Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH:10]([CH2:21][CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24])[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1>[CH2:1]([S:8][CH2:9][CH:10]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(CSCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC(CSCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a cooled solution (5° C.) of dibenzyl 2-[(benzylsulfanyl)methyl]pentanedioate (15.2 g, 33.9 mmol) in tetrahydrofuran (750 ml) was added 0.1 N NaOH (745 ml, 74.5 mmol NaOH) with stirring. The cloudy reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture had become homogenous. The solution was concentrated under reduced pressure to remove the tetrahydrofuran. The remaining aqueous solution was washed with ethyl acetate, then made acidic (pH 1) with concentrated HCl. The mixture was extracted twice with ethyl acetate. The ethyl acetate was removed under reduced pressure and the resulting waxy solid was purified by column chromatography to yield 6.9 g (76%) of white solid. 1H NMR (d6-DMSO): δ 1.7 (m, 2H), 2.2 (t, 2H), 2.3-2.6 (m, 3H), 3.8 (s, 2H), 7.3 (s, 5H).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][Si](C(C)(C)C)(C)C)=[CH:38][CH:37]=2)[OH:35])=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si](C(C)(C)C)(C)C)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([OH:35])[C:36]2[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=2)=[CH:32][CH:33]=1)[CH2:9][C@@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3cccc(Cl)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
To a solution of [4-[2-[N-benzyl-N-[(2R)-2-[[tert-butyl (dimethyl) silyl]oxy]-2-(3-chlorophenyl) ethyl]amino]-ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]oxy]phenyl]-methanol (1.1 g) in tetrahydrofuran (15 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (5.0 ml) at 0° C., and the mixture was stirred at room temperature for 24 hours under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-[[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenyl](hydroxy)methyl]phenol (550 mg).
Reaction SMILES: CN(C)[C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)=[O:4].P(Cl)(Cl)(Cl)=O.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:21]=12.C([O-])(=O)C.[Na+]>O.ClCCCl.ClCCl>[CH3:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3]([C:19]1[N:20]2[CH2:25][CH2:24][CH2:23][CH:22]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:21]2=[CH:17][CH:18]=1)=[O:4]
Reactant: CC(C)OC(=O)C1CCCn2cccc21
Reactant: CN(C)C(=O)c1cccn1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)OC(=O)C1CCCn2c(C(=O)c3cccn3C)ccc21
Temperature: 25 °C

Procedure:
A solution of 1.40 g. of N,N-dimethyl-1-methylpyrrole-2-carboxamide in 30 ml. of anhydrous dichloromethane containing 1.53 g. of phosphorous oxychloride is refluxed for 30 minutes under an argon atmosphere. To this solution is added a solution of 895 mg. of isopropyl 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 20 ml. of 1,2-dichloroethane. The reaction mixture is refluxed under an argon atmosphere for 50 hours, cooled to room temperature and treated with a solution of 4.1 g. of sodium acetate dissolved in 15 ml. of water. The resultant mixture is refluxed for 30 minutes further, and then cooled, the organic phase is separated and the aqueous phase extracted with chloroform. The combined organic solutions are washed with saturated sodium chloride solution (2×10 ml.), dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The oily residue is purified by t.l.c. using ethyl acetate:methylene chloride as eluant, to yield isopropyl 3-(N-methyl-2-pyrroyl)-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (XIV, R=H, Q=CH 3, R2 =iC3H7, n=1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][N:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: FC(F)(F)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1
Solvent: CO
Product: FC(F)(F)c1cnc(N2CCNCC2)nc1
Temperature: 60 °C
Yield: 90.3 %

Procedure:
To a solution of 2-(4-Benzyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidine (0.63 g) in methanol was added Palladium-C (Degussa E101N; 5%), and the reaction mixture was heated at 60° C. under hydrogen atmosphere. The reaction mixture was then allowed to cool down to room temperature, the catalyst was filtered off, and solvent was removed in vacuo to yield the title compound as a colorless solid (0.41 g). MS (m/e): 233.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=[O:20].[OH-].[Na+].O>C(O)(=O)C>[O:1]=[C:2]1[NH:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)=[N:5][CH:4]=[C:3]1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (34.4 g) and sodium hydroxide (10 g) are added to water (300 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (300 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylic acid (21.5 g). M.p. 252°-254° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.N1CCCC1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.CO.C(Cl)Cl.O.C(O)(=O)C>[CH2:19]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: BrCc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNC1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(Cc1ccccc1)C(=O)CC2
Temperature: -5 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
7-methoxy-3,4-dihydronaphthalen-2(1H)-one (41 g, 233 mmol) was dissolved in MeOH (250 mL). Then pyrrolidine (18.2 g, 256 mmol) was added dropwise. The mixture was stirred for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in acetonitrile (500 mL). The solution was cooled to −5° C. and benzyl bromide (43.8 g, 256 mmol) was added. The solution was stirred overnight at room temperature. The solvent was reduced under reduced pressure. The residue was dissolved in 480 mL of a mixture of MeOH/CH2Cl2/H2O (1:1:1) and 30 mL of glacial acetic acid were added. The mixture was stirred overnight. The reaction mixture was put on ice water and extracted with CH2Cl2. The combined organic layers were washed with a NaHCO3 solution and with brine. The organic phase was dried on MgSO4 and the solvent was evaporated. The residue (80 g) was purified by flash-chromatography on silica gel (100% dichloromethane). 58.8 g (221 mmol, 95%) of the product were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O=O>[CH2:12]([S:6][C:3]([CH3:5])([CH3:4])[C@H:2]([C:7]([OH:9])=[O:8])[NH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(SCc1ccccc1)[C@@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
D-Penicillamine (5)(140 9: 938 mmol) and sodium hydroxide (43 g; 938 mmol) were dissolved in a mixture of oxygen-free water (670 ml) and oxygen-free isopropanol (830 ml) at 0° C. To the resultant solution, benzyl bromide (208.6 g; 1219 mmol) was dropwise added, and the mixture was stirred at room temperature overnight. The reaction mixture was made neutral with 2N aqueous sodium hydroxide, stirred at -20° C. to precipitate crystals, which were collected by filtration to give Compound (6) (157.3 g; yield 70%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][CH2:9][CH:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH:8]([CH2:9][CH:10]1[CH2:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[C:13]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:12]=2[NH:11]1)[C:5]([CH3:6])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCC1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 0.33 h

Procedure:
iv. 7 ml of acetic anhydride were added to a solution of 6.16 g of crude 2-aminomethyl-7-chloro-2,3-dihydro- 5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was layered with 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate solution, dried over sodium sulphate and evaporated to leave 6.2 g of resinous 2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150°C for 10 minutes. The cooled mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue (5.7 g) was chromatographed over 120 g of silica gel using 20% methanol in methylene chloride. The clear fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5-a][1,4]benzodiazepine. A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1.5 hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue crystallised from diethyl ether to yield 8-chloro-6-(2-fluorophenyl)-1-metnhyl-4H-imidazo[1,5-a][1,4]benzodiazepine of melting point 152°-154° C. An analytical sample was recrystallised from methylene chloride/hexane.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][N:3]4[C:4]5[C:9](=[CH:8][CH:7]=[N:6][CH:5]=5)[CH:10]=[CH:11][C:2]4=[O:1])[CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2ccncc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3ccncc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of 0.32 g of (2-oxo-1,7-naphthyridin-1(2H)-yl)acetaldehyde in 10 mL of dichloromethane, 0.59 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 97 μL of acetic acid were added, then, 0.54 g of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours 30 minutes. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.15 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oily substance.
Reaction SMILES: C1[O:6][C:5]([CH2:11][C:12]([OH:14])=[O:13])([CH2:7][C:8]([OH:10])=[O:9])[C:3](=[O:4])[O:2]1.C(N(CC)CC)C.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:22]([CH:7]([C:5]([CH2:11][C:12]([OH:14])=[O:13])([C:3]([OH:2])=[O:4])[OH:6])[C:8]([OH:10])=[O:9])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCO
Reactant: O=C(O)CC1(CC(=O)O)OCOC1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCC(C(=O)O)C(O)(CC(=O)O)C(=O)O
Yield: 82.7 %

Procedure:
To a suspension of 2 (50.0 g, 0.245 mole), in ethanol-free chloroform (500 ml), was added triethylamine (75 ml, 0.538 mole) followed by octanol (80 ml. 0.508 mole). The resulting solution was refluxed for 45 hours, cooled and the chloroform removed by evaporation at 40° C. The residue was dissolved in ethyl acetate (400 ml) and this solution washed 3 times with cold saturated sodium bicarbonate solution (200 ml). The combined bicarbonate extract was washed twice with ethyl acetate (200 ml). The bicarbonate extract was then adjusted to pH 2 by the drop wise addition of concentrated HCl (≈78 ml). The cloudy solution was extracted with three portions of ethyl acetate (200 ml), the combined ethyl acetate extract dried (magnesium sulfate), filtered and evaporated, finally in high vacuum at 50° C. to give 3a (61.7 g, 90%) as an oil. The oil was dissolved in 200 ml of hot toluene on the steam bath and filtered from some insoluble material. The filtrate was kept at room temperature overnight, then, the crystals were collected, washed with toluene and dried to give 3a (43.09 g, 58%), mp 65.8°-66.7° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][F:20])[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[C:21]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=3)[CH2:14][CH:15]2[CH2:19][F:20])[CH:28]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: O=C(c1ccc([N+](=O)[O-])c(F)c1)N1CCNC(CF)C1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])c(F)c3)CC2CF)c1
Temperature: 60 °C
Yield: 57.3 %

Procedure:
A stirred mixture of (3-fluoro-4-nitrophenyl)(3-(fluoromethyl)piperazin-1-yl)methanone (456 mg, 1.6 mmol), N-tert-butyl-3-(chloromethyl)benzamide (361 mg, 1.6 mmol), triethylamine (3.1 mmol, 341 mg) and sodium iodide (1.6 mmol, 240 mg) in acetonitrile (10 mL) was heated to 60° C. for several hours. The reaction was concentrated under reduced pressure. The residue was then dissolved in dichloromethane and extracted with water (×3). The organic phase was dried (sodium sulfate) and concentrated under vacuum. The crude material was purified using silica chromatography to give the title compound (435 mg). MS (ESI) m/z 475.7[M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:4][CH:3]=1.O1CCC[CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:8]2[CH:24]([CH3:33])[C:25]([OH:27])=[O:26])=[CH:30][CH:31]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1c(Sc2ccccc2)c2cc(F)ccc2n1Cc1ccc(Cl)cc1
Product: CC(C(=O)O)c1c(Sc2ccccc2)c2cc(F)ccc2n1Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 6, but using ethyl 1-(p-chlorobenzyl)-5-fluoro-3-phenylthioindole-2-acetate (Example 8, Step 1) as the starting material and tetrahydrofuran as the solvent, the title compound was prepared, mp 80°-82°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9](Cl)=[O:10])[O:5][CH:6]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([N:12]=[N+:13]=[N-:14])=[O:10])[O:5][CH:6]=1
Reactant: O=C(Cl)/C=C/c1cc(Br)co1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC(=O)/C=C/c1cc(Br)co1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.3 %

Procedure:
A solution of (E)-3-(4-bromofuran-2-yl)acryloyl chloride (4.0 g, 16.99 mmol) in 10 mL of 1,4-dioxane was added to a solution of sodium azide (2.21 g, 34.0 mmol) in 10 mL of water and 10 mL of 1,4-dioxane. The reaction mixture was stirred for 2.5 h at room temperature. The reaction mixture was mixed with ethyl acetate and water. Phases were separated and the aqueous phase was extracted with ethyl acetate (twice). The combined organic phases were washed with brine, dried, filtrated and concentrated to give 4 g of the title compound (yield: 97%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13].Cl.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:36][C:35]3[CH:34]=[N:33][N:32]([CH3:37])[C:31]=3[NH:30][C:29]3[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:28]2=3)=[O:26])=[CH:21][C:20]=1[F:43].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>ClCCl>[Cl:42][C:39]1[CH:40]=[CH:41][C:28]2[N:27]([C:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:18][NH:17][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])=[C:20]([F:43])[CH:21]=3)=[O:26])[CH2:36][C:35]3[CH:34]=[N:33][N:32]([CH3:37])[C:31]=3[NH:30][C:29]=2[CH:38]=1
Reactant: CCCC(=O)Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1F
Reaction time: 1 h
Yield: 65 %

Procedure:
DIEA (0.135 ml, 0.78 mmol) and butyryl chloride (0.027 ml, 0.27 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydro-chloride from Example E102.2 (110 mg, 0.26 mmol) in di-chloromethane (3 ml) at room temperature. The mixture was stirred for 1 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (77 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=2[CH:15]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:3]([O:16][CH3:17])=[CH:4][C:5]3[CH2:11][NH:10][CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH3:14])[C:6]=3[CH:15]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CNCc2cc(OC)c(N)cc21
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCN1C(=O)CNCc2cc(OC)c(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)cc21
Temperature: 130 °C

Procedure:
The title compound was prepared from 8-Amino-1-ethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.095 g, 0.0004 mol), (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (0.127 g, 0.000367 mol), p-toluenesulfonic acid monohydrate (0.17 g, 0.00089 mol) and isopropyl alcohol (4 mL). The mixture was heated in a microwave at 130° C. for 30 min. The reaction was evaporated and the residue treated with a 10% sodium carbonate solution and DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with DCM/10% ammonia/methanol (10-1) giving the product as tan solid (0.041 g, 19%). Mp 179-184° C.; LCMS (m/e) 545 (M); 1H-NMR (DMSO, 400 MHz) δ 9.43 (s, 1H), 8.40-8.36 (d, 1H), 8.33 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.55-7.48 (t, 1H, J=7.32 Hz), 7.32-7.29 (t, 1H, J=7.83 Hz), 7.04 (s, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 3.55-3.40 (m, 3H), 3.03 (s, 2H), 1.23-1.14 (d, 6H, J=6.82 Hz), 0.90-0.86 (t, 3H, J=7.08 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN(CCOS(C)(=O)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
The product from Example 1 (10.0 g; 38 mmol) is dissolved in anhydrous pyridine (185 ml), and methanesulphonyl chloride (3.7 ml; 46 mmol) is slowly added dropwise at 0° C. The solution is stirred at room temperature for 6.5 h. Subsequently, the solution is diluted with dichloromethane (740 ml) and extracted twice with a 10% solution of sodium hydrogen carbonate (250 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated, and the residue is subsequently distilled repeatedly with toluene. Yield: 10.79 g (85%), brown oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Br:11].C(N1C=CN=C1)(N1[CH:18]=[CH:17]N=C1)=O.C(O)C>C(#N)C>[CH2:17]([O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[C:3]([Br:11])[CH:4]=[N:5][CH:6]=1)[CH3:18]
Reactant: O=C(O)c1cncc(Br)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1cncc(Br)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A suspension of 4,5-dibromonicotinic acid (10 g, 36 mmol) in acetonitrile (160 mL) under nitrogen was treated with 1,1′-carbonyldiimidazole (8.65 g, 53.4 mmol) in portions over 10 min. The resulting mixture was stirred for 3 h at room temperature. Ethanol (24 mL) was added and the mixture was heated to 55° C. for 16 h. The solution was then filtered and the filtrate evaporated in vacuo. The residual oil was dissolved in ethyl acetate and the solution was washed with water followed by brine. The organic fraction was then dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to afford 9 g (82%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.70 (s, 1H), 8.74 (s, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H).