Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]#[N:20])=[CH:8][CH:7]=2.CS(C)=[O:28]>O>[NH2:1][CH2:2][C:3]1[N:4]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:19]([NH2:20])=[O:28])=[CH:8][CH:7]=2
Reactant: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(C#N)ccc2c1=O
Reactant: CS(C)=O
Solvent: O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(C(N)=O)ccc2c1=O
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile (20.0 g), 2N aqueous sodium-hydroxide solution (6 ml), dimethyl sulfoxide (100 ml) and water (40 ml) was stirred at an inner temperature of 85° C. for 30 min. The reaction mixture was cooled to 40° C., cooled to not higher than 5° C. and stirred for 1 h. The precipitated crystals were collected by filtration and washed twice with water (40 ml) to give the title compound (21.7 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.[CH:29]1([C:34]2[CH:35]=[C:36]3[N:41]([C:42]=2[C:43](=[O:47])[C:44](Cl)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[CH:29]1([C:34]2[CH:35]=[C:36]3[N:41]([C:42]=2[C:43](=[O:47])[C:44]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([N:12]4[CH2:13][CH2:14][N:9]([C:4]5[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=5)[CH2:10][CH2:11]4)=[CH:16][CH:17]=2)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C(=O)c1c(C2CCCC2)cc2n1CCCC2
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(C5CCCC5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
A solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 94; 0.20 g, 0.71 mmol) and triethylamine (0.3 mL, 2.1 mmol) in THF (5 mL) was cooled to 0° C. A solution of (2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-oxo-acetyl chloride (prepared as described in Reference Example 22, 0.24 g, 0.85 mmol) in THF (2 mL) was added and the mixture stirred under N2 atmosphere at 0° C. for 1 h and then at room temperature for 1 h. The mixture was quenched with sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (60-120 mesh) eluting with 12% ethyl acetate/chloroform to afford 2-(2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide (0.17 g, 46%) as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([O:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])(=[O:26])=[O:25])=[CH:18][C:17]=1[Cl:35])=[CH:8]2)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:22][C:21]1[CH:20]=[C:19]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])(=[O:26])=[O:25])[CH:18]=[C:17]([Cl:35])[C:16]=1[O:15][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=2
Reactant: COC(=O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ncc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)cc2c1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a solution of 3-[2,6-Dichloro-4-(2,4-dichloro-benzenesulfonylamino)-phenoxy]-quinoline-6-carboxylic acid methyl ester (181) (200 mg, 0.35 mmol) in THF/MeOH(2 ml/2 ml) was added 4N NaOH (0.1 ml, 0.4 mmol). This mixture was refluxed for 2.5 hr. The reaction mixture was cooled to room temperature and was neutralized with 2N HCl, and then concentrated. The residue was extracted twice with AcOEt. Organic layer was washed by Brine, dried over anhydrous MgSO4, and concentrated to give a solid. Crude product was recrystallized by Hexane/AcOEt to afford compound 183 (153 mg, 78%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]([C:13]2[NH:14][C:15](=[O:22])[C:16]([CH:19]([CH3:21])[CH3:20])([CH3:18])[N:17]=2)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[OH:23][CH:24]([CH3:29])[CH2:25][C:26](O)=[O:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH:19]([C:16]1([CH3:18])[C:15](=[O:22])[NH:14][C:13]([C:6]2[N:5]=[CH:4][C:3]([CH:1]3[O:23][CH:24]([CH3:29])[CH2:25][C:26](=[O:27])[O:2]3)=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[N:17]1)([CH3:20])[CH3:21]
Reactant: CC(O)CC(=O)O
Reactant: COC(=O)c1cc(C=O)cnc1C1=NC(C)(C(C)C)C(=O)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C2OC(=O)CC(C)O2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Yield: 20 %

Procedure:
A solution of methyl 5-formyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (0.55 g, 0.0018 mol), 3-hydroxybutyric acid (0.28 g, 0.0027 mol) and a catalytic amount of para-toluenesulfonic acid in chloroform (25 mL) is heated at reflux temperature for 113 hours. During this time, water is removed by placement of an addition funnel containing 3 angstrom molecular sieves between the reaction flask and the reflux condensor. The reaction mixture is poured into aqueous saturated sodium bicarbonate and the layers are separated. The aqueous portion is extracted with additional methylene chloride and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (0.14 g, 20%) as a white solid, mp 65°-75° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:12]([C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[O:18][C:19]1[C:24]([N:25]=[C:26]=[S:27])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]>ClCCCl>[C:12]([C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[O:18][C:19]1[C:24]([NH:25][C:26]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[S:27])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N=C=S
Reactant: CC(C)(C)c1cccc(N)c1
Solvent: ClCCCl
Product: CC(C)(C)c1cccc(NC(=S)Nc2cccnc2Oc2ccccc2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
To a solution of 3-tert-butylaniline (104 mg, 0.70 mmol) in DCE (3 mL) was slowly added 1c (100 mg, 0.35 mmol). The reaction was stirred 18 h at rt and concentrated. The crude mixture was dissolved in methanol and filtered through an SCX cartridge and concentrated to afford 97a (158 mg, quantitative) as a yellow oil. This material was carried to the next step without further purification.
Reaction SMILES: COC([C:5]1[C:6]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])=[N:7][CH:8]=[CH:9][CH:10]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:33]1CCC[CH2:34]1>>[OH:33][CH2:34][C:8]1[N:7]=[C:6]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[CH2:20][C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[CH:5]=[CH:10][CH:9]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccnc1-c1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(-c3cccc(CO)n3)cc12

Procedure:
A solution of 5-(3-MethoxycarbonyI-2-pyridyl)-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole (393 mg, 1.073 mmol) (see Example 62) in tetrahydrofuran (2.5 ml) was added dropwise, with stirring, to a flask containing a solution of lithium aluminium hydride in tetrahydrofuran (35.9 mg of LiAIH4 in 10.0 ml THF) under a nitrogen atmosphere. The reaction was stirred for 24 hours whereupon the reaction mixture was quenched with aqueous sodium carbonate and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane/methanol/ammonium hydroxide (90:10:0.7), to afford, after combination and evaporation of the appropriate fractions, the title compound as a white foam (298 mg). Found: C,71.55; H,6.93; N,12.20. C20H22N3O.1/5CH2Cl2 requires: C,71.70; H,6.97; N,12.42%.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[K+]>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1cccc(-c2nc3n(C4CCCC4)[nH]c(CC)c-3c(=O)n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCC(=O)O)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a slurry of 1-cyclopentyl-3-ethyl-6-[3-(ethoxycarbonylmethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one (1.23 g, 3.0 mmol) in ethanol (10 ml) was added water (100 ml), followed by 85% KOH (0.4 g). The reaction mixture was heated on a steam bath for 3 hours, cooled to room temperature and filtered. The filtrate was chilled and acidified with acetic acid to afford a white precipitate, which was collected by filtration and washed with water, then ethanol, and finally ether. The product was combined with the product from another experimental run and then was recrystallized from DMF/CH3CN to afford 0.98 g of 1-cyclopentyl-3-ethyl-6-[3-(carboxymethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 299°-300° C.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C[O-].[Na+].[C:8]([Si:12]([CH3:33])([CH3:32])[O:13][CH2:14][CH2:15][C:16]([CH3:31])([CH3:30])[CH2:17]/[CH:18]=[C:19]1\[C:20](=[O:29])[NH:21][C:22]2[C:27]\1=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C>CO>[C:8]([Si:12]([CH3:32])([CH3:33])[O:13][CH2:14][CH2:15][C:16]([CH3:31])([CH3:30])[CH2:17][CH:18]([CH:19]1[C:27]2[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:29])[CH2:4][N+:1]([O-:3])=[O:2])([CH3:10])([CH3:9])[CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C/C=C1\C(=O)Nc2cc(Cl)ccc21)CCO[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC(C[N+](=O)[O-])C1C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of nitromethane (Aldrich) (0.21 g, 3.5 mmol) in methanol (20 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (0.74 g, 3.5 mmol). After the mixture was stirred at room temperature for 10 min, a solution of E/Z-3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentylidene]-6-chloro-1,3-dihydro-indol-2-one (0.68 g, 1.7 mmol) in methanol (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then acetic acid (0.6 g, 10 mmol) was added. The mixture was concentrated to a small volume, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10) to give the racemic 3-[5-(tert-butyl-dimethyl-silanyloxy)-3,3-dim ethyl-1-nitromethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one as a white foam (0.5 g, 64%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:5]=[N:4][CH:3]=1.[CH3:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH2:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:13][C:14]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:15]=1[NH:16][C:10](=[O:11])[CH:9]=[CH:8][C:6]1[CH:7]=[N:2][CH:3]=[N:4][CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)C=Cc1cncnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)C=Cc1cncnc1
Reaction time: 0.5 h

Procedure:
To a suspension of the product of step 3 (2.05 g) in anhydrous dichloromethane (30 ml), a solution of 2-methyl-5-nitroaniline (3.04 g) and triethylamine (8 ml, excess allowed) in dichloromethane (15 ml) was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for 30 min in an ice-bath, and then at room to temperature for 3 h. Completion of reaction was indicated by TLC. Potassium carbonate solution (10%) was added to the mixture. Then the mixture was extracted with EtOAc (20 ml*3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to recover the solvent. The residue was purified on silica gel column (EtOAc/petroleum ether 4:1). The eluent was collected, concentrated under reduced pressure to give a yellow powdered solid.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:23])(=[O:22])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH:7]=1.CO>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:24])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:22])=[O:23])[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc(OC)c2)c1
Solvent: CO
Product: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(3-methoxyphenyl-sulfamoyl)-phenyl]-acrylic acid methyl ester (4i) (0.42 g, 1.2 mmol) in methanol (5.5 ml) 1N NaOH solution (3.6 ml, 3.6 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.38 g, 95%). 1H NMR DMSO-d6, HMDSO), δ 3.65 (3H, s); 6.40–6.78 (4H, m); 7.16 (1H, m); 7.45–8.09 (5H, m); 10.32 (1H, br s).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[C:19]([OH:21])=O.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.C(OCC)(=O)C>[OH:25][CH2:24][C:23]([NH:22][C:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)=[O:21])([CH3:27])[CH3:26]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.3 %

Procedure:
WSC HCl (1.94 g, 10 mmol) was added to a mixture of 2-pyrazinecarboxylic acid (0.99 g, 8 mmol), 2-amino-2-methyl-1-propanol (0.80 g, 9 mmol) and HOBt (1.36 g, 10 mmol) in methylene chloride (30 ml), and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine, successively, dried over Na2SO4 and concentrated under a reduced pressure. The residue was suspended in methanol (10 ml), added 2N aqueous NaOH to and stirred for 30 minutes. Methanol was evaporated under a reduced pressure, diluted with saturated aqueous NaHCO3and extracted with chloroform. The extract was washed with with saturated aqueous NaHCO3 and brine, successively, dried over Na2SO4. After the solvent was evaporated, the obtained crystal was washed with hexane and dried to give the title compound (0.27 g; 18%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[NH:22][C:28]2=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g), CDI (668 mg), and DBU (1.2 mL) in THF (25 mL) was heated at 60° C. overnight. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=97/3 to 9/1) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (993 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([SH:16])=[N:14][N:15]=1.[OH-].[Na+].I[CH3:20]>O.ClCCl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([S:16][CH3:20])=[N:14][N:15]=1
Reactant: CI
Reactant: Cc1cccc(C)c1NCc1nnc(S)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CSc1nnc(CNc2c(C)cccc2C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred mixture of 16.2 g (0.0688 mol) 2-(2,6-dimethylphenylaminomethyl)-5-mercapto-1,3,4-oxadiazole in 200 ml water and 200 ml dichloromethane was added quickly 2.8 g (0.0688 mol) sodium hydroxide. To the resulting reaction mixture was then added 9.9 g (0.0688 mol) iodomethane. The reaction mixture was stirred at about 25° C. for 1 hour and then heated under reflux for 1 hour. After the reaction mixture was allowed to stand overnight at 25° C., the organic layer was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a yellow solid. Trituration with ethyl ether/petroleum ether gave 8.8 g of 2-(2,6-dimethylphenylaminomethyl)-5-methylthio-1,3,4-oxadiazole, m.p. 84°-85° C. The product is tabulated in Table I as Compound No. 24-A.
Reaction SMILES: [C:1](O[C@H]1[C@H](OC(=O)C)[C@@H](OC(=O)C)[C@H](C2C=C(CC3C=CC(OCC)=CC=3)C(Cl)=CC=2OCC=C)O[C@@H]1COC(=O)C)(=[O:3])[CH3:2].[CH2:45]([C:52]1[C:61]([Cl:62])=[C:60]2[C:55]([CH2:56][CH2:57][CH2:58][O:59]2)=[C:54]([C@H:63]2[C@H:68]([OH:69])[C@@H:67]([OH:70])[C@H:66]([OH:71])[C@@H:65]([CH2:72][OH:73])[O:64]2)[CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[C:58]([O:71][C@H:66]1[C@H:67]([O:70][C:63](=[O:64])[CH3:54])[C@@H:68]([O:69][C:68](=[O:69])[CH3:67])[C@H:63]([C:54]2[CH:53]=[C:52]([CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:61]([Cl:62])=[C:60]3[C:55]=2[CH2:56][CH2:57][CH2:58][O:59]3)[O:64][C@@H:65]1[CH2:72][O:73][C:1](=[O:3])[CH3:2])(=[O:59])[CH3:57]
Reactant: OC[C@H]1O[C@@H](c2cc(Cc3ccccc3)c(Cl)c3c2CCCO3)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccccc3)c(Cl)c3c2CCCO3)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Similar procedure with preparation of 25 proceeded except for using compound 175 to obtain the compound 176.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.[OH-].[Li+].Cl>C1COCC1>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:5]([CH2:4][C:3]([OH:19])=[O:2])=[CH:6][N:7]=[CH:8]2)=[CH:12][CH:13]=1)#[N:18]
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CC(=O)O)cc1

Procedure:
A solution of [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester (4.44 g, 17.4 mmol ) in THF (100 ml) and 1 M lithium hydroxide (17.4 ml, 17.4 mmol) was stirred at room temperature for 18 hr. 1 M HCl (17.4 ml) was added and the THF was removed by evaporation in vacuo. The aqueous solution was lyophilized to afford the title compound containing lithium chloride as a solid.
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([Cl:13])=[O:12])=[C:9]([I:14])[C:8]([NH:15][CH3:16])=[C:7]([I:17])[C:3]=1[C:4]([Cl:6])=[O:5].[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:13][C:11]([C:10]1[C:9]([I:14])=[C:8]([N:15]([CH3:16])[C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24])[C:7]([I:17])=[C:3]([C:4]([Cl:6])=[O:5])[C:2]=1[I:1])=[O:12]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CNc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)N(C)c1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
2,4,6-Triiodo-5-methylamino-isophthaloyl dichloride (20 g, 32.8 mmol) was dissolved in DMA (60 ml) and acetoxyacetyl chloride (15.32 ml, 142 mmol) was added. The reaction was stirred overnight at room temperature with nitrogen bubbling through the reaction mixture. The reaction mixture was poured slowly onto ice-water (300 ml) and a white solid was isolated by filtration. The solid was dissolved in ethyl acetate and washed with water. The ethyl acetate was collected, dried over MgSO4, filtered and evaporated to give a white solid. This was purified by silica column chromatography eluting with petrol:ethyl acetate to give acetic acid [(3,5-bis-chlorocarbonyl-2,4,6-triiodo-phenyl)-methyl-carbamoyl]-methyl ester (16.25 g, 22.9 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[C:18]([NH2:28])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: C[C@@H](OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: O=C1C[C@H](C(=O)O)CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](OCc1cc(Cl)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-ylamine (79 mg) in chloroform (0.4 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (26 mg) prepared according to the same procedures as Preparation 14 and WSC.HCl (47 mg) at room temperature, and the mixture was stirred for 2 hours. This reaction mixture was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration and was dried under reduced pressure to give the titled compound (43 mg).