Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.O[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[NH:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][CH:36]=2.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([C:7]2([C:6]3[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:19][CH:18]=3)[C:41]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][C:33]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:8]2)=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: Oc1ccccc1-c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3)Oc3ccccc3-c3[nH]c4ccccc4c32)cc1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
7.7 g of 4,4'-bisdimethylaminobenzophenone was dissolved in 50 ml of chloroform, and the solution was stirred. Phosphorus oxychloride (5 g) and 10 ml of chloroform were added thereto, and the mixture was stirred for 30 minutes at room temperature (about 20°-30° C.). Then, 6 g of 2-(2'-hydroxyphenyl)indole was added thereto, and the mixture was stirred at room temperature for 3 hours. The mixture was heated under reflux for an additional 2 hours. The heated mixture was cooled to room temperature, and poured into ice water, and neutralized with an aqueous solution of sodium hydroxide. Furthermore, 200 to 300 ml of chloroform was added for extraction. The chloroform layer was washed with water, dried, and distilled under reduced pressure to remove the chloroform. The remaining oily substance was dissolved in a small amount of methanol by heating, and the solution was cooled. The crystals precipitated were separated by filtration, and dried to obtain 4 g of the objective compound having a melting point of 165° to 168° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.NN>C(O)C.[Ni]>[NH2:23][C:4]1[CH:3]=[C:2]([F:1])[C:7]([CH3:8])=[CH:6][C:5]=1[NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]1
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1F
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1F
Temperature: 45 °C
Yield: 91.7 %

Procedure:
1,1-Dimethylethyl 4-[(4-fluoro-5-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate (D27) (0.96 mmol, 340 mg) in ethanol (20 mL) was treated under argon at room temperature with Raney Nickel (suspension, 50% in water, 0.5 mL) then dropwise with hydrazine hydrate (9.6 mmol, 10 eq) in ethanol over 15 min. The mixture was heated at 45° C. for 50 min. The Raney nickel was filtered off and washed with ethanol. The reaction mixture was concentrated under vacuum to give the title compound (0.88 mmol, 284 mg, 92% yield). M+H=324.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.CC(O)=O.S(=O)(=O)(O)O.C1C(=O)N([I:33])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([I:33])[C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cl)c(-c2cccc(F)c2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1I
Reaction time: 7 h
Yield: 85.1 %

Procedure:
A round-bottom flask was charged with 2-chloro-3′-fluoro-5-methoxy-1,1′-biphenyl (1.288 g, 5.44 mmol), DCM (8.00 ml), AcOH (8.00 ml), and sulfuric acid (0.160 ml, 2.99 mmol) to give a clear solution. n-Iodosuccinimide (1.224 g, 5.44 mmol) was added in one portion to give a maroon-colored solution. After 7 h, the mixture was diluted with DCM, washed with water, washed with saturated aq. sodium thiosulfate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel column, 0-5% EtOAc/Heptane) give 2-chloro-3′-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (1.68 g, 4.63 mmol, 85% yield) as a clear oil. m/z (ESI) 362.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[C:23](Cl)(=[O:25])[CH3:24]>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (190 mg; 0.58 mmol; 1.0 eq.) and TEA (242 μl; 1.74 mmol; 3.0 eq.) in DMF (3.8 mL) was added acetyl chloride (46 μl; 0.70 mmol; 1.2 eq.) and the reaction mixture was stirred overnight at RT. Reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a white solid. 1H NMR (300 Mz, DMSO) δ: 13.36 (brs, 1H), 8.29 (s, 1H), 8.47 (t, J=5.9 Hz, 1H), 8.36 (dt, J=8.0 Hz, J=1.0 Hz, 1H), 8.01 (d, J=8.6 Hz, 2H), 7.60 (dt, J=8.4 Hz, J=1.0 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 7.47-7.41 (m, 1H), 7.28-7.23 (m, 1H), 4.34 (d, J=5.9 Hz, 2H), 1.90 (s, 3H). HPLC (Condition A): Rt 2.81 min (purity 97.7%). MS (ESI+): 333.2, MS (ESI−): 331.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[F:20])[CH2:9]2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)[C:34]([NH:36][CH3:37])=[O:35]>C(O)(C)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[N:5]=[CH:4][N:3]=[C:2]([NH:30][C:31]4[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=4)[C:34]([NH:36][CH3:37])=[O:35])[N:7]=3)[CH2:9]2)=[C:14]([F:20])[CH:15]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1cc(Cl)ccc1OC1CN(c2ncnc(Cl)n2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ncnc(N3CC(Oc4ccc(Cl)cc4F)C3)n2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a solution of 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 2.54 mmol) in Isopropanol (8 mL, 3 mL/mmol) was added DIPEA (0.7 mL, 3.81 mmol) and 3-amino-N-methylbenzamide (0.382 g, 2.54 mmol) and the reaction mixture was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography to obtain 3-(4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazin-2-ylamino)-N-methylbenzamide (0.527 g, 53%) as a solid. Observed mass (M+1): 428.9
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.Br[C:16]1[CH:30]=[CH:29][C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1>>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:20]([C:19]2[CH:29]=[CH:30][C:16]([NH:1][C:2]3[C:6]([C:7]#[N:8])=[CH:5][N:4]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:3]=3)=[CH:17][CH:18]=2)=[O:21])[CH2:23][CH2:24]1
Reactant: N#Cc1cn(-c2ccccc2)nc1N
Reactant: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Product: CN1CCN(C(=O)c2ccc(Nc3nn(-c4ccccc4)cc3C#N)cc2)CC1

Procedure:
3-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-1-phenyl-1H-pyrazole-4-carbonitrile was prepared according to the general procedure in Example 7 Step 2 using 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (50 mg, 0.271 mmol) and 1-(4-bromobenzoyl)-4-methylpiperazine (77 mg, 0.271 mmol) as the starting materials.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:30]/[OH:31])/[C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O:27][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:26])=[C:15]([CH2:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C([O-])=S)=C(CC4CCCCO4)CS[C@H]23)cs1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(CC2CCCCO2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 62.5 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(tetrahydropyran-2-yl)methylthio-3-cephem-4-carboxylate (65 mg) was reacted with iodomethyl pivalate (46 mg) in accordance with the procedure of Example 4. The crude reaction product was purified by a column chromatography on a silica gel column (12 g) with elution using chloroform-methanol (10:1 by volume) as eluent to collect fractions containing the titled compound. The fractions so collected were concentrated to a small volume, to which was added diisopropylether dropwise and slowly, resulting in the deposition of crystals. The crystals were taken up by filtration, followed by washing with diisopropylether and drying, affording the titled compound (48 mg; 62%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1.P(Br)(Br)[Br:24]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:24][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1
Reactant: BrP(Br)Br
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCBr)cc1
Temperature: 25 °C

Procedure:
A solution of 2-{2-[4-(2-Hydroxy-ethyl)-phenyl]-ethyl}-isoindole-1,3-dione (Preparation 10, 22.37 g) and phosphorus tribromide (8.20 g) in toluene (500 mL) was refluxed for 4 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (300 mL) and carefully quenched with sodium bisulphite/sodium bicarbonate (1:1) in water (100 mL). The organic layer was separated and washed with further sodium bisulphite/sodium bicarbonate (1:1) in water (100 mL), dried over sodium sulphate and concentrated in vacuo. The resulting solid (24.26 g) was triturated with heptane:tert-butyl methyl ether (100 mL; 9:1, by volume) to give the title compound as a pale green solid, 17.94 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[Br:17]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:17][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[Cl:1]
Reactant: O=c1[nH]c2ccc(Cl)c([N+](=O)[O-])c2[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Br)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 28 °C
Reaction time: 120 h
Yield: 40.1 %

Procedure:
To a stirred solution of 6-chloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione (35 mg, 0.14 mmol) in DMF (0.35 mL), N-bromosuccinimide (39 mg, 0.22 mmol) was added and the solution was stirred at 28° C. for 5 days. The resulting solution was then diluted with water (3.5 mL) and the yellow solid was filtered, washed with water (2.0 mL) and dried to obtain 42 mg crude product as a yellow powder. It was purified by successive crystallization (three times) from DMSO-water (3:1) to furnish 18 mg (44%) of pure title compound as shining yellow flakes, m.p.>350° C.; 1H NMR (DMSO-d6): δ7.483 (s, 1H), 12.222 (s, 1H), 12.323 (br s, 1H); IR (KBr, cm-1): 3418, 3118, 1700, 1550, 1400, 1350, 1006, 675,562.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH3:12])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:17]>[Cu](Br)Br>[Br:17][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH3:12])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: Br
Reactant: CC1OC(=O)c2cc(N)ccc21
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: CC1OC(=O)c2cc(Br)ccc21
Reaction time: 2 h

Procedure:
58.25 g of 6-amino-3-methylphtalide (3-4) was dissolved in 1.5 l of 4.7% hydrobromic acid and 405.60 g of copper (II) bromide was added thereto, and under cooling with ice, 400 ml of aqueous solution of 41.92 g of sodium nitrite was dropped thereto. The resulting mixture was stirred at the same temperature for 2 hours and then stirred at a room temperature for 15 hours, and thereafter, extracted with chloroform. The resulting organic layer was washed with saturated sodium bicarbonate solution and saturated salt water in order, and dried over anhydrous magnesium sulfate, and thereafter, the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to obtain 71.56 g of 6-bromo-3-methylphtalide (3-5).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].I[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:30])[N:19]([CH:21]([C:26]([NH:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1>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.[Cu]I.C(Cl)(Cl)Cl>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:30])[N:19]([CH:21]([C:26]([NH:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])[CH3:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(I)cc2)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccc(C#CCO)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Prop-2-yn-1-ol (0.19 g), PdCl2(PPh3)2 (39 mg), CuI (21 mg) and TEA (0.17 g) were added to a chloroform (10 mL) solution of 4-iodo-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (0.52 g) as obtained in Example 20-(1). The mixture was stirred for 3 hours at room temperature in a nitrogen atmosphere, and then the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=50/50→0/100) to obtain 4-(3-hydroxyprop-1-yn-1-yl)-4′-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (white solid) (0.28 g, 63%).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=1.N1C=CN=C1>CN(C)C=O.CCOCC>[C:1]([Si:5]([O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=1[CH3:17])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(F)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
t-Butyldimethylchlorosilane (14.34 g, 93.24 mmol) is combined with 4-fluoro-2-methylphenol (10.00 g, 77.70 mmol) and 1H-imidazole (13.32 g, 194.24 mmol) in dimethylformamide (100 mL) and stirred at room temperature overnight. The reaction is diluted with ether (200 mL) and washed with water (2×100 mL) and brine. The organic portion is dried with sodium sulfate, filtered, and concentrated to afford 18.9 g (100%) of the title compound. GC-ES m/z 240 [M]+, TR=4.06 min.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:17]=[CH:16][N:15]([CH2:18][CH3:19])[C:11]=3[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2[C:10]3[N:17]=[CH:16][N:15]([CH2:18][CH3:19])[C:11]=3[N:12]=[N:13][CH:14]=2)[CH:3]=1
Reactant: CCn1cnc2c(-c3ccc(F)c(I)c3)cnnc21
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Product: CCn1cnc2c(-c3ccc(F)c(-c4ccc(S(C)(=O)=O)cc4F)c3)cnnc21

Procedure:
Prepared according to the method described above for Example 1 using 4-(3-iodo-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 11, 50 mg, 0.16 mmol) and 2-fluoro-4-(methylsulfonyl)phenylboronic acid (68 mg, 0.31 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH3:12][C:13]([CH:15]=[CH2:16])=O>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(O)(=O)C>[CH3:11][O:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:6]=[CH:12][CH:13]=[C:15]2[CH3:16]
Reactant: C=CC(C)=O
Reactant: COc1ccc(N)cc1OC
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2nccc(C)c2cc1OC
Temperature: 60 °C
Yield: 38 %

Procedure:
The Reference Compound No. 1-1 was prepared following the method described in J. Org. Chem., 62, 568-577 (1997). Namely, iron (III) chloride hexahydrate (5.7 g, 21 mmol) and 3,4-dimethoxyaniline (3.1 g, 20 mmol) were added to acetic acid (60 mL), and then the mixture was stirred at 60° C. After all the solids were dissolved, methylvinylketone (1.8 mL, 22 mmol) was added dropwise for 5 minutes. Then the mixture was stirred at 140° C. for 1 hour, and allowed to cool down to room temperature, and the resulting solid was filtered off. Ethyl acetate (200 mL) was added to the solid, and the resulting organic solution was washed with 0.1N sodium hydroxide aqueous solution (200 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with diethyl ether to give 1.6 g of the title reference compound as a light brown solid (Yield: 38%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:19][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](=[O:18])[NH:46][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:4]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)O)ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 14.3 %

Procedure:
1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2,6-dicarboxylic acid 2-methyl ester (49 mg, 0.13 mmol) and carbonyldiimidazole (25 mg, 0.15 mmol) were dissolved in THF (6 ml). After stirring for 1.5 hr at 60° C., the reaction was cooled to RT. Benzylamine (30 μl, 0.27 mmol, 2.1 equiv) was added and stirred for 3 hr. Removal of solvent followed by column chromatography yielded 9mg (15%) of 6-benzylcarbamoyl-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Cl-].[NH4+]>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[N:19]=[C:18]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[CH2:26][CH2:27]3)=[O:21])[CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc([N+](=O)[O-])cc4)CC3)n2)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(N)cc4)CC3)n2)cc1OC
Reaction time: 2 h
Yield: 90 %

Procedure:
To an ethanol (70 ml) and water (25 ml) mixed solution of 2.5 g of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-nitrophenyl)piperazine were added 0.15 g of ammonium chloride and 3.1 g of reduced iron, followed by 2 hours of heating under reflux. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to thus obtained residue, followed by extraction with chloroform. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and further, crystallization was carried out from acetonitrile-ethyl acetate to obtain 2.1 g of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(4-aminophenyl) piperazine as pale pink crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].O>CN(C)C=O>[C:23]([CH2:22][CH2:21][S:20][C:18](=[S:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)([OH:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(N=C=S)cc2)cc1
Reactant: O=C(O)CCS
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCSC(=S)Nc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 27.2 g of 4-(4-nitrophenyloxy)-phenylisothiocyanate (m.p. 124°-125° C) and 10 ml of 3-mercaptopropionic acid in 250 ml of anhydrous dimethyl formamide is stirred at room temperature. When the reaction is complete, the solution is poured, with stirring, into 250 ml of water. The resultant fine precipitate is collected by filtration, washed with water and dried under reduced pressure to yield the N-[4-(4-nitro-phenyloxy)-phenyl]-dithiocarbamic acid-(2-carboxyethyl)-ester with a melting point of 146° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[S:25]1(=[O:31])(=[O:30])[CH2:29][CH2:28][CH2:27][NH:26]1>>[O:30]=[S:25]1(=[O:31])[CH2:29][CH2:28][CH2:27][N:26]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=S1(=O)CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 72.4 %

Procedure:
Using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (435 mg) described in Preparation Example 133 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (310 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH2:24][CH2:25]I)[CH:12]=3)[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(#N)C>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][C:16]=1[O:22][CH3:23])[N:13]([CH2:24][CH2:25][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH:12]=[C:11]2[C:9]1[N:8]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]2[CH:10]=1
Reactant: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCI)c2cc1OC
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(-c3cc4cc(F)cnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCN3CCOCC3)c2cc1OC

Procedure:
But using 1 g of 5-fluoro-2-[1-(2-iodoethyl)-5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 0.223 g of potassium carbonate and 0.28 ml of morpholine in 100 ml of acetonitrile. 0.83 g of 2-[5,6-dimethoxy-1-(2-morpholin-4-ylethyl)-1H-indol-3-yl]-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows: