH:37]=[C:36]([C:33]([S:46][C:47]2[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=2)([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][N:19]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[C:14]([O:20][CH3:21])[CH:15]=3)[CH:10]2[CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:24][CH3:25])[CH:5]=2)[C:34]#[N:35])[CH:41]=[CH:40][C:39]=1[O:42][CH3:43]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CCCCCC(C#N)(Sc2ccc(C)cc2)c2ccc(OC)c(OC)c2)cc1OC
Yield: 61.1 %

Procedure:
The procedure of Example 49 is repeated using 0.345 g of tetrahydropapaverine hydrochloride and 0.30 g of α-(5-iodopentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile. This affords 0.263 g of the desired product as a yellow oil. MS(Hi res): m/z Calcd for C42H50N2SO6 711.34678 Found 711.3453
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.Cl.[NH2:17][CH:18]1[NH:23][CH2:22][CH:21]=[CH:20][NH:19]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:17]=[C:18]3[NH:23][CH2:22][CH2:21][CH2:20][N:19]3[C:9](=[O:11])[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1NC=CCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCCN2
Yield: 75.4 %

Procedure:
A mixture of 8.98 g (46.5 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate and 8.0 g (46.5 mmol) of 2-amino tetrahydropyrimidine dihydrochloride (prepared according to J. Org. Chem. 1955, 20, 829.) and 19.3 g (139.5 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 18 h. The cooled solution was evaporated to removed solvent and the residue was treated with water and extracted with dichloromethane. The extracts were dried and evaporated to give 8.0 g (75%) of product as a white powder. Mp: 219° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].[CH2:14]([SH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[CH2:14]([S:20][C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCS
Reactant: O=C1C=C(Br)C(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCSC1=CC(=O)NC1=O
Yield: 86 %

Procedure:
To bromomaleimide (300 mg, 1.69 mmol) and sodium acetate (138 mg, 1.69 mmol) in methanol (60 mL) was added hexanethiol (356 μL, 2.50 mmol). After 5 minutes solvent removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded 2,3 dihexanethiosuccinimide as a bright yellow paste (13 mg, 0.04 mmol) in 2% and hexylsulfanylmaleimide as a cream powder (alkene 310 mg, 1.46 mmol) in 86% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:29][C:28]1[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c2cc(Br)ccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5.57 g of ethyl 5-bromo-3-(phenylmethoxy)indole-2-carboxylate and 2.9 mL of 4-fluorobenzyl bromide in 40 mL of DMF at 0° C. was added 887 mg of a NaH suspension (60% in oil) and the resulting reaction mixture was warmed slowly to room temperature with continuous stirring. After 0.5 hour, the reaction was quenched with saturated aqueous NH4Cl and extracted twice with ethyl acetate/ether 1:1. The organic phase was washed with water (4×), brine and dried over anhydrous Na2SO4. Flash chromatography (toluene) and recrystallization from hexane yielded 5.99 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2ncnc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (59 mg), 2-hydroxy-5-methylbenzophenone (279 mg), and 4-dimethylaminopyridine (168 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 10 min. The reaction solution was cooled to room temperature, the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (97 mg, yield 92%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:22]=[CH:21][C:10]3[CH2:11][CH2:12][N:13]([CH:16]([CH3:20])[CH2:17][CH2:18]O)[CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:23])=[N:3]1.S(Cl)([Cl:26])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:26][CH2:18][CH2:17][CH:16]([N:13]1[CH2:12][CH2:11][C:10]2[CH:21]=[CH:22][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:23])[CH:5]=3)=[CH:8][C:9]=2[CH2:15][CH2:14]1)[CH3:20]
Reactant: Cc1cc(-c2ccc3c(c2)CCN(C(C)CCO)CC3)n(C)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccc3c(c2)CCN(C(C)CCCl)CC3)n(C)n1

Procedure:
To a stirred solution of 3-[7-(1,3-dimethyl-1H-pyrazol-5-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]-1-butanol (0.25 g) (intermediate 9) in chloroform (8 ml), at room temperature, thionyl chloride (0.11 ml) was added dropwise. After 2h, saturated aqueous sodium hydrogencarbonate (5 ml) was added, the reaction mixture was extracted with dichloromethane (15 ml), the organic phase dried with sodium sulphate and the solvent evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with 80% cyclohexane-ethyl acetate to give the title compound (0.23 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:19])[CH:13]3[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4].CN(C)C=O.[C:25]([O-:30])(=[O:29])[C:26]([CH3:28])=[CH2:27].[Na+].[I-].[Na+]>O>[C:25]([O:30][CH2:2][C:3]([O:5][CH:6]1[CH:10]2[O:11][C:12](=[O:19])[CH:13]3[CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH:7]1[CH2:8][CH:9]23)=[O:4])(=[O:29])[C:26]([CH3:28])=[CH2:27]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Reactant: C=C(C)C(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCC(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A mixture of 28.9 g of the 2-chloroacetic ester obtained in Example 1-1-1 and 40 g of dimethylformamide was added dropwise to a mixture of 12.4 g of sodium methacrylate, 3.0 g of sodium iodide and 50 g of dimethylformamide at a temperature below 30° C. The mixture was stirred at the temperature for 8 hours. 100 ml of water was added below 30° C. This was followed by ordinary post-treatment and recrystallization from toluene and n-hexane, obtaining 29.1 g of the target compound (yield 86%).
Reaction SMILES: C[O:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH:4]=1.[O-:18][C:19]#[N:20].[K+].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:19]([NH2:20])=[O:18])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[CH2:4]1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
22.3 g (0.1 moles) of 10-methoxy-5H-dibenz(b,f)azepine prepared according to U.S. Pat. No. 27,622 are dissolved in 150 ml of toluene. 8.92 g (0.11 moles) of potassium cyanate and 10.8 g (0.11 moles) of 96% sulfuric acid are added. The mixture is heated between 40° and 50° C. stirring vigorously for 24 hours. When the analytical control detects a starting product content<2%, 50 ml of water are dropped into the mixture, which is stirred and the phases are separated. The organic phase is evaporated to dryness under vacuum and taken up into 100 ml of 10% sulfuric acid. The mixture is refluxed for 2-3 hours, cooled at room temperature and pump-filtered, washing with water; then it is recrystallized from dimethylacetamide (50 ml), filtered through charcoal washing the precipitate on the filter with acetone, and dried under vacuum. The product is identified by IR, NMR and mass spectroscopies.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:27].[CH3:17][C:14]1([CH3:16])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]2[C:2]([NH:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:3][C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:5][C:6]=2[O:15]1
Reactant: CCCCCC(C)C(C)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(NC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
A mixture of 0.87 g. (2.47 mmole) of 10-amino-5,5-dimethyl-8-(1,2-dimethylheptyl)-5H-[1]benzopyrano[4,3-c]-pyridine, 0.51 g. (2.47 mmole) of 4-piperidinobutyric acid hydrochloride, 0.56 g. (2.72 mmole) of dicyclohexylcarbodiimide, and 50 ml. of dry methylene chloride was stirred at room temperature for 72 hours. The mixture was cooled and filtered and the filtrate concentrated to a residue which was recrystallized from methylene chloride-ether, m.p. 185-186°.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([N:22]2[C:26]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)=[CH:25][C:24]([CH:32]=O)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:26]1[N:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]=[C:24]([CH2:32][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)[CH:25]=1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: c1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)cc1
Yield: 69.2 %

Procedure:
Compound 8 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[N+:19]([C:22]1[C:23]([OH:32])=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([CH:29]=1)[CH:27]=O)([O-:21])=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[OH:32][C:23]1[C:22]([N+:19]([O-:21])=[O:20])=[CH:29][C:26]([C@H:27]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)=[CH:25][C:24]=1[O:30][CH3:31]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (25.4 g,97.7 mmole), 5-nitrovanillin (16.73 g, 84.9 mmole), pyridinium para-toluenesulfonate (PPTS) (8.52 g, 33.9 mmole) and 100 ml dry benzene were refluxed under an argon atmosphere with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The reaction was cooled to room temperature and the precipitated PPTS removed by vacuum filtration. Hexane (100 ml) was added to the filtrate and the precipitate collected by vacuum filtration. The yellow solid was washed with cold water, followed by minimal cold methanol and finally cold diethyl ether to leave 28.62 g of a 1:1.3 cis/trans ratio of product. Six recrystallizations from ethyl acetate/hexane gives 4.3 g of pure trans diastereomer. An additional 2.4 g trans product can be obtained by repeating the above crystallization process from the material remaining in the mother liquors. Once 6.7 g of trans product was isolated,0.315 g of cis diastereomer was isolated by recrystallizing the combined mother liquors from above.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[C:12]3[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=3[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[O:10])=[CH:5][CH:4]=1>CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[C:12]3[CH:27]=[CH:26][CH:25]=[CH:24][C:13]=3[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Yield: 93 %

Procedure:
By essentially following the procedure outlined in Example 1, Part D, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-methoxyphenyl ketone (Part B) as a yellow solid in 93% yield following radial chromatography (SiO2; gradient of 20-40% EtOAc in hexanes).
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[CH2:8][O:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([OH:26])[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[CH:11][CH:10]=2)=[N:5]1)[CH3:3].Cl[C:28]1[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:24][O:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:19]=[C:14]([C:12]2[NH:13][C:9]([C:6]3[O:7][CH2:8][C@@H:4]([C@@H:2]([OH:1])[CH3:3])[N:5]=3)=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:26][C:28]2[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=2)[CH:17]=1)[CH3:25]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
3-(5-{(4S)-4-[(1S)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (880 mg, 2.44 mmol) synthesized in Example (112c) was dissolved in acetonitrile (20 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (630 mg, 3.27 mmol) synthesized in Example (97c) and potassium carbonate (1.20 g, 8.68 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. Water (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=1%-3%) to afford the desired compound (1.00 g, yield 79%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][CH2:40]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:40][CH2:39]/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)=[O:9]
Reactant: OCC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC/C=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-4{-4-(1-imidazolylmethyl)phenyl}-3-buten-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 400 mg (73.8%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][C:23]([C:18]3[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=3)([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(-n2cncn2)nc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)nc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 73.1 %

Procedure:
1.10 g (5.84 mmol) of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)ethanone, 1.42 g (5.84 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.84 g of toluene and 0.32 g (1.75 mmol) of tributylamine were fed and the mixture was stirred for 7 hours at 60° C. After leaving the reaction mixture for one night at room temperature, the solid was filtered under reduced pressure to obtain 1.84 g of 1-(6-(1H-1,2,4-triazol-1-yl)pyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 73.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]1[CH2:18][CH2:17][N:16](CC2C=CC=CC=2)[CH2:15][CH2:14]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1ccc2c(c1)C(=C1CCN(Cc3ccccc3)CC1)C(=O)N2
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C1CCNCC1)C(=O)N2
Temperature: 50 °C

Procedure:
A stirred mixture of 14 g of the product of Step A, 140 ml of acetic acid and 1.4 g of 9.6% palladized carbon was heated at 50° C. while saturated with hydrogen and when hydrogen absorption ceased, the mixture was filtered. The filtrate was evaporated to dryness and the residue was taken up in water. The aqueous phase was made alkaline with sodium hydroxide and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness to obtain 8.5 g of raw product. The latter was chromatographed over silica gel and was eluted with an 85-10-5 chloroform-methanol-triethylamine mixture to obtain 1,3-dihydro-5-methoxy-3-(piperidin-4-yl)-2H-indol-2-one with a Rf=0.15.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1.CCN(CC)CC.Cl[CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][S:41]([CH:40]=[CH2:39])(=[O:43])=[O:42])=[CH:23][CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:28]([CH3:30])[CH3:29])[NH:11]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3ccc(N)cc3)nc(=O)c1-2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)Nc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.14 mL (1.0 mmol) of Et3N in 4 mL of THF was added 0.063 mL (0.6 mmol) of 2-chloroethanesulfonyl chloride. The solution was stirred 1 h, warming to ambient temperature. The solution was poured into 10% aq. citric acid and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO4), and concentrated under reduced pressure. The crude product was chromatographed (elution with 1:1 EtOAc-hexanes) to afford 221 mg (80%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. 1H NMR (300 MHz, DMSO) δ 12.47(br. s, 1H); 9.92(br. s, 1H); 7.97(s, 2H); 7.17(d, 2H, J=8.4 Hz); 7.02(d, 2H, J 8.4 Hz); 6.69(dd, 1H, J=16.5, 9.9 Hz); 6.04(d, 1H, J=16.5 Hz); 5.96(d, 1H, J=9.9 Hz); 3.78(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([OH:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:15]([CH2:21][CH3:22])([CH3:20])[C:16]([O:19][CH3:23])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC1(C)C(O)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCC1(C)C(OC)=NN=C1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
A suspension of 49 mg (0.15 mmol) of 1-tert-butoxycarbonyl-4-(4-ethyl-3-hydroxy-4-methyl-(4H)-pyrazol-5-yl)piperidine (from Step A), 50 mg (0.36 mmol) of potassium carbonate and 0.06 mL (0.96 mmol) of methyliodide in 0.3 mL of acetonitrile was stirred at rt for 17 hours and 85° C. for 7 hours. The reaction was partitioned between 25 mL of EtOAc and 25 mL of brine. After separating phases, the organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 4:1 v/v of hexanes/acetone as the eluant to afford the title compound as a colorless film: RF: 0.21 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 0.65 (t, J=7.4, 3H), 1.21 (s, 3H), 1.45 (s, 9H), 1.57–1.66 (m, 2H), 1.73–1.81 (m, 4H), 2.37 (m, 1H), 2.73–2.78 (m, 2H), 3.27 (s, 3H), 4.15–4.20 (m, 2H); 13C-NMR (125 MHz) δ 54.4 (O—CH3).