Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)CCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(-c4ccco4)cc3C(F)(F)F)[C@@H]2C1

Procedure:
To a degassed solution of tetrakis(triphenylphospine)palladium(0) (3 mg, 0.002 mmol) in toluene (2 mL) was added N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (50 mg, 0.12 mmol). The resulting solution was degassed by exposure to vacuum and then an argon atmosphere (×3). To this solution was added 2-(tributylstannyl)furan (0.038 mL, 0.12 mmol). The resulting solution was degassed a final time and was then warmed to reflux conditions. The light yellow solution was maintained at reflux conditions for 14 h and became gray in color. The reaction was cooled, diluted with ethyl acetate, aqueous hydrogen chloride (1N), and saturated aqueous sodium chloride. The layers were separated and the aqueous layer was washed with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by radial chromatography (10–30% ethyl acetate in hexanes) to give the desired product as a clear residue (44 mg, 90%). MS (ESI) 423.3 (M+H).
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][CH:5]([CH:8](C)[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:26]CC)C>>[O:26]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: CC(CNS(=O)(=O)C(C)C)C1CCC(N)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)S(=O)(=O)NCCC1CCC(=O)CC1
Reaction time: 24 h
Yield: 100 %

Procedure:
N-[2-[4-aminocyclohexyl]propyl] 2-propanesulfonamide: To a suspension of 17 mg (0.45 mmol) of lithium aluminum hydride in 1 ml of diethylether, 25 mg (0.09 mmol) of the material prepared in Preparation 4 in 0.5 ml of diethyl ether was added. The mixture was stirred overnight for 24 hrs. Na2SO4.10H2O was added, and the mixture stirred for 30 min at ambient temperature. The solid was filtered and the organic solution was concentrated in vacuo. Afforded 24 mg (100%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(O)CCCCC1>[Cl:1][C:2]1[C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OC1CCCCC1
Solvent: O
Product: Nc1cc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 14 h
Yield: 84.9 %

Procedure:
Into a solution of 20.02 g of 4,5-dichloro-2-nitroaniline and 8.70 g of piperazine in 100 ml of cyclohexanol, 12.80 g of sodium carbonate was added and stirred at 150° C. for 14 hours. Cooling the reaction liquid to room temperature, water was added and the system was extracted with chloroform. The chloroform layer was dried on anhydrous magnesium sulfate and the solvent was distilled off. Thus obtained residue was washed with diisopropyl ether to provide 21.07 g of 4-chloro-2-nitro-5-(piperazin-1-yl) aniline as a yellow powder.
Reaction SMILES: C(S)CCC.[CH2:6]([N:8]([CH2:27][CH3:28])[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[C:22]([CH:23]=[C:14]2[C:13]([NH2:26])=[N:12]1)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=3)[CH3:7].[H-].[Na+].Cl.CN(C)C=[O:35]>>[NH2:26][C:13]1[NH:12][N:11]([CH2:10][CH2:9][N:8]([CH2:6][CH3:7])[CH2:27][CH3:28])[C:15]2[C:14]=1[CH:23]=[C:22]1[C:17](=[CH:18][C:19]([O:24][CH3:25])([OH:35])[CH:20]=[CH:21]1)[N:16]=2
Reactant: CN(C)C=O
Reactant: CCN(CC)CCn1nc(N)c2cc3ccc(OC)cc3nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCS
Product: CCN(CC)CCN1NC(N)=c2cc3c(nc21)=CC(O)(OC)C=C3

Procedure:
Butanethiol (5.34 ml) was added to a mixture of 13.0 g 1-[2-(diethylamino)ethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 22) and 2.0 g sodium hydride in 150 ml dimethylformamide, and the reaction mixture was heated at reflux for about 16 hours. The resulting mixture was treated with 2N hydrochloric acid to pH 7-8, the volatile materials removed by distillation and evaporation, and the residue acidified with 2N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was made strongly basic, extracted to remove starting material, and finally adjusted to PH 8 to obtain the desired product. There was obtained 2.5 g of 3-amino-1-[2-(diethylamino)ethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinolin-7-ol, orange solid, m.p. 232°-235° C.
Reaction SMILES: [N:1]1([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>ClCCl>[C:15]([N:4]1[CH2:3][CH2:2][N:1]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-piperazinyl)-tert-butoxycarboxamide (15 g) in dichloromethane (200 ml) was added acetic anhydride (7.74 ml) and pyridine (6.63 ml). The mixture was stirred at ambient temperature for 1 hour. The solution was washed with saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was collected, dried over magnesium sulfate, and concentrated. The residue was triturated with n-hexane to give N-(4-acetyl-1-piperazinyl)-tert-butoxycarboxamide (16.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[K+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(C#N)c(F)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
60 g of 3-fluoro-4-cyanophenol and 16 g of potassium hydroxide were dissolved in a solvent mixture of 600 ml of ethanol and 60 ml of water. To the resulting solution, was added dropwise 55.8 g of octyl bromide. After the completion of the addition, the obtained mixture was refluxed for six hours and then allowed to cool to room temperature. The solvent was distilled off and 300 ml of ethyl acetate was added to the residue. The organic layer was washed with water until the aqueous layer became neutral. The organic layer was dehydrated over anhydrous sodium sulfate and the solvent was distilled off. After purifying by distillation (main fraction: 0.5 mmHg, 157° to 160° C.), 63 g of 2-fluoro-4-octyloxybenzonitrile was obtained. Yield: 58%. 63 g of the 2-fluoro-4-octyloxybenzonitrile thus obtained was dissolved in 70 ml of absolute ether and 12.7 g of absolute ethanol was added thereto. The obtained mixture was cooled to -10° C. Then hydrogen chloride gas was bubbled therein for 30 minutes under stirring. After confirming that no hydrogen chloride was absorbed any more, the mixture was stirred at room temperature for 72 hours. 400 ml of absolute ether was added to the mixture. The crystals thus precipitated were filtered and vacuum-dried to thereby give 42 g of imino ester hydrochloride. Yield: 52%.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19]1([NH:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClC(Cl)Cl>[C:19]1([NH:25][C:26]2([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:28][N:29]([C:1]([O:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:10])[CH2:30][CH2:31]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1(Nc2ccccc2)CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1(Nc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3.7 parts of (phenylmethyl) carbonochloridate and 2.1 parts of N,N-diethylethanamine in 75 parts of trichloromethane is added dropwise a solution of 4.6 parts of methyl 4-(phenylamino)-4-piperidinecarboxylate in 30 parts of trichloromethane (exothermic reaction: cooling with ice-water is necessary to keep the temperature below 25° C). Upon completion, stirring is continued for 5 hours at room temperature. The reaction mixture is washed twice with water, dried filtered and evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 4.2 parts of O4 -methyl O1 -(phenylmethyl) 4-(phenylamino)-1,4-piperidinedicarboxylate; mp. 105.8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:26]I.[Cl-].[NH4+]>C1COCC1>[I:26][C:15]1[N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[N:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)n2cccn2)cc1
Reactant: II
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)n2nccc2I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
A solution of 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (2.0 g, 9.0 mmol) in THF (50 ml) was cooled to −78 C under a nitrogen atmosphere. To this was added tert butyl lithium (5.9 ml) in pentane (1.7M, 10 mmol). After 10 minutes iodine (2.53 g, 10 mmol) in THF (10 ml) was added and the reaction mixture was stirred for a further 30 minutes before allowing to warm to ambient temperature followed by stirring for 12 hours. A saturated solution of ammonium chloride was added and the mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 20-100% dichloromethane in hexane to give the product as a solid (0.96 g, 30%).
Reaction SMILES: [NH2:1][C@H:2]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[CH2:13][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[CH:11]=[CH:12][C:4]=2[CH2:3]1.[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]21[CH2:48][C:40]1[CH:41]=[N:42][C:43]([C:45](O)=[O:46])=[CH:44][C:39]=1[CH2:38]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:28]=[C:29]1[NH:37][C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]21[CH2:48][C:40]1[CH:41]=[N:42][C:43]([C:45]([NH:1][C@H:2]3[C:15](=[O:16])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=4)[CH2:13][C:5]4[C:6]5[CH:7]=[N:8][NH:9][C:10]=5[CH:11]=[CH:12][C:4]=4[CH2:3]3)=[O:46])=[CH:44][C:39]=1[CH2:38]2
Reactant: N[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Reactant: O=C(O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1Cc2ccc3[nH]ncc3c2CN(Cc2ccc(C(F)(F)F)cc2)C1=O)c1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(4-trifluoromethylbenzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one (86 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (79 mg, 0.28 mmol, described in Intermediate 5), HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (2×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1.CC(C)=[O:24]>>[F:21][C:2]([F:1])([F:20])[C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:24])=[O:13])=[CH:14][CH:15]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]=1
Reactant: O=Cc1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Reactant: CC(C)=O
Product: O=C(O)c1ccc(-n2c(C(F)(F)F)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzaldehyde (0.58 g, 2 mmol) in acetone (25 mL) was added Jone's reagent (1.0 mL, 2.0 M) at 0° C. After stirring at room temperature for 2 h, the mixture was partitioned between EtOAc and saturated NaHCO3 solution. After usual workup, the crude material was separated by silica gel chromatography (50% Hexane/EtOAc to EtOAc) to afford the intermediate acid 4-(2-Trifluoromethyl-benzoimidazol-1-yl)-benzoic acid as a while solid (490 mg).
Reaction SMILES: C([O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([Cl:14])=[CH:9][C:8]=1[NH:15][C:16]([O:18]C(C)(C)C)=O)(C)(C)C.[O:24]([C:31]1[CH:39]=[CH:38][C:34](C(Cl)=O)=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1COCC1>[Cl:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([C:6]([OH:5])=[O:23])=[C:8]([NH:15][C:16](=[O:18])[C:34]2[CH:38]=[CH:39][C:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:32][CH:33]=2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(F)cc1C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Cl)c(F)cc1C(=O)O)c1ccc(Oc2ccccc2)cc1
Reaction time: 2 h
Yield: 4 %

Procedure:
Under an atmosphere of Argon, 2-tert-butoxycarbonylamino-4-chloro-5-fluoro-benzoic acid tert-butyl ester (200 mg) and 4-phenoxy-benzoyl chloride ([1623-95-6], 269 mg) were dissolved in THF (5 mL). Triethylamine (0.24 ml) was added, and the mixture was heated to reflux overnight. The solvent was evaporated, and the residue was purified by column chromatography (silica gel/methanol/dichloromethane). The eluate, which contained two UV-absorbing components, was evaporated, and the residue was dissolved in a mixture of dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml). After 2 h, the volatiles were evaporated, and the title compound (9 mg, 0.4%) was isolated from the mixture by preparative, reversed-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 4.5 min, flow rate 30 ml/min). MS: m/e=384.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]=[O:23])[CH3:20].CCOC(C)=O>C1COCC1.Cl>[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]([C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1)[OH:23])[CH3:20]
Reactant: CCC(C=O)CC
Reactant: COc1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)C(O)c1ccnn1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a chilled reaction vessel at −78° C. containing 1-(4-methoxyphenyl)-1H-pyrazole (Tetrahedron Lett. 39(19), 2941-2944, (1998)) (1.096 g, 6.3 mmol) in THF (40 mL) was added a solution of n-butyllithium (2.5M in hexanes, 2.5 mL, 6.4 mmol) dropwise and the mixture was stirred for 1 h. 2-Ethylbutyraldehyde (0.93 mL, 7.5 mmol) was then added dropwise and, after 15 min, the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with 0.1N HCl and stirred for 15 min, then poured into a separatory funnel containing EtOAc. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The resulting oil was purified by column chromatography (SiO2, EtOAc/hexane, 1:4) to yield a pure oil in 68% yield.
Reaction SMILES: N(C(OCCCC)=O)=NC(OCCCC)=O.[CH3:17][O:18][C:19]([C:21]1[NH:22][CH:23]=[N:24][CH:25]=1)=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:49][C:48](=[O:56])[C:47]1([CH3:58])[CH3:57]>C1COCC1>[CH3:17][O:18][C:19]([C:21]1[N:22]=[CH:23][N:24]([CH:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[NH:49][C:48](=[O:56])[C:47]2([CH3:58])[CH3:57])[CH:25]=1)=[O:20]
Reactant: CC1(C)C(=O)Nc2ccccc2C1O
Reactant: COC(=O)c1cnc[nH]1
Agent: CCCCOC(=O)N=NC(=O)OCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C2c3ccccc3NC(=O)C2(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of di-butyl azodicarboxylate (145 mg, 0.6275 mmol) in 2 mL of dry THF is added dropwise to a suspension of 3H-Imidazole-4-carboxylic acid methyl ester (79 mg, 0.6275 mmol), PPh3 (165 mg, 0.6275 mmol), and 4-Hydroxy-3,3-dimethyl-3,4-dihydro-1H-quinolin-2-one (80 mg, 0.418 mg) in 3 mL of dry THF at 0° C. The resulting mixture is slowly warmed up to room temperature, and stirred for 2 h. The reaction is quenched with 2 M HCl and stirred for another 0.5 h. After concentration, the residue is dissolved in HCl (2 M) and extracted with ethyl acetate (20 mL×3). The aqueous layer is adjusted to pH 8-9 by addition of saturated NaHCO3 solution. Subsequently, the mixture is extracted with ethyl acetate (20 mL×3). The combined extracts are washed with brine, and dried over anhydrous Na2SO4. After concentration, the residue is purified by flash column first then by reverse phase HPLC and gives two title regioisomers.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH:16]1(/[CH:22]=[CH:23]/[C:24](Cl)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH:16]1(/[CH:22]=[CH:23]/[C:24]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=3[N:15]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Fc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-Cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 321.40; mp: 109.1-110.1° C.; 1H-NMR (CDCl3) δ: 8.76-8.72 (1H, m), 7.97 (1H, ddd, J=7.7, 7.7, 2.0 Hz), 7.47-7.40 (3H, m), 7.34 (1H, dd, J=9.0, 4.8 Hz), 7.11 (1H, dd, J=15.7, 7.1 Hz), 6.97 (1H, ddd, J=9.0,9.0,2.5 Hz), 6.38 (1H, dd, J=15.7, 1.3 Hz), 2.27-2.10 (1H, m), 1.84-1.57 (5H, m), 1.37-1.09 (5H, m).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(O)(=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:17][C:14]2[CH:15]=[CH:16][C:9]3[CH2:8][CH2:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:12][CH2:11][C:10]=3[CH:13]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2c(c1)CCN(C1CCCC1)CC2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCCC2)CC3)CC1

Procedure:
3-Cyclopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E4) (1.1 g, 4.8 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 5.7 mmol), di-tert-butyl azodicarboxylate (1.31 g, 5.7 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) were stirred at room temperature for 16 hours in tetrahydrofuran (20 ml). The mixture was acidified with acetic acid and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (1:9:90) to afford the title product (E5a); MS (ES+) m/e 415 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl.[CH3:28][O:29][C:30](=[O:42])[C@H:31]([CH2:40]O)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCl>[CH3:28][O:29][C:30](=[O:42])[CH:31]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:40][Cl:20]
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CCl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
A solution of triphenylphosphine (65.8 g, 0.251 mol)) and hexachloroethane (59.4 g, 0.251 mol) in dichloromethane (850 mL) was added in one portion to a solution of N-Boc-serine methyl ester (50 g, 0.228 mol) in dichloromethane (170 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and then the reaction was quenched with a saturated solution of NaHCO3 (150 mL). The organic product was extracted with dichloromethane (2×300 mL) and the combined organic layers was washed with brine (300 mL) and dried over anhydrous sodium sulphate. The solution was concentrated under reduced pressure and then triturated with Et2O (500 mL). After filtration and evaporation of the solvent, the crude product was purified by chromatography on a silica column eluted with 6-8% EtOAc in pet ether) which gave the title compound (42 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:23](Cl)(=[O:25])=[O:24])([CH3:13])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:23]([C:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[S:18][C:14]=1[CH:11]([CH3:13])[CH3:12])(=[O:24])=[O:25]
Reactant: Cc1noc(N)c1Br
Reactant: CC(C)c1sc2ccccc2c1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(C(C)C)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 using 4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 9.7 mg), NaH (1.4 mmoles, 5.5 mg), 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride (0.60 mmoles, 0.17 g) and THF (2 ml). Recrystallization from chloroform and hexanes provided 89 mg (39%) of a tan crystalline solid, m.p. 157.5°-159° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[S:45][CH2:44][C:43](=O)[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][NH:4][CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[S:45][CH2:44][CH2:43][N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)CSc2ccc(CCl)cc21
Product: COCCCN1CCSc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.570 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.359 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]thiazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.27 (1:1 EtOAc-heptane); Rt=6.14.