Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69])=[O:19])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: NC(CO)CO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4) (90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.111 mL, 0.633 mmol). After 5 min, the mixture was treated with 2-aminopropane-1,3-diol (38.5 mg, 0.422 mmol). The reaction mixture was stirred for 1 h, whereupon the bulk of solvent was removed and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (×2). The combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was dissolved in MeOH and dried (hydrophobic frit). The solvent was then removed in vacuo and the residue triturated with Et2O to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)benzamide (32 mg, 0.064 mmol, 30% yield) as a white solid. LCMS (HpH, 2 min), Rt=0.75 min, MH+=500.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.O>[C:15]1([C:2]2[CH:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccc2sc3ccccc3c2c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2ccc3sc4ccccc4c3c2)cc1
Yield: 52.6 %

Procedure:
2-bromo-dibenzo[b,d]thiophene (10 g), phenylboronic acid (5.1 g) tetrakis(triphenylphosphine)palladium (2.2 g) and potassium carbonate (18.38 g) were refluxed in a mixture of toluene (110 mL), ethanol (20 mL) and water (90 mL) overnight. The reaction was quenched with water and the toluene layer was removed and passed through a celite column and the toluene layer was evaporated in a rotary evaporator to yield 5.2 g 2-phenyl-dibenzo[b,d]thiophene. 2-phenyldibenzo[b,d]thiophene (5.2 g) was dissolved in anhydrous tetrahydrofuran (50 mL) under nitrogen atmosphere, and the solution was then cooled to −78° C. 20.0 mL of n-butyl lithium (1.6 M solution) was added dropwise into the reaction mixture, and continuously stirred to equilibriate to room temperature. The reaction mixture was then cool to −60° C., and trimethyborate (5.67 mL) was added and the reaction was allowed to stir overnight. The reaction was then quenched with 20% aqueous hydrochloric acid, and extracted the organic layer with ethyl acetate; ethyl acetate layer was then washed thoroughly with water and dried over anhydrous sodium sulfate, and was evaporated to dryness to yield 4.2 g of 8-phenyldibenzo[b,d]thiophene-4-boronic acid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([Cl:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:25]1([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:13][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([N:31]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CCOC(=O)CCNc1ccccc1
Reactant: CCOC(=O)c1c(Cl)nc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(c1ccccc1)c1nc(SC)nc(Cl)c1C(=O)OCC
Temperature: 100 °C
Reaction time: 7 h
Yield: 80.9 %

Procedure:
To a solution of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (47.0 g, 175.94 mmol) in DMF (470 mL) and diisopropylethylamine (100.43 mL, 582.7 mmol) was added ethyl 3-(phenylamino)propanoate (31.0 g, 160.4 mmol). The reaction mixture was heated to 100° C. and stirred for 7 h. Upon completion of the reaction (monitored by TLC), DMF was evaporated under reduced pressure and water (250 mL) was then added. The reaction mixture was extracted using EtOAc (200 mL×3). The combined organic layer was washed with water (500 mL×2), brine (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (using 0-20% Ethyl acetate in hexane) to afford ethyl 4-chloro-6-((3-ethoxy-3-oxopropyl)(phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (55 g, 80.8% yield). 1H NMR (400 MHz, CDCl3): δ 7.38 (t, J=8.0 Hz, 2H), 7.31 (d, J=7.6 Hz, 1H), 7.18 (d, J=7/2 Hz, 2H), 4.26 (t, J=7.6 Hz, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.47 (q, J=7.2 Hz, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.19 (t, J=7.2 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H). LCMS [M+H]; 424
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:13](OCC)=[O:14])[NH:10]2)=[CH:6][C:5]=1[Cl:24].O.C(O)(=O)C.[CH3:30][S:31]([CH3:33])=[O:32]>C1C=CC=CC=1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:13](=[O:14])[CH2:30][S:31]([CH3:33])=[O:32])[NH:10]2)=[CH:6][C:5]=1[Cl:24]
Reactant: CS(C)=O
Reactant: CCOC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CS(=O)CC(=O)c1[nH]c2cc(Br)c(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Stir sodium hydride (13 g) in a mixture of dimethylsulfoxide (100 ml) and benzene (100 ml), and heat at 65°-75° for 2 hours under nitrogen. To this mixture add ethyl 6-bromo-5-chloro-3-phenylindole-2-carboxylate in dimethylsulfoxide (50 ml) and benzene (30 ml) at 15°-20° and stir the mixture at room temperature for one hour. Cool the resulting mixture to 15° C. add 50 ml of water (very slowly) and then add an additional 550 ml of water. Add 25 ml of acetic acid, stir and then filter. Wash the resulting solid with water and then hexane. Crystallize the desired product from methanol-methylene chloride to obtain 6-bromo-5-chloro-2[(methylsulfinyl)acetyl]-3-phenylindole, m.p. 169°-170°.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13])(=[O:3])[CH3:2].[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:20]([OH:21])[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][N:14]=2)[C:5]1=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccccc21
Reactant: O=C(O)c1cnccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)C(=C(O)c2cnccn2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.38 g 1-acetyl-2-indolinone, 3.41 g pyrazine-2-carboxylic acid, 8.83 g TBTU, 4.21 g HOBT-hydrate and 21.8 ml ethyldiisopropylamine are stirred in 70 ml DMF for 15 hours at ambient temperature. The mixture is poured onto 400 ml ice water and 10 ml of conc. hydrochloric acid and stirred for 1 hour. The precipitate is suction filtered, washed with water, stirred with methanol, suction filtered again, washed with methanol and dried at 100° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7](O)[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].COS([O:17][CH3:18])(=O)=O.[OH-].[Na+].[NH4+].[OH-].[CH3:23]CO>O.C(OC(C)C)(=O)C>[CH3:23][O:4][C:3]1[CH:5]=[C:6]([CH3:11])[C:7]([O:17][CH3:18])=[C:8]([CH3:9])[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CCO
Reactant: COS(=O)(=O)OC
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: COc1cc(C)c(OC)c(C)c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
2,3,5-Trimethylhydroquinone (50.2 g) in 400 mL EtOH was treated with a solution of 10 g Na2S2O3.5H2O in 50 mL H2O followed by Me2SO4 (68 mL, 2.2 equiv.). To this was added slowly 10 M NaOH (100 mL, 3.0 equiv.) via dropping funnel until the reaction temperature reached 60° C. (65 mL added). The remaining 35 mL NaOH solution was added slowly, dropwise over 1 h to maintain a minimum 40° C. reaction temperature. After 2.0 h, the reaction vessel had returned to ambient temperature and an additional portion of Me2SO4 (10 mL, 13.3 g) was added causing a slight rise in temperature. After 1 h, the reaction had returned to room temperature, 100 mL conc. NH4OH was added and let stir overnight. The red-brown solution was diluted with isopropyl acetate, the organics washed with 200 mL H2O, 200 mL 1.0 M NaHCO3 and 2×200 mL saturated aqueous NaCl, dried over MgSO4 and concentrated to give 61.2 g of 1,4-dimethoxy-2,3,5-trimethylbenzene as a brown oil. 1H NMR (400 MHz, CDCl3) δ=6.53 (s, 1H), 3.78 (s, 3H), 3.66 (S, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14].CN(C)C=O.COC(OC)N(C)C.C(OCC)(=O)C>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[O:8][CH:9]=[CH:12]2
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A pressure tube was charged with methyl 4-chloro-2-methyl-3-nitrobenzoate (13 g, 57 mmol), N,N-dimethylformamide (10 mL, 200 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (26.5 mL, 200 mmol) and the reaction heated to 120° C. for 20 h. The solvents were removed and the resultant brown residue was redissolved in ethyl acetate (600 mL, 6000 mmol) and 130-270 mesh 60A silica gel (500 g, 6000 mmol) was added and the reaction stirred with a mechanical stirrer for 8 h. The silica gel was filtered off, washed with ethyl acetate (400 mL) and the organics were removed under vacuum and the residue purified by flash chromatography (330 g, 2-50% ethyl acetate/hexane) to obtain the two isomers in 14% yields each in almost 98% purity. MS m/z=226.2 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 8.35 (d, J=8.63 Hz, 1H), 7.95 (d, J=8.63 Hz, 1H), 7.76 (d, J=5.91 Hz, 1H), 6.61 (d, J=6.04 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a stirred solution of 1-bromo-4-iodobenzene (93.7 g, 331 mmol) in tetrahydrofuran (800 mL) under nitrogen at −78° C. was added drop-wise a solution of butyllithium (150 mL, 2.43 M in THF) over 30 min. The resulting solution was stirred for 2 h at −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (60 g, 301 mmol) in tetrahydrofuran (800 mL) was then added drop-wise with stirring at −78° C. over 30 min. The mixture was stirred for 1 h at −78° C., then the reaction was carefully quenched with water (350 mL). The resulting mixture was extracted with ethyl acetate (2×400 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:10) as the eluent to yield 91 g (85%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[CH:6][N:5]=[C:4]2[N:9]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:10]([C:12]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[NH:14][CH:13]=3)=[CH:11][C:3]=12.C(OC(N1C2C(=CC(OC)=C(OC)C=2)C(B(O)O)=C1)=O)(C)(C)C>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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:9]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:10]([C:12]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[NH:14][CH:13]=3)=[CH:11][C:3]=12
Reactant: COc1cc2[nH]cc(-c3cc4c(Cl)c(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cc2c(B(O)O)cn(C(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2[nH]cc(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC

Procedure:
4-Chloro-5-fluoro-2-(5,6-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine may be prepared by following the procedure described in Example 97c, but starting with 0.750 g of 1-(toluene-4-sulfonyl)-1H-2-iodo-4-chloro-5-fluoropyrrolo[2,3-b]pyridine, 0.534 g of 1-tert-butyloxycarbonyl-5,6-dimethoxyindol-3-boronic acid and 0.096 g of tetrakis(triphenylphosphine)palladium. 0.390 g of 4-chloro-2-(5,6-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: C([Li])CCC.C1([C:12](=[S:18](=[O:20])=[O:19])[C:13]([CH3:17])=[CH:14][CH2:15][OH:16])C=CC=CC=1.O1CCCC1.Cl[CH2:27][CH:28]=[C:29]([CH3:41])[CH:30]=[CH:31][C:32]1[C:37]([CH3:39])([CH3:38])[CH2:36][CH2:35][CH2:34][C:33]=1[CH3:40].[CH3:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[OH:16][CH2:15][CH:14]=[C:13]([CH3:17])[CH:12]([S:18]([C:44]1[CH:43]=[CH:42][CH:47]=[CH:46][CH:45]=1)(=[O:20])=[O:19])[CH2:27][CH:28]=[C:29]([CH3:41])[CH:30]=[CH:31][C:32]1[C:37]([CH3:39])([CH3:38])[CH2:36][CH2:35][CH2:34][C:33]=1[CH3:40]
Reactant: CCCCCC
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CCCl
Reactant: CC(=CCO)C(c1ccccc1)=S(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C=CC1=C(C)CCCC1(C)C)=CCC(C(C)=CCO)S(=O)(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
A solution of n-butyllithium in hexane (46.5 ml., 1.95 M) was added over 45 minutes to a solution of 10.4 g. of 1-phenyl sulfonyl-2-methyl-4-hydroxy-but-2-ene in 200 ml. of tetrahydrofuran at -65° to -70°C. The reaction mixture was stirred at -70°C. for 40 minutes and a solution of 1-chloro-3-methyl-5-(2,6,6-trimethylcyclohexen-1-yl)-penta-2,4-diene in 45 ml. of THF was added over 10 minutes at -65° to -70°C. The solution was stirred at this temperature for one hour and then raised to 0°C. over 15 minutes. The reaction mixture was then poured into 250 ml. of 4% by weight aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution and water and dried. Evaporation of the solvent gave 23.22 g. of crude product. Chromatography of a 19 g. portion on alumina afforded 7.71 g. of pure 1-hydroxy-3,7-dimethyl-4-(phenylsulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene (48% yield) as a pale yellow oil having a UV in isopropanol at λ max= 272- 3 mμ (ε=16800).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[H-].[Na+].[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30].[OH2:34]>CN(C)C=O>[CH3:27][N:28]([CH3:33])[S:29]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([C:20]3[N:24]([S:29](=[O:30])(=[O:34])[N:28]([CH3:33])[CH3:27])[CH:23]=[CH:22][N:21]=3)=[CH:3][C:2]=2[F:1])[C:7](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:8]1)(=[O:31])=[O:30]
Reactant: Fc1ccc(/C=C/c2n[nH]c3c(F)cc(-c4ncc[nH]4)cc23)cc1
Reactant: O
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1ccnc1-c1cc(F)c2c(c1)c(/C=C/c1ccc(F)cc1)nn2S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
36.5 mg of 7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(1H-imidazol-2-yl)-1H-indazole obtained by Example 603 was dissolved in N,N-dimethylformamide, and added with 14 mg of sodium hydride (containing 60%) under ice cooling and stirred for 10 minutes. Adding dropwise with 30.3 μl of N,N-dimethylsulfamoyl chloride, the solution was warmed to room temperature and stirred overnight. After stopping the reaction by adding water, the solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying the organic layer over magnesium sulfate, the solvent was evaporated. The crude product was purified by preparative TLC, to afford 14.2 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][NH2:16].C(N(CC)CC)C>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: NCc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1NCc1cc(F)cc(F)c1
Yield: 100.9 %

Procedure:
Reaction of 2-fluoronitrobenzene (3 g, 21 mmole), 3,5-difluorobenzylamine, (3 g, 21 mmole) and triethylamine (2.6 g, 26.2 mmole) substantially as described in 1C above produced 5.6 g (100%) of title compound as orange crystals: mp 104°-105°.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:23]=[CH:22][O:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:21]1[CH:22]=[CH:23][C:19]([C:2]#[C:1][N:3]2[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]3[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]2=3)=[CH:20]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccoc2)CCN(C)C1
Temperature: 80 °C
Yield: 5.1 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (180 mg, 0.81 mmol), 3-bromofuran (100 mg, 0.68 mmol), dichlorobis(triphenylphosphine)palladium (II) (14 mg, 0.02 mmol) and TBAF.3H2O (642 mg, 2.0 mmol) was heated at 80° C. for 5 min by microwave. After completion of reaction (monitored by TLC), the mixture was poured into water (10 mL) and extracted with EtOAc (3×10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain product, which was purified by reverse phase chromatography to obtain 10 mg of 5-furan-3-ylethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.70 (s, 1H), 7.50-7.4 (m, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 6.55 (s, 1H), 3.68 (s, 2H), 3.0-2.90 (m, 4H), 2.60 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH2:33]C.OO>O.S(=O)(=O)(O)O>[CH2:30]([C:21]1[C:20]2[CH:19]=[C:18]([F:22])[C:17]([F:23])=[CH:16][C:15]=2[N:14]=[C:13]2[C:24]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:27])[C:8]1[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=1[CH:25]=3)[CH2:31][CH2:32][CH3:33]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(F)c(F)cc3nc2-1
Reactant: CCCCC=O
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CCCCc1c2c(nc3cc(F)c(F)cc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of Stage 13d (100 mg; 0.25 mmol) is dissolved in a mixture of water (1.33 ml) and sulphuric acid at 95% (1 ml). Heptahydrated iron (II) sulphate (28 mg 0.10 mmol) and valeraldehyde (0.17 ml; 1.60 mmol) are added to this solution and the resulting solution is cooled down with an ice bath. The reaction medium is then treated dropwise with hydrogen peroxide at 30% (0.38 ml; 1 mmol), agitated for 5 hours at ambient temperature, then diluted with water (50 ml) and extracted with dichloromethane (4×50 ml). The combined extracts are washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography at medium pressure (SiO2, MeOH/CH2Cl2, 5/95) in order to produce the expected solid (m.p.>275° C.).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: COC(=O)c1ccc(Cl)nc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g), dimethyl 6-chloro-2,3-pyridinedicarboxylate (1.58 g; Kenji Niiyama et al. Bioorg. Med. Chem. Lett. 12, 21, 2002, 3041-3054) and cesium carbonate (4.4 g) in dry DMF (30 ml) was heated at 80° C. for 3 h. The cooled mixture was partitioned between water (20 ml) and ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (2×100 ml) and dried (Na2SO4). The solvent was evaporated to give an oil which was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E231); MS (ES+) m/e 411 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([CH2:9][C:10]([O:12]CC)=O)(=O)[CH:5]([CH3:7])[CH3:6]>C(O)C>[CH:5]([C:4]1[CH2:9][C:10](=[O:12])[NH:2][N:3]=1)([CH3:7])[CH3:6]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)C1=NNC(=O)C1
Temperature: 22.5 °C
Yield: 66.5 %

Procedure:
70 g (1.26 mol) of hydrazine hydrate were added dropwise at 10 to 30° C. to a solution of 100 g (0.62 mol) of ethyl isobutyrylacetate in 60 ml of ethanol. After the exothermic reaction had subsided, the mixture was stirred at 20 to 25° C. for a further 14 hours approximately and was then cooled to approximately −10° C. 52 g of the title compound were isolated by filtration.