Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CCN(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCn1nc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
To a solution of ethyl 3-tert-butyl-1-(2-(dimethylamino)ethyl)-1H-pyrazole-5-carboxylate (0.47 g, 1.8 mmol) in THF (10 mL) was added aqueous LiOH (0.22 g, 5.3 mmol, 5 mL) and the mixture was stirred for 16 h at RT. Solvents were removed, the thick liquid was diluted with water (5 mL) and acidified with 50% aq. acetic acid solution to pH 5-6. The product was extracted with EtOAc (2×50 ml) and the combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 3tert-butyl-1-(2-(dimethylamino)ethyl)-1H-pyrazole-5-carboxylic acid as a pasty mass (0.12 g, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.56 (s, 1H), 4.66 (t, J=6.0 Hz, 2H), 3.17 (t, J=6.0 Hz, 2H), 2.53 (s, 6H), 1.17 (s, 9H); MS (ESI) m/z: 240.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([I:9])=[CH:4][C:3]=1[OH:10].N1C=CC=CC=1.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[S:18]([O:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([I:9])=[CH:4][C:3]=1[O:10][S:18]([C:21]([F:22])([F:23])[F:24])(=[O:17])=[O:19])(=[O:19])=[O:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cc(I)c(I)cc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cc(I)c(I)cc1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a flame-dried round-bottomed flask was added 1,2-dihydroxy-4,5-diiodobenzene (1 equiv., 7.85 mmol, 2.84 g), CH2Cl2 (55 mL), and pyridine (5 equiv., 39 mmol, 3.10 g, 3.16 mL). The solution was cooled to 0° C. and Tf2O (2.2 equiv., 17.3 mmol, 4.88 g, 2.91 mL) was added dropwise via syringe over 10 min. The reaction was stirred for 6 h while warming to ambient temperature, then cooled to 0° C. and quenched with H2O (30 mL). The separated aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried with MgSO4 and filtered through a tall pad of silica. The pad was washed carefully with CH2Cl2 to avoid the elution of impurities, and the filtrate was concentrated in vacuo to afford 4,5-diiodo-1,2-phenylene bis(trifluoromethanesulfonate) (4.90 g, 7.82 mmol, quantitative) as an off-white solid. The product is optionally purified by column chromatography (10% EtOAc/Hex). TLC Rf=0.60 (10% EtOAc/Hex); Melting point 46.5-47.7° C.; 1H NMR (400 MHz): δ 7.91 (s, 2H); 13C NMR (100 MHz): δ 139.6, 133.4, 118.5 (q, JC,F=321.0 Hz), 108.0. FTIR: 1429, 1335, 1215, 1125, 1105, 868, 788, 745, 689 cm−1. HRMS-ESI: calc. for C8H2F6I2NaO6S2 (M+Na)+: 648.7184. found: 648.7164.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:7]([C:16]([OH:18])=O)=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2>C(Cl)Cl>[OH:5][C:6]1[C:7]([C:16]([Cl:3])=[O:18])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: ClCCl
Product: O=C(Cl)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
Thionyl chloride (906 mg, 7.61 mmol) was added drop wise to a cold solution of 8-hydroxyquinoline-7-carboxylic acid (1.2 g, 6.34 mmol) in dry DCM (18 mL). The reaction mixture was allowed to warm to RT and was then stirred under nitrogen for 4 h. The reaction mixture was then concentrated to dryness affording the title compound (1.3 g, 6.26 mmol) that was used in the next steps without any further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)C)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][CH2:10][CH2:11][N:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1
Reactant: CN(CCN1Cc2ccccc2C1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNCCN1Cc2ccccc2C1

Procedure:
A mixture of the title compound of Step 15 (2.00 g, 7.51 mmol) and 20% Pd(OH)2 /C in MeOH (50 mL) was placed under a hydrogen atmosphere (60 psi) at room temperature for 37 hours. The filtrate was concentrated to give the title compound as a clear, yellow oil (1.34 g). The proton NMR spectral data showed that the desired product was contaminated with a small amount of unreacted starting material (5%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][C:35](=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCCCC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-n-pentanoylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][C:36]3[CH:40]=[C:41]([S:45](Cl)(=[O:47])=[O:46])[C:42]([F:44])=[CH:43][C:35]2=3)=[C:30]([O:49][CH3:50])[CH:29]=1)#[N:27]>C1COCC1>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][C:36]3[CH:40]=[C:41]([S:45]([NH:8][C:9]4[S:10][CH:11]=[CH:12][N:13]=4)(=[O:47])=[O:46])[C:42]([F:44])=[CH:43][C:35]2=3)=[C:30]([O:49][CH3:50])[CH:29]=1)#[N:27]
Reactant: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Cl)c(F)cc21
Reactant: COc1ccc(CNc2nccs2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)c(F)cc21
Reaction time: 1 h

Procedure:
To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.055 g, 0.250 mmol) was added THF (0.743 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.273 ml, 0.273 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(4-cyano-2-methoxyphenyl)-6-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.087 g, 0.227 mmol) in THF (0.6 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was stirred for 1 hr (ice melt) providing a brown solution and product as the primary species according to LC-MS (m/z=567) with consumption of starting material. The solution was added to ice, the mixture diluted with EtOAc and extracted with water and EtOAc. The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material, a light yellow/brown foam (115 mg) was added DCM (5 ml) and TFA (1.5 ml) and the mixture stirred at room temp for 60 mins affording about 85% conversion to desired product. Stirring for another hr did not afford further conversion. Additional TFA (1 ml) was added and stirring at room temperature continued. After another hr LC-MS indicated no further conversion.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3].[F:7][CH:8](C)[CH:9](O)CO>[OH-].[K+]>[F:7][CH:8]([CH:3]1[CH2:5][O:4][C:1](=[O:6])[O:2]1)[CH3:9]
Reactant: CC(F)C(O)CO
Reactant: COC(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CC(F)C1COC(=O)O1
Temperature: 60 °C
Reaction time: 12 h
Yield: 136 %

Procedure:
2.0 g of potassium hydroxide and 50 g of dimethyl carbonate were added to 108.0 g (1.00 mol) of 3-fluoro-1,2-butanediol, and the resulting mixture was stirred at 60° C. for 12 hours. After filtering off potassium hydroxide, the mixture was distilled to obtain 101.2 g of 4-(1-fluoroethyl) -1,3-dioxolan-2-one (yield 75.5%). An elemental analysis was performed and the following values were observed:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([CH2:14][O:15]S(C)(=O)=O)[N:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.[OH-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([CH2:14][O:15][C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)=[CH:32][CH:31]=2)[N:13]=1
Reactant: CS(=O)(=O)OCC1COC(c2c(F)cccc2F)=N1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1C1=NC(COc2ccc(-c3ccc(Cl)cc3)cc2)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.2 %

Procedure:
A mixture of 200 mg (0.687 mmol.) of 2-(2,6-difluorophenyl)-4-methanesulfonyloxymethyl-2-oxazoline, 232 mg (1.00 mmol.) of 4-(4-chlorophenyl)phenol, 24 mg (1.0 mmol.) of sodium hydroxide and 3 ml of N,N-dimethylformamide was stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was poured into 50 ml of a 10% aqueous solution of ammonium chloride and extracted twice with ethyl acetate. The residue was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 50 mg of 2-(2,6-difluorophenyl)-4-{[4-(4-chlorophenyl) phenoxy]methyl}-2-oxazoline as a white solid (m.g. 99.5° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1
Reactant: COCCNCCOC
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CCOC)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of N,N-bis(2-methoxyethyl)amine (2.40 g) and triethylamine (2.27 g) in dichloromethane (30 ml) was added 3-nitrobenzoyl chloride (2.78 g) in an ice-water bath. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified with column chromatography eluting with dichloromethane-methanol to give N,N-bis(2-methoxyethyl)-3-nitrobenzamide (4.12 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[N:39][CH:40]=2)O1.C(=O)(O)[O-].[Na+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:42]([NH:41][C:38]1[N:39]=[CH:40][C:35]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:36][CH:37]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3cnn(C(C)C)c3c2)cn1
Temperature: 120 °C
Yield: 80.2 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.24 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]acetamide (104 mg, 0.4 mmol) in DME/water (3 mL:1 mL). PdCl2(dppf)-CH2Cl2 (10.76 mg, 0.013 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (66.4 mg, 0.79 mmol) was added, the vessel was sealed, and the insoluble mixture was heated in a microwave at 120° C. for 20 min. Water was added and the solids that precipitated were filtered off. DCM was added to the solids and it was purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOAc was added, it was sonicated and the solids that precipitated were filtered, washed with hexanes and dried to afford the title compound (91 mg, 72%) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 10.65 (s, 1H) 8.84 (d, J=2.27 Hz, 1H) 8.64 (t, J=4.93 Hz, 1H) 8.39 (s, 1H) 8.25-8.30 (m, 1H) 8.15-8.24 (m, 2H) 7.89-7.93 (m, 1H) 5.89 (s, 1H) 5.18 (quin, J=6.63 Hz, 1H) 4.40 (d, J=4.80 Hz, 2H) 2.22 (s, 3H) 2.13 (s, 3H) 2.12 (s, 3H) 1.51 (s, 3H) 1.50 (s, 3H). MS (ES) [M+H]+ 473.1.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16](OC)=[O:17])=[N:10]1)[CH3:8]>C1COCC1>[CH2:7]([N:9]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([CH2:16][OH:17])=[N:10]1)[CH3:8]
Reactant: CCc1cn(CC)nc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cn(CC)nc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Lithium aluminum hydride (433 mg, 11.4 mmol) was stirred in anhydrous THF (50 mL). A solution of methyl 1,4-diethyl-1H-pyrazole-3-carboxylate (1.28 g, 7.6 mmol) in anhydrous THF (10 mL) was added at 0° C., and then stirred at room temperature for 1.5 hours. The reaction was quenched with an aqueous solution of sodium hydroxide and extracted 5 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (1,4-diethyl-1H-pyrazol-3-yl)methanol was obtained (710 mg, 65% yield) and used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH2:14][OH:15])=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH2:14][OH:15])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cn2ccnc2CO)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cn2ccnc2CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
A mixture of [1-(4-nitrobenzyl)-1H-imidazol-2-yl]methanol (3.6 g), 10% palladium carbon (400 mg) and ethanol (50 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave [1-(4-aminobenzyl)-1H-imidazol-2-yl]methanol (2.53 g, 95%) as colorless prism crystals. melting point: 125° C. (decomposition)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:7])=[O:6].C(=O)(O)[O-].[Na+].[C:13]([O:18][CH:19]([O:21][C:22](OC1CC(=O)NC1=O)=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]>O.C(#N)C.C(OCC)C>[C:13]([O:18][CH:19]([O:21][C:22]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:7])=[O:6])=[O:23])[CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: NCCCS(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CC(OC(=O)NCCCS(=O)O)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-aminopropylsulfinic acid (10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) is added a solution of compound (17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction is stirred at ambient temperature for 16 h. The reaction mixture is diluted with diethyl ether (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 mL). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (31) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:24])=[N:10][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([F:36])[CH:35]=1>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]3[NH:8][C:7]4[C:2]([C:32]5[CH:31]=[C:30]([F:29])[CH:35]=[C:34]([F:36])[CH:33]=5)=[CH:3][C:4]([C:25]([F:27])([F:26])[F:28])=[CH:5][C:6]=4[N:10]=3)[C@H:12]([CH3:24])[CH2:13]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: C[C@@H]1CN(c2ncccc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)cc(F)c3)c2[nH]1

Procedure:
7-Bromo-2-[(2R)-4-(3-chloropyridin-2-yl)-2-methylpiperazin-1-yl]-5-(trifluoromethyl)-1H-benzoimidazole (95 mg, 0.2 mmol, Example 77) and 3,5-difluoro-phenylboronic acid (39 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 508 (M+1).
Reaction SMILES: OCCOP(CC1C=CC(N)=C(OC)C=1)(=O)OCCO.[F:21][C:22]([F:46])([F:45])[CH2:23][O:24][P:25]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[C:36]([O:43][CH3:44])[CH:35]=1)(=[O:32])[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[F:46][C:22]([F:21])([F:45])[CH2:23][O:24][P:25]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([O:43][CH3:44])[CH:35]=1)(=[O:32])[O:26][CH2:27][C:28]([F:29])([F:30])[F:31]
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1[N+](=O)[O-]
Agent: COc1cc(CP(=O)(OCCO)OCCO)ccc1N
Product: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1N
Yield: 77 %

Procedure:
The title compound was prepared according to the procedure for Compound 113A using bis(2,2,2-trifluoroethyl)(3-methoxy-4-nitrobenzyl)phosphonate (Compound 114B, 2.8 g, 6.81 mmol). The reaction mixture was filtered and the filtrate was concentrated to give the desired product (2 g, 77%). 1H NMR (DMSO-d6, 400 MHz): δ=3.29 (d, J=21.2 Hz, 2H), 3.68 (s, 3H), 4.50-4.61 (m, 4H), 4.64 (s, br, 2H), 6.50-6.60 (m, 2H), 6.67 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([S:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Sc2ccncc2)cc1)N1CCCC1CN1CCCC1

Procedure:
For example, (4-bromo-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-yl)methanone (where Y═Br) is treated with a suitable nucleophile, in this case, 4-mercaptopyridine in a suitable solvent such as DMF with potassium carbonate and the reaction heated to reflux for 1-3 days to yield [4-(pyridin-4-ylsulfanyl)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1>>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ccc(I)cn1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nc2)CC1
Yield: 43.2 %

Procedure:
tert-butyl 4-piperidinylcarbamate (0.30 g, 1.50 mmol; Astatech) and 2-chloro-5-iodopyridine (0.287 g, 1.50 mmol; Aldrich) were processed according to the procedure of Example 1A to provide the title compound as a yellow oil (0.202 g, 43%). (DCI/NH3) m/z 312 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]([CH3:44])[CH3:43])[CH:37]=1>C1COCC1.CN(C=O)C.O>[C:33]([C:27]1[CH:28]=[N:29][C:30]2[C:25]([C:26]=1[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:42]([CH3:43])[CH3:44])[CH:37]=1)=[CH:24][C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])=[CH:32][CH:31]=2)#[N:34]
Reactant: CC(C)c1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C(C)C)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
Dissolved 695 mg (8.27 mmol) 2-butynoic acid in 40 ml THF and chilled to 0° C. under N2. Added 1.08 ml (8.30 mmol) isobutyl chloroformate and 910 μl (8.27 mmol) N-methylmorpholine and stirred for 10 minutes. Dropwise added a solution of 1.00 g (3.31 mmol) 6-amino-4-[(3-isopropylphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml DMF and 15 ml THF. Removed ice bath at 15 minutes and stirred at 25° C. overnight. Stripped solvent, slurried residue with water, and collected solid. Recrystallized from ethyl acetate and dried in vacuo, giving 329 mg of yellow-green solid: mass spectrum (electrospray m/e): M+H=369.2.
Reaction SMILES: [NH2:1][C:2]1C=C(OC)C=C[C:3]=1C1CCCC2C=C(O)C=CC=2C1.[Si:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]2[CH2:39][CH:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3N)[CH2:37][CH2:36][CH2:35][C:34]=2[CH:49]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]2[CH2:39][CH:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=3[CH2:3][CH2:2][NH2:1])[CH2:37][CH2:36][CH2:35][C:34]=2[CH:49]=1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:23])[CH3:24]
Reactant: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(N)c1
Reactant: COc1ccc(C2CCCc3cc(O)ccc3C2)c(N)c1
Product: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCN)c1

Procedure:
Synthesized from 6-(2-amino-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol according to an analogous synthetic method to Example 201 described below, 2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenylamine (1.3 g) was used according to an analogous synthetic method to Example 36 to provide the title compound (1.1 g).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C@H:4]([OH:19])[CH2:5][O:6][C:7]([CH3:18])([CH3:17])[CH2:8][N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:7]([CH3:18])([CH3:17])[O:6][CH2:5][C@@H:4]([OH:19])[CH2:3][N:2]([CH3:1])[CH3:20])[N:10]=1
Reactant: [H][H]
Reactant: CN(C)C[C@H](O)COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C[C@H](O)COC(C)(C)Cn1ccc(N)n1
Yield: 86.9 %

Procedure:
Compound (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol was prepared by reacting 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole (0.39 g, 1.62 mmol), isopropyl alcohol (6 mL), and dimethylamine (3 mL, 6 mmol, 2 M in dioxane) under microwave conditions at 130° C. for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure to yield (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.4 g, 87%). This compound was reduced under the following conditions. The mixture of (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.39 g, 1.66 mmol), ethyl acetate (30 mL), ethanol (30 mL) was added to a Parr bottle with 10% Pd/C (0.22 g) and subjected hydrogen gas (20 psi) for 2 h under the Parr Shaker Apparatus conditions. Work up by filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (S)-1-[2-(3-amino-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-3-dimethylamino-propan-2-ol as an oil (0.37 g, 97.5%).