Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([Cl:22])[CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>C(O)C.O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([Cl:22])[CH:13]=3)[CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)cc1Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)cc1Cl

Procedure:
2-Phenylamino-N-(3-chloro-4-sulphamoylphenyl)-acetamide (34 g) was dissolved in ethanol (300 ml) and paraformaldehyde (6.0 g) in water (600 ml) added. The mixture was refluxed 4 hrs and cooled. The product was worked up as in Example 1(c) to yield: 18 g, m.p. 257°-259°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([F:36])[CH:25]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([F:36])[CH:25]=1
Reactant: OC(c1ccc(Br)cc1F)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.2 %

Procedure:
Dess-Martin periodinane (16.57 g, 39.06 mmol) was added to a solution of 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanol (10.66 g, 39.06 mmol) in DCM (100 mL) and the reaction mixture was stirred at rt for 1.5 h. Na2S2O3 (10% aq., 100 mL) was added and the resulting mixture extracted with CH2Cl2 (100 mL). The organic layer was washed with Na2S2O3 (50 mL×2), NaHCO3 (satd. aq., 100 mL×2), and brine (100 mL×2). The organic layers were dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (3.20 g, 30%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.[C:27](O)(=[O:31])[C@H:28]([CH3:30])[OH:29]>>[OH:29][C@@H:28]([CH3:30])[C:27]([N:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1)=[O:31]
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)[C@H](C)O)C3)ccc1-2

Procedure:
Following the procedure for 318, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene free base 235 and L-(+)-lactic acid were reacted to give 323 isolated as an off-white solid after freeze-drying (42 mg, 29%). LCMS: RT=10.71 min, [M+H]+=440. 1H NMR δ (ppm) (CDCl3): 8.40-8.33 (1H, m), 7.90 (1H, s), 7.10 (1H, t, J=6.16 Hz), 6.99 (1H, d, J=8.83 Hz), 5.91-5.83 (1H, m), 4.62-4.36 (5H, m), 4.21 (3H, m), 4.18-4.08 (1H, m), 3.93-3.84 (1H, m), 3.40 (2H, t, J=5.01 Hz), 1.61 (6H, d, J=6.62 Hz), 1.34 (3H, d, J=6.57 Hz)
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.[OH-].[Na+].Cl[S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1Cl)(=[O:12])=[O:11].[ClH:23]>O1CCOCC1.O>[Cl:23][C:20]1[CH:21]=[C:13]([S:10]([NH:6][C:5]2[S:1][N:2]=[CH:3][N:4]=2)(=[O:12])=[O:11])[CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: Cl
Reactant: Nc1ncns1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncns2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
1,2,4-Thiadiazol-5-amine (770 mg, 7.61 mmol, 1.5 eq) was dissolved in dioxane (10 ml), a solution of sodium hydroxide (550 mg, 14 mmol, 2.7 eq) in water (3 ml) was added and the reaction mixture stirred at room temperature for 10 minutes. 4-(chlorosulfonyl)-3-chlorobenzoic acid (Preparation 41, 1.3 g, 5.1 mmol, 1 eq) was added portionwise and the reaction mixture stirred at room temperature for 2 hours. The mixture was dropped into 2M HCl (10 ml) and concentrated in vacuo up to apparition of a solid. The resultant precipitate was discarded and filtrate filtered again to yield the title compound as a white solid (243.3 mg, 0.763 mmol, 15%).
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[N:41][C:40]([C:43]#[N:44])=[CH:39][N:38]=2)=[O:35])=[CH:27][C:26]=1[Cl:45])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.C(OCC)C>O1CCOCC1.C(#N)C>[ClH:45].[Cl:45][C:26]1[C:25]([CH2:24][CH2:23][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=[CH:30][C:29]([O:31][CH3:32])=[C:28]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[N:41][C:40]([C:43]#[N:44])=[CH:39][N:38]=2)=[O:35])[CH:27]=1
Reactant: COc1cc(CCN(Cc2ccc(N3CCN(C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc(CCNCc2ccc(N3CCN(C)CC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 155.6 %

Procedure:
A 3 N HCl solution in 1,4-dioxane (10 mL) was added to a stirred solution of tert-butyl-2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxyphenethyl(4-(4-methylpiperazin-1-yl)benzyl)carbamate (0.5 g) in acetonitrile (50 mL) at 5° C. The reaction mixture was allowed to warm to room temperature and stirring continued for 1 hour. Diethylether (150 ml) was added and the precipitated solid collected by filtration. The solid was triturated with diethylether, methanol, diethylether then dried at reduced pressure to yield the title compound (0.35 g, 70%) as a yellow solid.
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Br[CH2:29][CH2:30][OH:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][CH2:30][OH:31])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: OCCBr
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCCO)ccc-2c(C(=O)OCC)c1N
Yield: 15 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-bromoethanol the title compound of m.p. 190-192° C. is obtained in 15% yield.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>>[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[O:1][C:38](=[O:39])[N:37]([CH3:41])[CH3:36])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: CN(C)C(=O)Cl
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC(=O)N(C)C)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with N,N-dimethyl-carbamoyl chloride
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:22]=2[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:30][C:27]1[CH:28]=[CH:29][C:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:25][CH2:24][C:23]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2CC1
Temperature: 130 °C

Procedure:
3,4-difluoronitrobenzene (664 mg, 4.18 mmol) was added to a mixture of 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (WO 02/40471) (1 g, 3.8 mmol) and potassium carbonate (1.3 g, 9.49 mmol) in dimethylformamide (10 ml) and the reaction heated at 130° C. for 3 hours. The reaction was cooled, diluted with ethyl acetate, washed with water and then with a mixture of water:brine (1:1), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ethyl acetate:pentane (1:10) to afford the title compound. MS (ES+) m/e 303 [M-COOtBu]+.
Reaction SMILES: [CH:1]1[CH:7]=[CH:6][N:5]([O-:8])[C:3](=[S:4])[CH:2]=1.[Na+].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12].[OH-:16].[Na+]>O>[CH:1]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:3]([SH:4])[CH:2]=1.[C:10]([O-:14])(=[O:16])[C:11]([CH3:13])=[CH2:12]
Reactant: [OH-]
Reactant: [O-]n1ccccc1=S
Reactant: C=C(C)C(=O)Cl
Agent: [Na+]
Solvent: O
Product: C=C(C)C(=O)[O-]
Product: [O-][n+]1ccccc1S
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A 2-liter beaker was charged with 158.8 g of 40% aqueous sodium pyrithione (0.5 mole) and 200 ml of water. A dropping funnel was charged with 90.4 ml of methacryloyl chloride (0.75 mole). The 2-liter beaker was cooled to +5° C. with an ice/water bath. The acid chloride was added dropwise over 90 minutes. During addition the temperature of the solution was maintained between +5° C. and +9° C. After addition was completed the solution was stirred at +6° to +7° C. for 1 hour. A solution of 20 g sodium hydroxide (0.5 mole) in 300 ml of water was added over 10 minutes. After stirring an additional 15 minutes at +8° to +10° C. the solution was brought to room temperature and stirred for 1 hour. The yellow solid that had formed was filtered and then washed with 200 ml of water. The solid was dissolved in 800 ml of methylene chloride and extracted three times with 500 ml of 4% sodium hydroxide. The methylene chloride solution was dried over 60 g of magnesium sulfate for 15 minutes, filtered, and concentrated via roto-evaporation, to give 69.18 g of a yellow solid for a 66.7% yield, with an assay of 94.1%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[CH2:19]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([N:26]1[CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(Cc4ccccc4)c3)ccnc21
Temperature: 100 °C
Yield: 74.3 %

Procedure:
4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.000306 mol) was combined with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.113 g, 0.000398 mol) in toluene (3.0 mL, 0.028 mol) and ethanol (0.5 mL, 0.008 mol). Potassium carbonate (0.084 g, 0.00061 mol) dissolved in water (1.0 mL, 0.056 mol) was added and the reaction mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.000069 mol) was added, and again the mixture was degassed with nitrogen for 5 min. The reaction was heated in sealed tube to 100° C. in a microwave for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a crude residue. The product was purified by FCC on silica gel using ethyl acetate:hexane 3:7, to give 4-(1-benzyl-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine 0.092 g as a semisolid residue, LC/MS (M+H)+: 405.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][C@H:9]1[CH2:25][O:24][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@H:21](O)[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:43]=[N+:44]=[N-:45].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[CH2:7][O:8][C@H:9]1[CH2:25][O:24][C:12]2=[CH:13][CH:14]=[C:15]3[C:19]([N:18]([CH2:20][C@@H:21]([N:43]=[N+:44]=[N-:45])[CH3:22])[N:17]=[CH:16]3)=[C:11]2[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@@H](O)Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3c(c21)C[C@@H](OCC(=O)OC(C)(C)C)CO3)N=[N+]=[N-]
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a solution of the product from Step B (0.68 g, 1.88 mmol) and triethylamine (0.76 g, 1.04 mL, 7.51 mmol, 4.0 equiv.) in anhydrous THF (50 ml) at 0° C. was added methanesulfonic anhydride (0.59 g, 3.38 mmol, 1.8 equiv.). The mixture was stirred for 10 min and sodium azide (1.22 g, 18.8 mmol, 10 equiv.) was added. The solvent was removed by evaporation and anhydrous dimethyl sulfoxide (20 mL) was added. This mixture was heated at 95° C. for 3 h, cooled, poured into a saturated solution of sodium bicarbonate (80 mL), and extracted with ethyl acetate (3×60 mL). The combined extracts were dried (MgSO4), filtered, and evaporated to an oil, which was purified by chromatography (silica, 10% ethyl acetate in hexane) to give a solid (0.61 g, 84%): mp 77-78° C.; LC/MS (+ESI) m/z 388 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Al:21](C)C>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[O-:19])([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=1[O-:19])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Al+2:21]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(C)(C)C)c([O-])c(C(C)(C)C)c1
Product: C[Al+2]

Procedure:
In a sufficiently dried egg-plant type flask provided with a stirrer was sufficiently dried 0.525 g (2 mmol) of 2,4,6-tri-tert-butylphenol recrystallized from hexane. After completion of the drying, 3.3 ml of methylene chloride was added thereto. Then, under nitrogen atmosphere, 0.9 ml (1 mmol) of trimethylaluminum was slowly added dropwise with ice-cooling and stirring, and the mixture was mixed in the dark at room temperature for 1 hour to obtain a methylene chloride solution of methylaluminum bis(2,4,6-tri-tert-butylphenoxide) (mmol/3.3ml).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([SH:11])[CH:3]=1.[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1S
Reactant: Cc1ccnc(C#N)c1
Solvent: c1ccncc1
Product: Cc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Yield: 32 %

Procedure:
A mixture of 4-chloro-2-mercaptobenzoic acid (3.0 g, 15.9 mmol), 2-cyano-4-methylpyridine (1.9 g, 16.0 mmol) and pyridine (15 ml) was refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration, subjected to a silica gel column chromatography, eluted with ethyl acetate-methanol (5:1, v/v) and recrystallized from chlorobenzene-hexane to give the titled compound (1.47 g, 32%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.[CH3:17][NH2:18]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH:18][CH3:17])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-2-methoxy-1-nitronaphthalene (5.64 g, 20 mmol) in 100 ml of dry N,N-dimethylformamide saturated with methylamine was stirred in a stoppered flask at 80° C. for 4 h. During the reaction period the mixture was saturated twice with a further quantity of methylamine. The cooled mixture was poured into 1 1 of ice/water. After stirring for 1 h, the orange solid was collected by filtration and washed with water, and dried in vacuo over phosphorus pentoxide affording 5.43 g (96%) of the title compound. M.p. 169°-170 ° C.: 1H-NMR (CDCl3): 3.11 (d, J=5 Hz, 3H, CH3), 7.00 (d, J=9 Hz, 1H, ArH), 7.45-7.78 (m, 3H, ArH), 8.60 (d, J=9 Hz, 1H, ArH), 8.7 (broad, 1H, NH).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=[O:27])=[CH:20][CH:19]=1>O1CCCC1.C(OCC)C>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH:1]1[CH2:3][CH2:2]1)([OH:16])[CH2:11][CH2:10]2.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2([CH:1]2[CH2:3][CH2:2]2)[OH:27])=[CH:20][CH:19]=1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: O=C1CCc2ccc(Cl)cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(C2CC2)CCc2cc(Cl)ccc21
Product: OC1(C2CC2)CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45 ml (22.5 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were added to 2.50 g (15.0 mmol) of a mixture of 5-chloro-2,3-dihydro-1H-inden-1-one and 6-chloro-2,3-dihydro-1H-inden-1-one in 56 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate gradient) and preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 71.0 mg (2% of theory) of a mixture of 5-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-ol and 6-chloro-1-cyclopropyl-2,3-dihydro-1H-inden-1-ol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Cl)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH3:20]
Reactant: CCOc1cccc(CCl)c1
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 51.3 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), the above-mentioned 3-ethoxybenzyl chloride (636 mg) and potassium carbonate (515 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 60° C. for 14 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to remove the solvent, and the residue was subjected to purification using silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-(3-ethoxybenzyloxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (308 mg) as a yellow amorphous substance.
Reaction SMILES: ClN1[C:6](=O)[CH2:5][CH2:4][C:3]1=[O:8].[C:9]1([Se][Se]C2C=CC=CC=2)[CH:14]=CC=C[CH:10]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].O>CN(C=O)C>[O:8]1[CH:3]=[CH:4][CH:5]=[C:6]1[C:9]([CH3:14])=[CH:10][N:27]1[C:23](=[O:33])[C:24]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]2[C:26]1=[O:28]
Reactant: c1ccc([Se][Se]c2ccccc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1CCC(=O)N1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=CN1C(=O)c2ccccc2C1=O)c1ccco1
Temperature: 90 °C
Yield: 299.9 %

Procedure:
To a solution of 8.35 g (0.077 mole) of the olefin of Step A in 310 ml of DMF was added 12.37 g (0.093 mole) of N-chlorosuccinimide and 1.46 g (0.0047 mole) of diphenyl diselenide. After 3 hours at room temperature the mixture was partitioned between 500 ml of hexane and 1000 ml of 5% Na2S2O3. The hexane was distilled off at atmospheric pressure and the residue was dissolved in 200 ml of DMF, 9.49 g (0.051 mole) of potassium phthalimide was added and the mixture was warmed to 90° C. under N2. After 45 min. the cooled reaction mixture was poured into water and the precipitated product was filtered off and recrystallized from ethylacetate/2-propanol, affording 3.57 g colorless crystals, mp. 136°-137° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[N:24]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:29]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:30])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)N1CCCC1
Solvent: c1ccncc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (0.26 mmol) in pyridine (1 mL) was treated with 1-pyrrolidinecarbonyl chloride (0.29 mmol). The reaction stirred for 18 h at room temperature and was then concentrated. Purification of the residue by Gilson reverse phase HPLC provided the title product as a white powder (52%). ESMS [M+H]+: 401.2