Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[N:7][OH:8])CCC[CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>C(Cl)Cl>[N:7]([CH:1]([O:18][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=1)[CH2:2][CH3:3])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: ON=C1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CCC(N=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of cyclohexanone oxime (3.11 g, 42.58 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (18.88 g, 42.58 mmol) and 4-nitrobenzoic acid (71.16 g, 425.8 mmol) in methylene chloride (300 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL) and 3% sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was recrystallized in diethyl ether/petroleum ether (1:1) in a −5° C. freezer to give 1-Nitroso-1-para-nitrobenzoxypropane as bright blue crystals (25-30% yield): Rf 0.5 (pentane/ethyl acetate=20:1); 1H NMR (300 MHz, CDCl3) δ 1.69 (s, 6H), 8.31-8.48 (d, 4H); 13C NMR (300 MHz, CDCl3) δ 21.1 (2CH3), 122.6 (O—C—N), 124.0 (2Ph-CH), 131.4 (2Ph-CH), 135.6 (Ph-C), 151.2 (Ph-C), 162.9 (C═O).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([NH:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6](Cl)=[N:7][CH:8]=1.[CH3:14][S:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(#N)C>[Br:2][C:3]1[C:4]([NH:10][CH:11]([CH3:13])[CH3:12])=[N:5][C:6]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([S:15][CH3:14])[CH:17]=2)=[N:7][CH:8]=1
Reactant: CSc1cccc(N)c1
Reactant: CC(C)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: CSc1cccc(Nc2ncc(Br)c(NC(C)C)n2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
0.14 ml of a 4 molar solution of hydrogen chloride in dioxane and 0.17 ml of water are added to a solution of 0.152 g (0.61 mmol) of (5-bromo-2-chloropyrimidin-4-yl)-isopropylamine and 0.077 g (0.55 mmol) of 3-methylsulphanylphenylamine in 2 ml of acetonitrile, and the mixture is then stirred at 50° C. for 24 hours. After cooling, the mixture is added to saturated sodium bicarbonate solution. It is extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. Removal of the solvent and recrystallization of the residue from ethyl acetate/hexane 9/1 result in 0.17 g (79% of theory) of the product.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]2[CH2:14][C:15](=[CH:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][C:29]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)([OH:32])[CH2:28][CH2:27]3)[C:16]3[C:17]([O:22][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[N:18][CH:19]=[CH:20][CH:21]=3)(=O)C.[OH-].[Na+].O.C(OCC)(=O)C>C(O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:29]2([OH:32])[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH:23]=[C:15]3[C:16]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[O:22][C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:13]=4[CH2:14]3)[CH2:31][CH2:30]2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: OCCOc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Yield: 92.8 %

Procedure:
To a solution of 1-[3-(7-(2-acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol (Example 50)(140 mg) in ethanol (5 ml) were added 15% sodium hydroxide aqueous solution (2 ml) and the mixture was heated to reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[C:4]([CH3:16])[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30]([N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:16])[CH3:15])=[O:31]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CNc1cnccc1-c1ccc(F)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 4-(4-fluoro-2-methylphenyl)-N-methylpyridin-3-amine (60 mg, 0.28 mmol, example 23, intermediate a) and DIPEA (97 μL, 0.56 mmol) was added 3,5-dichlorobenzoyl chloride (87 mg, 0.42 mmol, CAS RN 2905-62-6) in CH2Cl2 (2 mL). After stirring for 16 hours, the reaction mixture was loaded directly onto a silica gel column and elution with EtOAc gave the title compound (43 mg, 40%). MS (ESI): m/z=388.9 [M+H]+.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6]OCC1.[CH2:8]1[CH2:12]O[CH2:10][CH2:9]1.[CH:13]([OH:16])([CH3:15])[CH3:14]>>[OH:16][C:13]1[CH:15]=[C:9]([CH3:10])[CH:8]=[CH:12][C:14]=1[CH2:6][CH2:7][OH:2]
Reactant: CC(C)O
Reactant: C1COCCO1
Reactant: C1CCOC1
Agent: Cl
Product: Cc1ccc(CCO)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Part C. A solution of the MOM compound from Part B (1.84 g, 9.38 mmol) was dissolved in 1:1 THF-isopropanol (20 mL), and treated with HCl in dioxane (2.5 mL, 4 N, 10.0 mmol). The reaction was stirred at ambient temperature overnight. Aqueous workup gave sufficiently pure product, 2-(2-hydroxy-4-methylphenyl)ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][O:13][CH:12]([CH2:17][NH2:18])[C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CCOC2CN
Yield: 72.8 %

Procedure:
To a mixture of 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (6.0 g, 0.014 mol) in ethanol (100 ml) was added hydrazine hydrate (1.4 ml, 0.028 mol). The reaction mixture was heated at reflux for 1 h, cooled and the precipitate filtered off. The filtrate was evaporated in vacuo and to theresidue was added water (100 ml) and the resulting mixture was extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 2.9 g (71%) of 2-amino-7-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[N:14]([C:16]1(O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH2:17]1)=O.C([OH:29])C>>[CH3:1][N:2]1[C:3]2([O:29][C:17]3[CH:18]=[CH:19][C:20]4[C:25]([C:16]=3[N:14]=[CH:13]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:4]([CH3:11])([CH3:12])[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCO
Reactant: O=NC1(O)CC=Cc2ccccc21
Reactant: C=C1N(C)c2ccccc2C1(C)C
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(ccc3ccccc13)O2

Procedure:
A mixture of 1,3,3-trimethyl-2-methyleneindoline (3.62 g; 0.021 mol) and 1-nitroso-naphthol (3.46 g; 0.02 mol) in ethanol (80.0 ml) was heated under reflux for 2 h. The solution was evaporated and the residue flash-chromatographed over silica (eluent: dichloromethane) to give 1,3,3-trimethylspiro[2H-indole-2,3'-3H-naphth[2,1-b][1,4]oxazine] as a pale yellow solid (3.96 g; 60%), m.pt. 127°-130° C. ##STR29##
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:9]Br)[CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:9][NH:4][CH2:3][CH2:2][OH:1])[CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrCC1CCC1
Product: OCCNCC1CCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3-chloro-2-methylphenyl isothiocyanate to give 2-(3-chloro-2-methylphenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][CH2:21]S)[CH2:18][C@@H:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:16]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[CH2:15][C:14]=2[CH:36]=1)#[N:9]>C1COCC1.C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH2:20][CH2:21][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C@@H:17]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:16]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:31])=[O:32])[CH2:15][C:14]=2[CH:36]=1)#[N:9]
Reactant: CS(N)(=O)=O
Reactant: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCS)C[C@H]1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCS(=O)(=O)N1Cc2cc(C#N)ccc2N(CCNS(C)(=O)=O)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonamide (23.8 mg, 0.25 mmol) was added to a suspension of sodium hydride (10 mg, 0.25 mmol, 60% in oil, washed with hexanes) in THF (1.5 mL). The mixture was stirred at rt for 30 min. and Compound B of Example 27 (47.6 mg, 0.1 mmol) was added. The resulting mixture was stirred at reflux temperature for 16 hours. The reaction mixture was cooled to rt, diluted with DCM (10 mL) and washed with water. The DCM solution was dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC (Column: YMC S-5 ODS 100×20 mm; UV: 220 nm; Flow rate: 20 mL/min; solvent: gradient from 50-90% MeOH in water containing 0.1% TFA in 10 min.). The fractions containing the desired products were pooled and concentrated to afford the title compound as a colorless foam, 5.2 mg (10.6%) MS m/e 491 (M+H)+; 489(M−H)−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:12]([NH:14][CH2:15][CH3:16])=O)[CH2:11][CH2:10]CC=1.[CH3:17][CH2:18]OCC>>[CH:16]1([CH2:15][NH:14][CH2:12][CH:7]2[CH2:11][CH2:10]2)[CH2:18][CH2:17]1
Reactant: CCOCC
Reactant: CCNC(=O)C1=CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C1CC1CNCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of lithium aluminum hydride (1.3 g, 9.35 mmol) in 10 mL dry ether, a solution of N-cyclopentenoyl-ethylamine (1.7 g, 13.3 mmol) in dry ether (10 mL) was added under a nitrogen atmosphere. This reaction was stirred at RT for 8 h and the reaction mixture was then quenched with saturated sodium sulfate solution, filtered, and the precipitate was washed with diethyl ether. The filtrate was concentrated to afford the title amine (0.8 g, yield: 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:40]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:41])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(C1CCCCC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
(5-Chloro-benzo[1,3]-dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.22 mmol) and DIEA (0.11 mL, 0.66 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclohexanecarbonyl chloride (0.04 mL, 0.26 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 71 (43 mg, 33% yield) as a white fluffy solid. LC-MS (M+H=453, obsd.=453).
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:23][CH:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:21]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1.[C:36]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:35][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH:22]([N:24]([CH3:36])[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23]3)[N:9]=2)[C:6]2[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NS(C)(=O)=O)C2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(N(C)S(C)(=O)=O)C2)n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a solution of compound N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide (Example 30) (182 mg, 0.36 mmol) in DMF (4 mL) was added dry powdered K2CO3 (1.0 g, 7.3 mmol) and iodomethane (0.5 mL, excess). The reaction mixture was stirred at 20° C. for 20 hrs and diluted with water. The resulting precipitate was collected by filtration, washed with water, and dried. Recrystallization from CH2Cl2/MeOH gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}-N-methylmethanesulfonamide in 83% yield: mp (CH2Cl2/MeOH) 290-291; 1H NMR (DMSO-d6) δ7.99 (d, J=7.8 Hz, 1H), 7.75 (t, JHF=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 4.78-4.71 (m, 1H), 4.46-4.26 (m, 4H), 3.98 (s, 3H), 3.80-3.79 (m, 4H), 3.69 (m, 4H), 2.93 (s, 3H), 2.91 (s, 3H); Anal. Calcd. for C21H26F2N8O4S: C, 48.1; H, 5.0; N, 21.4. Found: C, 47.9; H, 4.9; N, 21.5%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
Starting materials: (2{-(E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A7) (0.460 mmol), CH2Cl2 (50 ml), TFA (5 ml). Reaction conditions: room temperature, 18 hours.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12]Cl)=[C:8]([C:14]([Cl:17])([Cl:16])[Cl:15])[CH:7]=1)([O-:5])=[O:4]>C(OCC)C>[CH3:1][NH:2][S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=1[C:14]([Cl:17])([Cl:16])[Cl:15]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: CCOCC
Product: CNSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
At 0° C., 10 liters of methylamine is passed into a solution of 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 200 ml of diethyl ether. After the mixture has been stirred for 6 hours at 25° C., it is poured onto ice water, and the aqueous phase is separated and evaporated to dryness. There is obtained 51 g (85% of theory) of N-methyl-4-nitro-2-trichloromethylphenylsulfenamide as an oil (nD20 :1.6610).
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:38].S>C(O)C>[C:1]1([C:7]2[S:38][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[CH:9][C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)c1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc1
Agent: S
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc1

Procedure:
A 1-liter stirred autoclave was charged with 55.6 g (0.150 mole) of 1,2-diphenyl-4-p-t-butylphenylbutane-1,4-dione, 100 ml of xylene, 33.3 g (0.075 mole) of phosphorus pentasulfide and 130 g of hydrogen sulfide. The reactor was cooled and vented. The residue was stirred with 150 ml of absolute ethanol. Filtration gave a first crop of 18 g (32.6%) m.p. 108°-112° C. Chilling the filtrate and refiltering gave a second crop of 24 g (43.4%) m.p. 102°-105° C. The two crops were combined for recrystallization from a mixture of 50 ml of dioxane and 100 ml of absolute ehtanol. The pure product (31.3 g, 56.6%) had a m.p. of 117°-119° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH:13]=[CH:12][S:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2sccc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3sccc23)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
To a vial containing 4-chloro-5-nitrothieno[2,3-b]pyridine (138.2 mg, 0.6439 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 325.5 mg, 1.625 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA (201.4 mg, 1.558 mmol), then the mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (228.4 mg, 94%). LCMS calc. for C17H23N4O4S (M+H)+: m/z=379.1. found 379.2.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]#N)[CH:6]=1)([CH3:4])[CH3:3].[OH-:17].[Na+].[OH2:19].Cl>C(O)C>[OH:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]([OH:19])=[O:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: [OH-]
Reactant: O
Reactant: CC(C)(O)c1cc(C#N)nc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(O)c1cc(C(=O)O)nc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To a solution of 4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridine-2-carbonitrile (0.088 g, 0.38 mmol, from Step C) in ethanol (4 mL) was added 1.0M sodium hydroxide in water (1.5 mL, 1.5 mmol) and the reaction was heated to 90° C. for 20 minutes. Upon cooling to room temperature, the reaction was acidified by the addition of 1N HCl to achieve pH 5 and the ethanol was removed in vacuo. The remaining aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were dried over sodium sulfate, decanted and concentrated to afford product, used without further purification (80 mg, 84%). 1H NMR (400 MHz, CD3OD) δ 8.43 (d, J=1.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 1.57 (s, 6H); 19F NMR (376 MHz, CD3OD) 5-69.39 (s); LCMS (M+H)+: 250.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2C2CCCCO2)=[C:8]([NH2:23])[N:7]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:1][CH:2]([CH3:24])[CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[NH:12]2)=[C:8]([NH2:23])[N:7]=1
Reactant: COc1nc2c(N)nc(OCCC(C)C)nc2n1C1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1nc2c(N)nc(OCCC(C)C)nc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(3-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (210 mg) in dry MeOH (2.1 mL) was added TFA (0.21 ml) and the mixture was stirred at room temperature for 24 h. The reaction was concentrated in vacuo to give a yellow residue which was triturated with Et2O (15 mL) and filtered under reduced pressure to give the title compound as an off-white solid (143 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]([OH:25])=O)[C:13]3=[O:29])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:42]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1.O>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]([CH:21]([CH2:26][CH2:27][CH3:28])[CH2:22][C:23]([NH:51][S:48]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)(=[O:50])=[O:49])=[O:25])[C:13]3=[O:29])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: C1CCOC1
Product: CCCC(CC(=O)NS(=O)(=O)c1ccccc1)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid (56 mg, 0.14 mmol) is dissolved in dry THF (1.0 mL) and 1,1′-carbonyl diimidazole (50 mg, 0.29 mmol) is added into it at room temperature. The mixture is stirred for 30 min and then it is heated at 55° C. for 1 hr. After the mixture is cooled down to room temperature, benzenesulfonamide (46 mg, 0.29 mmol) is added and after 10 min, 1,8-diazabicyclo[5,4,0]undec-7-ene (0.044 mL, 0.29 mmol) is added. The mixture is stirred for 3 hr at room temperature. Then 1.0 M HCl (3 mL) is added followed by water (30 mL). The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC using 2% MeOH in CH2Cl2 affords 63 mg (84%) of N-{3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]hexanoyl}-benzenesulfonamide. LCMS (ESMS): m/z 548.11 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:25])[NH:8][C:9]3[C:10]([N:16](C)[CH2:17]C4C=CC=CC=4)=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2].C(O)C.[OH-].[Na+]>[Pd]>[CH2:1]([C:3]1[N:15]2[C:6]([C:7](=[O:25])[NH:8][C:9]3[C:10]([NH:16][CH3:17])=[N:11][CH:12]=[N:13][C:14]=32)=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncc2c(=O)[nH]c3c(N(C)Cc4ccccc4)ncnc3n12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1ncc2c(=O)[nH]c3c(NC)ncnc3n12

Procedure:
Prepared by hydrogenation of the product of Example 19 with palladium on carbon in ethanol containing 2 eq. NaOH, at 50 psi and 50° C. for 24 h. The catalyst was removed and the product was precipitated by addition of a saturated solution of ammonium chloride. The solids were filtered and washed with water and ethanol to provide the title compound.