Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCC1C(C2C=CC=CC=2Cl)=NC2C(N=1)=C(Cl)C=CC=2.Br[CH2:22][C:23]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:40])[N:24]=1.CN(C=O)C.[N-:46]=[N+:47]=[N-:48].[Na+]>>[N:46]([CH2:22][C:23]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[Cl:40])[N:24]=1)=[N+:47]=[N-:48]
Reactant: Clc1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: Clc1ccccc1-c1nc2cccc(Cl)c2nc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc2cccc(Cl)c2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirring solution of a mixture of 3-(bromomethyl)-5-chloro-2-(2-chlorophenyl)quinoxaline and 2-(bromomethyl)-5-chloro-3-(2-chlorophenyl)-quinoxaline (8.5418 g, 23.21 mmol) in DMF (100.0 mL, 23.21 mmol) was added sodium azide (3.017 g, 46.42 mmol) at room temperature and the mixture was stirred at room temperature. After 40 min, the mixture was partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with brine (100 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-(azidomethyl)-5-chloro-3-(2-chlorophenyl)quinoxaline as a brown liquid: LC-MS (ESI) major peak of m/z 330.1 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1(O)[CH:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:7][C:16]1([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][N:10]=2)[CH:21]2[CH2:22][N:18]([CH2:19][CH2:20]2)[CH2:17]1
Reactant: OC1(c2cnccn2)CN2CCC1C2
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: FC1(c2cnccn2)CN2CCC1C2
Reaction time: 24 h
Yield: 14.8 %

Procedure:
Diethylaminosulphur trifluoride (0.42 g, 2.62 mmol) was added to a stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (0.5 g, 2.62 mmol) in dichloromethane (30 ml), at -65° C. After 24 h, water (20 ml) was added, basified with potassium carbonate, and extracted into dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4), evaporated, and the residue chromatographed through silica-gel, eluting with dichloromethane-methanol (90:10) to give 3-fluoro-3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptane (75 mg). The compound was further purified as the hydrogen chloride salt, m.p. 245° C. (dec.) (isopropylalcohol); (Found: C, 52.33; H, 5.79; N, 17.97. C10H12F.HCl requires C, 52.29; H, 5.66; N, 18.30%) m/e 193 (M+ for free base); δ(360 MHz, CDCl3) 1.06-1.13 (1H, m, CH of CH2 --N); 1.44-1.55 (1H, m, CH of CH2 --N); 2.58 (1H, dd, J=3.1 and 9.7 Hz, CH of CH2 --N); 2.65-2.72 (1H, m, CH of CH2 --N); 2.83-2.91 (2H, m, CH-bridgehead and CH of CH2 --N); 3.09-3.24 (2H, m, 2 of CH of CH2 --N); 3.59 (1H, ddd, J=3.1, 13.6 and 20.8 Hz, CH of CH2 --N); 8.50-8.53 (2H, m, 2 of pyrazine-H); 8.91 (1H, d, J=1.2 Hz, pyrazine-H).
Reaction SMILES: NCC(N1C2C(=CC(/C=C/[CH:16](C3C=C(Cl)C(F)=C(Cl)C=3)[C:17]([F:20])([F:19])[F:18])=CC=2)C=C1)=O.[Cl:30][C:31]1[CH:32]=[C:33]([CH:39]([C:62]([F:65])([F:64])[F:63])/[CH:40]=[CH:41]/[C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[N:47]([C:51](=[O:61])[CH2:52][NH:53][C:54](=[O:60])OC(C)(C)C)[CH:46]=[CH:45]3)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:39]([C:62]([F:65])([F:63])[F:64])/[CH:40]=[CH:41]/[C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[N:47]([C:51](=[O:61])[CH2:52][NH:53][C:54](=[O:60])[CH2:16][C:17]([F:20])([F:19])[F:18])[CH:46]=[CH:45]3)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(F)(F)F)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(E)-2-Amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone (BI23): To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH:37][CH2:38][C:39](O)=[O:40])(=[O:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([NH:21][C:39](=[O:40])[CH2:38][NH:37][C:34](=[O:36])[CH3:35])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A mixture of 4-(5-amino-1-benzene sulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.12 mmol), N-acetylglycine (0.30 g, 2.5 mmol), HBTU (1.0 g, 2.8 mmol) and DIEA (1.1 mL, 6.4 mmol) in DMF (5 mL) was stirred at ambient temperature for 20 h. Diluted with water and the solid was collected by filtration, washed with water and dried in vacuum oven at 50° C. for 20 h to afford 4-[5-(2-Acetylamino-acetylamino)-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.20 g, 99%). This intermediate was suspended in acetic acid (6 mL) and heated at 100° C. for 7 h. Cooled, diluted with DCM and stirred over aqueous sodium bicarbonate solution. Organic layer separated, washed with water, brine dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to afford 4-[2-(acetylamino-methyl)-6-benzenesulfonyl-6H-1,2,3,5,6-tetraaza-as-indacen-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.26 g, 24%): LCMS (Method E, ESI): RT=1.53 min, m+1=553.2.
Reaction SMILES: [O:1]1[CH2:15][C@H:2]1[CH2:3][N:4]1C(=O)C2=CC=CC=C2C1=O.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].C1CCN2C(=NCCC2)CC1.NN>C1(C)C=CC=CC=1.C(O)(C)C>[NH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15][O:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH3:16]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1CO1
Reactant: Cc1ccc(O)c(C)c1
Agent: NN
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: Cc1ccc(OC[C@H](O)CN)c(C)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of (R)—N-(2,3-epoxypropyl)-phthalimide (3.0 g, 14.8 mmol) and 2,4-dimethylphenol (1.6 g, 13.0 mmol) in toluene (30 mL) was added DBU (1.3 mmol) and the resulting mixture was heated at 120° C. for 18 h. The reaction mixture was cooled to 75° C., diluted with isopropanol (50 mL) and treated with hydrazine (4 mL). After stirring the mixture at 80° C. for 4 h, cooled to room temperature and solvents were evaporated in vacuo. The residue was dissolved in aq. NaOH (100 mL, 5 N) and extracted with chloroform (2×100 mL). The combined organic layer was washed with brine (100 mL) and dried over Na2SO4. The solvent was filtered and evaporated in vacuo to afford the desired product as an off-white solid. Yield: 1.7 g, 59% LCMS [M+H]+ 196.1 The product can be recrystallized from isopropyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[Si:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>C(OCC)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH:13][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[F:21])=[CH:6][C:7]=1[Si:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: C[Si](C)(C)c1cc(NN)nnc1Cl
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(NNC(=O)c2ccccc2F)nnc1Cl
Temperature: -4 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a stirred mixture of 3-chloro-6-hydrazino-4-(trimethylsilyl)pyridazine (6.34 g, 29.3 mmol) and anhydrous triethylamine (4.9 ml, 35.2 mmol) in anhydrous diethyl ether (100 ml), cooled under nitrogen to −4° C., was added dropwise, over 13 min, 2-fluorobenzoyl chloride (3.5 ml, 29.4 mmol) keeping the temperature below 5° C. The thick mixture was then stirred for 30 min at 0-5° C., then quenched with anhydrous methanol (1 ml). The mixture was diluted with hexane (100 ml) and filtered. The collected solid was washed with diethyl ether (2×25 ml), then water (100 ml), then dissolved in dichloromethane (300 ml) and methanol (20 ml), washed with saturated aqueous NaCl (100 ml), dried (Na2SO4), and evaporated in vacuo to leave 9.72 g (98%) of the title compound as a pale brown solid; 1H NMR (360 MHz, CDCl3) δ 0.36 (9H, s), 7.07 (1H, s), 7.20 (1H, dd, J=11.7 and 8.2 Hz), 7.30 (1H, t, J=7.6 Hz), 7.55 (1H, m), 8.00 (1H, br s), 8.07 (1H, td, J=7.7 and 1.8 Hz), 9.19 (1H, br s); MS (ES+) m/e 339/341 [MH]+, 217/219 [M-COC6H4F+2H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[C:25]([NH2:26])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O>[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[C:25]([NH:26][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:24][NH:23][N:22]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Product: O=C(Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.1 %

Procedure:
2-Fluorobenzoic acid (36 mg, 0.25 mmol) was added to a solution of 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (50 mg, 0.23 mmol), EDC (53 mg, 0.27 mmol) and HOBt (37 mg, 0.27 mmol) in DMSO (1 ml). The reaction mixture was stirred at room temperature for 24 hours and purified by preparative LC/MS. Evaporation of product-containing fractions yielded the product as a white solid (15 mg, 19%). (LC/MS: Rt 3.91, [M+H]+342.66).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].O=[C:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>C1COCC1>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:10])[NH:11]2)=[CH:16][CH:15]=1)#[N:13]
Reactant: NC(=O)Nc1ccc(F)cc1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2ccc(F)cc2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
154 mg (1.0 mmol) N-[4-fluorophenyl]urea, 101 mg (0.77 mmol) 4-cyanobenzaldehyde, and 100 mg (0.77 mmol) ethyl 3-oxobutanoate are suspended in 2 ml of THF, and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6]2.CN(C=O)C.[Cl-:20]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([Cl:20])=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: [Cl-]
Reactant: COc1cc2c(cc1C(=O)O)CCC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1C(=O)Cl)CCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-methoxyindan-6-carboxylic acid (3.84 g), DMF (0.1 ml) and tetrahydrofuran (50 ml) was added oxyalyl chloride (2.1 ml) dropwise. The mixture was stirred at room temperature for 1 hour, at the end of which time the solvent was distilled off to give 5-methoxyindan-6-carboxylic acid chloride. This chloride was dissolved in dichloromethane (50 ml) and after addition of 2,6-di-tert-butylphenol (4.12 g), tin tetrachloride (2.6 ml) was added dropwise with ice-cooling. The mixture was stirred under ice-cooling for 30 minutes and, then, poured in diluted hydrochloric acid. The organic layer was washed with water and dried (MgSO4) and the solvent was distilled off. To the residue was added ethanol-hexane to give crystals of 5-(3,5-di-tert-butyl-4-hyroxybenzoyl)-6-methoxyindan (4.23 g, 55.7%). Recrystallization from ethanol gave colorless prisms, m.p. 154°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([S:28][C:29]3[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C=CC=CC1=O>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([S:28][C:29]3[C:30]([CH3:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Sc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of 4-aminobenzonitrile (184 mg, 1.56 mmol) in 1-methyl-2-pyridone (2 mL) was added NaH (62 mg, 1.56 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidine (118 mg, 0.31 mmol) in 1-methyl-2-pyridone (2 mL) was added to the mixture. The mixture was stirred at room temperature for 4 h, then poured into ice water and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 123 mg (83%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenylsulfanyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>O1CCOCC1>[CH:3]1([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OC1CCCCC1
Reaction time: 1 h

Procedure:
To 40 ml of a dioxane suspension containing 0.92 g of 60% sodium hydride was added 2.5 ml of cyclohexanol at room temperature over a 15-minute period, and the mixture was stirred at the same temperature for 1 hour and then at 50° C. for 3.5 hours. The temperature of the reaction solution was returned to room temperature, 10 ml of a dioxane containing 3.2 g of 2-fluoronitrobenzene was added dropwise, and the mixture was stirred at room temperature overnight. The dioxane was evaporated, the residue was extracted with chloroform, and the chloroform layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated to give an oil, which was then distilled under reduced pressure to give 3.8 g of 2-cyclohexyloxynitrobenzene.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26]>>[CH3:30][C:29]([CH3:32])([CH3:31])[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCC(C)(C)C)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid 2,2-dimethyl-propyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2,2-dimethylpropyl chloroformate (131 μl, 0.89 mmol). The title compound was obtained as yellow powder (245 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([CH3:31])=[N:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COCN(c1cc(C)cnc1C(=O)c1c(C)ccnc1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(C(=O)c2c(C)ccnc2C)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A mixture of 4-chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (260 mg, 0.49 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) was refluxed for 3 h. Reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified by flash chromatography (SiO2, 70% EtOAc-hexanes) to afford 4-chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (78 mg) as an off white solid (after lyophilization) in 33% yield. ESMS m/z (relative intensity): 484 (M+H)+ (100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.[Li]CCCC>C1COCC1.C1(C)C=CC=CC=1>[CH3:8][C:4]1[C:3]([CH3:9])=[C:2]([B:10]([OH:15])[OH:11])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1nccc(Br)c1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nccc(B(O)O)c1C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2,3-dimethyl-pyridine (1.38 g) and triisopropyl borate (2.05 mL) in 4 mL dry THF and 14 mL dry toluene was strirred on a dry ice-aceton bath to an internal temperature of −65° C. and 3.56 mL n-BuLi in hexanes was added dropwise over 0.5 h. Stirring continued at −65° C. for additional 2 h, then the bath was removed the mixture allowed to warm to −20° C. Reaction was quenched by addition of 10 mL 2M HCl, then allowed to warm to rt and diluted with more THF. 5M NaOH was added until the mixture reached pH 7, layers formed and the organic layer was collected. Several more extractions with THF were done and the combined organic extracts were dried with brine and Na2SO4 and concentrated under reduced pressure. The product crystallized and two crops were collected, for a total of 304 mg of 2,3-dimethylpyridine-4-boronic acid. LCMS (m/z) 153.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(O)(=O)C.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[Cl:22])(=[O:12])[CH3:11]>O.C(O)C>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[CH:16][C:15]=1[Cl:22])(=[O:12])[CH3:11]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)cc1Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1Cl
Reaction time: 0.75 h
Yield: 90 %

Procedure:
A solution of 0.73 g (0.008 mole) of thiosemicarbazide (Aldrich T3,340-5) in 24 mL of water containing 1.6 mL of glacial acetic acid was added to a solution of 1.58 g of (0.008 mole) 4-acetamido-3-chlorobenzaldehyde (24) in 20 mL of ethanol at 70°. The mixture was stirred at this temperature for 45 minutes. A white precipitate developed in the reaction mixture, which was filtered after cooling to give 1.95 g (90%) of 25 as off white crystals, mp 235-2380°. Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3423, 3260, 3132, 1701 (C=O), 1594, 1508, 1303 cm−1. 1H nmr (90 MHz, DMSO-d6):δ 11.47 (1 H, s, thiosemicarbazone NH), 9.35 (1 H, s, amide NH), 8.15-7.91 (5H; m; H-2, H-5, imine H and thiosemicarbazone NH2), 7.6 (1H; dd, 3JH5-H6=8.1 Hz, 4JH2-H6=1.8 Hz; H-6) 2.18 (3H, s, CH3). Anal. Calcd. for C10H11CIN4OS (270.73): C, 44.36; H, 4.10; Cl, 13.10; N, 20.69; S, 11.84. Found: C, 44.51; H, 4.14; Cl, 12.91; N, 20.67; S, 12.27.
Reaction SMILES: CSC.[CH2:4]([O:8][Si](C)(C)C)[CH2:5][C:6]#[CH:7].Cl.[NH4+].[Cl-].[CH3:16]COCC.[CH3:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCOCC>[CH3:21][C:22](=[CH2:16])[CH2:23][CH2:24][CH2:25][C:6](=[CH2:7])[CH2:5][CH2:4][OH:8]
Reactant: C#CCCO[Si](C)(C)C
Reactant: CCOCC
Reactant: CCCCC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Product: C=C(C)CCCC(=C)CCO
Reaction time: 2 h

Procedure:
2.1 Grams (10.0 mmol) of the above complex is suspended in 15 ml of dry ether, and 12 ml of dimethyl sulfide is added under nitrogen. The resulting solution is cooled to -60° and another 14 ml of dimethyl suflide is added to dissolve the precipitate that forms. The Grignard reagent (24 ml, 9.6 mmol) from B above is added at -60° over 5 min and the reaction is stirred at -45° for 2 hr. Trimethylsilyl 3-butynyl ether (1.4 g, 9.8 mmol) (preparation follows) in ether/pentane (5 ml/30 ml) is added at -45°; the mixture is allowed to warm to -25° with stirring for several hours. The reaction is then poured into a pre-cooled (<-10°) solution of HCl/sat. NH4Cl, allowed to warn to RT and stirred overnight. The reaction is worked up by water and extraction with ether (2×). The ether phases are combined, washed with sat (NH4)2SO4, water and brine, filtered and solvent removed to give 7-methyl-3-methylene-7-octen-1ol.