Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:30]([N:27]([CH2:28][CH3:29])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:8](=[O:10])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1)(=[O:26])=[O:25])[CH3:31]
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Reactant: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of diphenylacetic acid (223 mg, 1.05 mmol), 4-Amino-N,N-diethyl-benzenesulfonamide (240 mg, 1.05 mmol), HOBT (213 mg, 1.58 mmol), and EDC (242 mg, 1.26 mmol) in dichloromethane (20 mL) was stirred at 23° C. for 15 hours. The reaction mixture was washed with 1N aqueous sodium hydroxide (10 mL), 1N aqueous hydrochloric acid (10 mL), and saturated aqueous sodium chloride (10 mL). The organics were dried over magnesium sulfate and were concentrated. Flash chromatography (20% THF in hexanes grading to 40% THF in hexanes) provided the title compound as orange oil that solidified upon standing (224 mg). MS 423 (M+1)
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C=O.[CH3:23][N:24]([CH2:26]N(C)C)[CH3:25].Cl>CCO.C1C=CC=CC=1>[CH3:23][N:24]([CH2:26][C:8]1[C:9]([OH:20])=[CH:10][C:11]2[CH2:12][CH2:13][C@@H:14]3[C@@H:5]([C:6]=2[CH:7]=1)[CH2:4][CH2:3][C@@:2]1([CH3:1])[C@H:15]3[CH2:16][CH2:17][C:18]1=[O:19])[CH3:25]
Reactant: CN(C)CN(C)C
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: C=O
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: CN(C)Cc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 80 °C
Reaction time: 20 h
Yield: 66.7 %

Procedure:
To a suspension of estrone (11, 5.40 g, 20 mmol) in EtOH (100 mL) and benzene (60 mL) were added paraformaldehyde (0.600 g, 20 mmol) and N,N,N',N'-tetramethyldiaminomethane (5.5 mL, 40 mmol), and stirred for 20 h at 80° C. After the reaction mixture was cooled to 0° C., 5 N HCl was added. The aqueous layer was washed with Et2O, and basified with aqueous NH4OH. The precipitate was collected by filtration and washed with H2O, and recrystallized from EtOH to afford 4.37 g of 72 (67% yield) mp: 172-173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[C:34]1([S:40]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1ccc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.5 mmol of benzenesulfonyl chloride in 6 ml of DMF were added. The reaction solution was then stirred at RT for a further 12 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[S:16]1(=[O:24])(=[O:23])[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:19]4([CH2:20][CH2:21][S:16](=[O:24])(=[O:23])[CH2:17][CH2:18]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: O=C1CCS(=O)(=O)CC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: O=C1NC2(CCS(=O)(=O)CC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
To a stirred solution of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol) in acetic acid (3 mL) were added tetrahydro-4H-thiopyran-4-one 1,1-dioxide (0.068 g, 0.46 mmol) and p-toluenesulfonic acid (0.0040 g, 0.023 mmol). The mixture was heated at 80° C. overnight. Then, the solvent was removed and the obtained residue was taken up in methanol (20 mL). Solid NaHCO3 (1.5 g) was added, and the mixture was stirred for 10 min. The cloudy suspension was filtered and the collected solids were washed with methanol (20 mL) followed by water (30 mL) to give the title compound (0.0195 g, 24%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[NH:9][C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]1[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])=[CH:7]2.CN(C=O)C.S(Cl)([Cl:40])=O>C1(C)C=CC=CC=1>[Cl:40][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[CH:7]=[C:8]([C@@H:13]([NH:15][C:16](=[O:32])[O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:14])[N:9]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (345) (58 g, 130 mmol, 1.0 eq) and DMF (0.5 mL) in toluene (300 mL), sulfurous dichloride (78 g, 0.65 mol, 5.0 eq) was added slowly, and the resulting mixture was stirred at reflux for 2.5 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (5-20% ethyl acetate-petroleum ether) to afford (S)-(9H-fluoren-9-yl)methyl 1-(1,8-dichloroisoquinolin-3-yl)ethylcarbamate (346).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)[C:5]([F:8])([F:7])[F:6].Br[C:18]1[CH:23]=[CH:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]3[N:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[N:29]([CH3:35])[C:28]=3[CH:36]=2)[C:20](=[O:37])[CH:19]=1>CC(N(C)C)=O>[CH:32]1([C:30]2[N:29]([CH3:35])[C:28]3[CH:36]=[C:24]([N:21]4[CH:22]=[CH:23][C:18]([O:15][CH2:14][C:12]5[N:13]=[C:9]([C:4]([F:3])([F:16])[C:5]([F:8])([F:7])[F:6])[S:10][CH:11]=5)=[CH:19][C:20]4=[O:37])[CH:25]=[CH:26][C:27]=3[N:31]=2)[CH2:33][CH2:34]1
Reactant: OCc1csc(C(F)(F)C(F)(F)F)n1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)C(F)(F)F)n4)cc3=O)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
NaH (60% in oil, 51.5 mg) was added to a solution of (2-(perfluoroethyl)thiazol-4-yl)methanol (300 mg) in DMA (5 ml) at 0° C. After being stirred at 0° C. for 30 min, 4-bromo-1-(2-cyclopropyl-1-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2(1H)-one (295 mg) was added to the reaction mixture. The mixture was stirred at 120° C. under N2 atmosphere for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by crystallization from EtOH-water to give the title compound (25 mg) as a white solid.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)=[CH:35]C(O)=O)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C(Cl)Cl>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([C:34]([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=2)=[CH:35][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:44][CH:43]=1
Reactant: COc1ccc(C(=CC(=O)O)c2ccc(OC)cc2)cc1
Reactant: O=CN1CCNCC1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=CC(=O)N2CCNCC2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.41 ml of diphenylphosphoryl azide and 1.09 ml of 1-formylpiperazine were added to a 60 ml of a methylene chloride solution of 3.00 g of 3,3-bis(4-methoxyphenyl)acrylic acid and 2.94 ml of triethylamine. The reaction mixture was then stirred for 2 hours at room temperature, after which it was poured into a saturated aqueous solution of sodium bicarbonate and extracted twice with methylene chloride. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 80 ml of methanol, and 40 ml of a 10% w/v aqueous solution of sodium hydroxide were added to the resulting solution. The reaction mixture was stirred for 18 hours at room temperature and then poured into water; it was then extracted twice with methylene chloride. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography through 80 g of silica gel eluted with mixtures of methylene chloride and methanol ranging from 19:1 to 4:1 by volume to give 3.00 g of 1-[3,3-bis(4-methoxyphenyl)acryloyl]piperazine as a powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:9]=1[C:10](=[O:13])[CH2:11]Br.[CH3:19][C:20]1[C:21]([CH3:29])=[N:22][C:23]([SH:28])=[C:24]([CH:27]=1)[C:25]#[N:26]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:27]=[C:24]2[C:25]([NH2:26])=[C:11]([C:10](=[O:13])[C:9]3[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:8]=3[F:7])[S:28][C:23]2=[N:22][C:21]=1[CH3:29]
Reactant: Cc1cc(C#N)c(S)nc1C
Reactant: O=C(CBr)c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2c(N)c(C(=O)c3cc(F)ccc3F)sc2nc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.399 g, 2.89 mmol), 2,5-difluorophenacyl bromide (0.408 g, 1.73 mmol) and 5,6-dimethyl-2-mercaptonicotine nitrile (0.19 g, 1.16 mmol) in dry DMF (4 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound with a m.p. of 188° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:14])[C:11]=1[CH2:12][OH:13])[C:5]([O:7][CH3:8])=[O:6].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[N:23]=[C:24]=[O:25]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:14])[C:11]=1[CH2:12][O:13][C:24]([NH:23][C:17]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:16]=1[Cl:15])=[O:25])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(CO)c(Br)c1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(COC(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl 3,5-dibromo-4-(hydroxymethyl)benzoate (11 g, 34 mmol, 1 eq) in CH2Cl2 (50 mL) was added 2,6-dichlorophenylisocyanate (7 g, 37.2 mmol, 1.1 eq) and 4-N,N-dimethylaminopyridine (few crystals). Stirred at rt. After 15 min, the flask was thick with precipitate. Added 50 L CH2Cl2 to facilitate stirring and let stir overnight. Removed the CH2Cl2 under reduced pressure. Triturated the residue with Et2O and collected the solids giving methyl 3,5-dibromo-4-[({[(2,6-dichlorophenyl)amino]carbonyl}oxy)methyl]benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1N.N([O-])=O.[Na+].O.[BrH:18]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:18][C:3]1[C:2]([Cl:1])=[C:8]([Cl:9])[CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Br
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
Substituted nitrobenzenes, not hitherto described in the chemical literature, used in the preparation of substituted anilines as hereinbefore described in Reference Example 2, were prepared as follows: (a) 2,3-Dichloro-6-nitroaniline [29 g; prepared by a modification (reaction at 125° C.) of the procedure described by Beilstein and Kurbatow, Ann., 192, 235 (1878)] was dissolved with stirring at 55°-60° C. in glacial acetic acid (350 ml). A solution of sodium nitrite (11 g) in concentrated sulphuric acid (80 ml) was then added to the solution thus obtained with stirring over 15 minutes at a temperature of 55°-60° C. maintained by intermittent cooling with water. The red solution obtained was cooled to 15° C. and poured, with stirring, into a solution of cuprous bromide (20 g) in concentrated hydrobromic acid (200 ml) and ice (500 g). The mixture was allowed to attain laboratory temperature, heated for one hour at 60° C. and then steam-distilled. The distillate obtained was extracted with diethyl ether (6×500 ml). The combined ethereal extracts were washed successively with aqueous sodium hydroxide solution (2N; 3×750 ml and water (2×500 ml), dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated to dryness to give a yellow powder, which was then crystallised from hexane (125 ml) to give 2-bromo-3,4-dichloronitrobenzene (26.7 g), m.p. 73° C., in the form of yellow crystals.
Reaction SMILES: O.C([O:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:25]([O:27][CH3:28])[CH3:26])=[N:15][N:16]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH3:28][O:27][CH:25]([C:14]1[C:13]2[C:17](=[CH:18][C:10]([OH:9])=[CH:11][CH:12]=2)[N:16]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:15]=1)[CH3:26]
Reactant: [H][H]
Reactant: COC(C)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)c1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
5% Palladium on carbon-STD-type-50% wet with water (79.5 mg; manufactured by N. E. Chemcat Corp.) and 6-(benzyloxy)-3-(1-methoxyethyl)-1-(tetrahydro-2H-pyran-2-yl)-indazole (195 mg) which can be prepared according to the method described in Reference example 25, etc. were dissolved in THF (5.6 mL; manufactured by Kanto Chemical Co., Inc.). After replacing the reaction system with hydrogen, it was stirred overnight at room temperature under hydrogen atmosphere. After replacing the reaction solution with nitrogen, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (167 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[H-].[Na+].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19].O>C(OCC)C>[F:16][C:17]([F:23])([F:22])[S:18]([O:13][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]([F:11])([F:12])[F:10])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OC(c1ccc(Cl)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=S(=O)(OC(c1ccc(Cl)cc1)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (1.20 g, 5.70 mmol) was dissolved in diethyl ether (80 mL), and the resulting solution was cooled to 0° C. Then, 63% sodium hydride (217 mg, 5.70 mmol) was added thereto, and the resulting mixture was stirred for 1 hour. Thereafter, trifluoromethanesulfonyl chloride (0.910 mL, 8.55 mmol) was added dropwise thereto. Then, the temperature of the reaction solution was raised to room temperature, and the reaction solution was stirred for 2 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 93:7 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (495 mg, yield: 25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.O1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(Br)(CC)C>O>[CH:10]([N:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:7]=[N:6]1)([CH2:11][CH3:12])[CH3:9]
Reactant: COc1cn[nH]c1
Reactant: C1CCOC1
Solvent: CCC(C)Br
Solvent: O
Product: CCC(C)n1cc(OC)cn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
A mixture of 23.6 g (0.21 mol) of potassium tert.-butylate, 19.6 g (0.2 mol) of 4-methoxypyrazole (for the preparation, see Archiv der Pharmazie 300 (1967), pages 704-708), 100 ml of tetrahydrofuran and 28.7 g (0.21 mol) of sec.-butyl bromide was stirred at 70° C. for 18 hours. 300 ml of water were then added and the mixture was extracted 3 times with 100 ml of chloroform each time. The combined organic phases were dried over sodium sulphate and evaporated in vacuo. 13.2 g (42% of theory) of 1-sec.-butyl-4-methoxypyrazole were obtained from the residue, by vacuum distillation, in the form of a colorless oil with a boiling point of 60° C./0.2 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[N+:24]([O-])([OH:26])=[O:25]>C(OCC)(=O)C>[F:1][C:2]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:5]2[N:6]([CH2:10][C:11]3[N:15]=[C:14]([CH3:16])[O:13][N:12]=3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(Cn2c(=O)sc3cc(F)ccc32)no1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1nc(Cn2c(=O)sc3cc(F)c([N+](=O)[O-])cc32)no1
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A compound of 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2(3H)-benzothiazolone (11.5 g) was added portionwise to concentrated sulfuric acid (200 g) which had been cooled to a temperature of 5° to 10° C. The reaction mixture was stirred at a temperature of 0° to 5° C. for 10 minutes. To the reaction mixture was dropwise added a 98% nitric acid (3 g). The reaction mixture was stirred at a temperature of 0° to 5° C. for 2 hours, and then poured onto ice. Ethyl acetate (1 liter) was added to the mixture, and the whole was stirred. The ethyl acetate layer was separated, washed with water, with a saturated aqueous sodium bicarbonate solution, and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol, so that the aimed product, i.e. 6-fluoro-3-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-5 -nitro-2(3H)-benzothiazolone (13.0 g) was obtained. m.p. 192°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:13][CH3:14])([CH3:12])[C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:13][CH3:14])([CH3:12])[CH2:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCC1(C)C(=O)Nc2cc(Cl)ccc21
Solvent: CO
Solvent: C1CCOC1
Product: CCC1(C)CNc2cc(Cl)ccc21
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
BH3-Me2S (2 M in THF, 5.7 mL, 11.5 mmol) was added to a solution of 6-chloro-3-ethyl-3-methyl-1,3-dihydro-indol-2-one (240 mg, 1.1 mmol) in THF (10 mL). The reaction mixture was stirred at 70° C. for 3 h. The reaction was cooled to room temperature and MeOH (ca. 20 mL) was carefully added. The resulting solution was heated at reflux for 2 h. The solvents were then removed in vacuo and the residue was purified by flash chromatography to give the title compound (147 mg) as a colourless oil. MS: [M+H]+=196.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[CH3:30][S:31]([CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1([CH3:43])[CH3:42])(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:42][C:37]1([CH3:43])[N:36]([CH2:35][CH2:34][S:31]([CH3:30])(=[O:32])=[O:33])[CH2:41][CH2:40][N:39]([CH2:2][C:3]2[N:4]([CH3:29])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH2:27][CH3:28])[N:6]=3)[CH2:38]1
Reactant: CC1(C)CNCCN1CCS(C)(=O)=O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)C(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 1-(2-methanesulfonylethyl)-2,2-dimethylpiperazine (68 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) and (Si—PCC, MeOH:DCM 0-5%). The resulting residue was further purified by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 5:95) to afford 310 as a white solid (40 mg, 26%). LCMS (Method G): RT 6.68 min, [M+H]+ 596.3. 1H NMR (CDCl3, 400 MHz): δ 8.04-7.99 (m, 1 H); 7.77-7.72 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.87 (m, 7 H); 3.69 (s, 2H); 3.36 (q, J=7.5 Hz, 2 H); 3.11-3.03 (m, 5 H); 2.92 (m, 2 H); 2.62 (m 2 H); 2.51 (m, 2H); 2.37-2.22 (m, 2 H); 1.45 (t, J=7.5 Hz, 3 H) and 1.09 (s, 6 H)
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.ClCCl>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:6]2[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of 2.34 g (12 mmol) of 6,11-dihydro-5H-dibenz[b,e]azepine, 2.23 g (12 mmol) of 4-nitrobenzoyl chloride, 1.94 g (15 mmol) of diisopropylethylamine and 70.5 mg of 4-(dimethylamino)pyridine in 25 ml of dichloromethane is stirred at room temperature for 2 hours, refluxed for 3 hours and allowed to stand at room temperature for 2 days. The mixture is washed with water, 1N sodium bicarbonate, water, 1N HCl, brine and dried (Na2SO4). The solvent is removed to give 4.0 g of solid. Trituration with ethyl acetate and filtering gives 2.85 g of off-white crystals, m.p. 185°-188° C.