Azzindani/Open_Reaction_Data huggingface dataset:
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][S:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O.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>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccsc1
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#Cc2ccsc2)CCN(C)C1
Yield: 6.5 %

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (165 mg, 0.736 mmol), 3-bromothiophene (100 mg, 0.613 mmol), TBAF.3H2O (580 mg, 1.84 mmol), and dichlorobis(triphenylphosphine)palladium (II) (13 mg, 0.018 mmol) were heated by microwave at 80° C. for 5 min. The reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product obtained was purified by HPLC to yield 12.2 mg of 2,8-dimethyl-5-thiophen-3-ylethynyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 7.50 (s, 1H), 7.40 (d, 1H), 7.38(d, 1H), 7.20 (m, 2H), 7.10 (d, 1H), 3.68(s, 2H), 2.98 (t, 2H), 2.90 (t, 2H), 2.58(s, 3H), 2.42 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC.[CH:42]([N:44]1[C:52](=[O:53])[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]1=[O:54])=[CH2:43]>C(C#N)(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:5][C:4]1[CH:3]=[C:2](/[CH:43]=[CH:42]/[N:44]2[C:45](=[O:54])[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]2=[O:53])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)C#N
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: Nc1cc(/C=C/N2C(=O)c3ccccc3C2=O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.8 %

Procedure:
3-Bromo-5-(trifluoromethyl)aniline (5.00 g, 0.0208 mol) was dissolved in AcCN (200 mL) and the solution was degassed with N2. Pd(OAc)2 (230 mg, 1.02 mmol), tris(2-methylphenyl)phosphine (630 mg, 2.07 mmol), and Et3N (5.75 mL, 0.041 mol) were added and the bright orange solution was allowed to stir at rt for 1 h. To this solution was added 2-vinyl-1H-isoindole-1,3(2H)-dione (3.61 g, 0.021 mol) and the reaction mixture was degassed and heated at reflux for 16 h. The reaction was filtered through Celite. The filtrate was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 2-{(E)-2-[3-amino-5-(trifluoromethyl)phenyl]vinyl}-1H-isoindole-1,3(2H)-dione (1.99 g, 24% yield). LCMS: (FA) ES+ 334.
Reaction SMILES: [F-].[Cs+].[OH:3][C@@H:4]([C@H:30]1[C@@H:34]([CH2:35][OH:36])[O:33][C:32]([CH3:38])([CH3:37])[O:31]1)[C:5]1[N:9]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:8]([C:16]([O:18][Si](C(C)C)(C(C)C)C(C)C)=[CH2:17])=[N:7][C:6]=1[CH3:29].[NH4+].[Cl-]>C(O)C>[C:16]([C:8]1[N:9]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[C:5]([C@@H:4]([OH:3])[C@H:30]2[C@@H:34]([CH2:35][OH:36])[O:33][C:32]([CH3:37])([CH3:38])[O:31]2)=[C:6]([CH3:29])[N:7]=1)(=[O:18])[CH3:17]
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)c1nc(C)c([C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2CO)n1S(=O)(=O)N(C)C
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CCO
Product: CC(=O)c1nc(C)c([C@@H](O)[C@@H]2OC(C)(C)O[C@@H]2CO)n1S(=O)(=O)N(C)C
Temperature: 65 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Cesium fluoride (315 mg, 2.08 mmol) was added to a solution of 5-((R)-hydroxy((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-N,N,4-trimethyl-2-(1-(triisopropylsilyloxy)vinyl)-1H-imidazole-1-sulfonamide (567 mg, 1.04 mmol) in ethanol (10 ml) and warmed to 65° C. After 1 hour, the reaction was cooled to room temperature and treated with saturated aqueous NH4Cl (1 ml), then concentrated. The crude product was purified by flash chromatography over silica gel (5% methanol:dichloromethane eluent) to provide 2-acetyl-5-((R)-hydroxy((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-N,N,4-trimethyl-1H-imidazole-1-sulfonamide (380 mg, 94% yield) as a white foam: M+1=392.1.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[NH:21]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@H:22]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:23][CH2:24][C:25](=O)[OH:26].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:21]([C:38]([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39])[C@H:22]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:23][CH2:24][C:25]([NH:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:26]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Then, H-Val-Gly-OBzl•HCl and Z-Glu-OBzl (5.57 g, 15.0 mmol) were dissolved in methylene chloride (50 ml), and the solution was kept at 0° C. Triethylamine (2.30 ml, 16.5 mmol), HOBt (1-hydroxybenzotriazole, 2.53 g, 16.5 mmol), and WSC•HCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 3.16 g, 16.5 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in heated ethyl acetate (1500 ml). The solution was washed with water (200 ml), 5% citric acid aqueous solution (200 ml× twice), saturated brine (150 ml), 5% sodium hydrogencarbonate aqueous solution (200 ml× twice), and saturated brine (150 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The deposited crystals were collected by filtration, and dried under reduced pressure to obtain white crystals of Z-Glu(Val-Gly-OBzl)-OBzl (6.51 g, 10.5 mmol).
Reaction SMILES: [Br:1][CH:2]([CH3:12])[C:3]([NH:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])=O.C(N(CC)CC)C.ClC(OCC)=O>CC(C)=O>[Br:1][CH:2]([C:3]1[O:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[N:5]=1)[CH3:12]
Reactant: CC(Br)C(=O)NC(C)(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(Br)C1=NC(C)(C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a stirring mixture of 2-(2-bromo-propionylamino)-2-methyl-propionic acid (50.0 g; 0.21 mol), triethylamine (23.37 g; 0.23 mol) and 150 mL acetone, cooled with an ice bath, was added a solution of ethyl chloroformate (25.07 g; 0.23 mol) in 40 mL acetone over a period of 10 minutes. The reaction mixture was then allowed to warm to room temperature and was stirred for 2 hours. The mixture was then filtered, and the solid was washed with 150 mL ether. The combined filtrate was concentrated under vacuum. Ether (100 mL) was added to the residue, and the mixture was filtered. After removal of the solvent under vacuum, the filtrate residue was distilled under reduced pressure (63-64° C.; 1 mmHg) to give 34.73 g (75%) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:13]1[O:17][N:16]=[C:15]([N:18]=[C:19]=[O:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C1COCC1>[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[O:20])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)c1cc(N=C=O)no1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Temperature: 50 °C
Yield: 80 %

Procedure:
to THF (300 ml, degassed w/ argon) was added 3-aminophenol (4.36 g, 40 mmol) and 5-tert-butyl-3-isocyanatoisoxazole (6.64 g, 40 mmol) and the mixture was heated at 50° C. overnight. After cooling to room temperature, the reaction was concentrated in vacuo, and the resulting foam purified by column chromatography (25-75% EtOAc/hexanes) to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea (8.81 g, 32 mmol, 80%). 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1h), 9.37 (s, 1h), 8.69 (s, 1h), 7.06 (t, 1h), 7.01 (s, 1h), 6.78 (d, 1h), 6.49 (s, 1h), 6.41 (d, 1h), 1.29 (s, 9h); LC-MS (ESI) m/z 275 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:15])[CH2:13][CH:12]2[NH:14][CH:9]([CH2:10][CH2:11]2)[CH2:8]1.[CH3:16][O:17][C:18]1[C:23]2[O:24][C@H:25]([CH2:28]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[C:23]2[O:24][C@@H:25]([CH2:28][N:14]3[CH:12]4[CH2:11][CH2:10][CH:9]3[CH2:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)([OH:15])[CH2:13]4)[CH2:26][O:27][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc2c1O[C@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: OC1(c2ccccn2)CC2CCC(C1)N2
Product: COc1cccc2c1O[C@@H](CN1C3CCC1CC(O)(c1ccccn1)C3)CO2
Yield: 70 %

Procedure:
The title compound was prepared by the same procedure described in Example 1, Step 4 using 3-(2-pyridinyl)-8-azabicyclo[3.2.1]octan-3-ol in place of 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]octan-3-ol, and (S)-toluene-4-sulfonic acid 8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester in place of (S)-toluene-4-sulfonic acid 8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl ester. Yield: 70%, white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.O.C(OCC)(=O)C>C(OCC)C.O1CCCC1>[CH:12]1([C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:11])[CH3:10])[CH2:14][CH2:13]1
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: Br[Mg]C1CC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)(c1ccc(F)cc1F)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.50 g (9.61 mmol) of 2′,4′-difluoroacetophenone were dissolved at 0° C. in 8 ml of diethyl ether, and 38.4 ml (19.21 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. Stirring at 0° C. for 1 h was followed by warming to RT, and the reaction solution was mixed with water and ethyl acetate, and the phases were separated. The organic phase was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water gradient) to result in 0.63 g (33% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:3]1[CH:4]=[CH:5][C:6]([CH:8]=[CH2:9])=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: C=Cc1ccc(F)c(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C=Cc1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C

Procedure:
A mixture of 2-Bromo-1-fluoro-4-vinyl-benzene (8 g), morpholine (20 mL), Pd2(dba)3 (1.83 g), di-t-butyl-biphenylphosphine (1.2 g), K3PO4 (17 g) in DME (60 mL) was stirred at reflux for 4 h. The reaction mixture was cooled down to room temperature, diluted with methylene chloride, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by Flash Chromatography of Biotage eluting with 7% ethyl acetate in hexanes to give the title compound as an oil (5 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]2[C:24]3[C:7]1=[N:8][NH:9][C:10]=3[N:11]=[C:12]([S:25][CH3:26])[N:13]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[CH2:17]([N:15]1[C:14]2[C:24]3[C:7](=[N:8][NH:9][C:10]=3[N:11]=[C:12]([S:25][CH3:26])[N:13]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:16]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)c2nc(SC)nc3[nH]nc1c23
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2c3c(n[nH]c3n1)C(C(=O)O)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
5-Benzyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3-carboxlic acid ethyl ester (3.0 g, 8.1 mmol) and ethanol (55 ml) were placed in a round-bottomed flask. To the sirring mixture was slowly added sodium hydroxide (10% w/w in ethanol, 30 mL, 75 mmol) and allowed to stir at room temperature overnight. The reaction was quenched by addition of citric acid (10% w/v in water, 20 mL) until pH 8. The basic solution was washed with EtOAc (2×100 mL) and then acidified to pH 3 with citric acid (10% w/v in water, 50 mL). The resulting acidic solution was extracted with EtOAc (3×100 mL) and dichloromethane (1×50 mL). The organic washes were combined, dried over MgSO4, and concentrated under reduced pressure to yield a yellow solid (2.25 g, 6.6 mmol). 1H-NMR (DMSO-d6): 13.1 (bs, 1H), 7.40-7.22 (m, 5H), 4.36 (dd, J=5.1, 13.2 Hz, 3H), 4.22 (t, J=5.2 Hz, 2H), 3.86-3.76 (m, 3H), 3.17 (d, J=5.2 Hz, 1H). LC: Rt=1.19 min. MS 342.42 [M+H]
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.Br[CH2:12][C:13]1[O:14][C:15]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:16]=2[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CN(C)C=O>[CH:22]([C:19]1[CH:20]=[CH:21][C:15]2[O:14][C:13]([CH2:12][N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[O:1][CH2:2][CH2:3]3)=[CH:17][C:16]=2[CH:18]=1)=[O:23]
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=Cc1ccc2oc(CBr)cc2c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2oc(CN3CCOc4ccccc43)cc2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of 2,3-dihydro-1,4-benzoxazine (1.07 g, 7.94 mmol), 2-bromomethyl-5-formyl benzofuran (1.9 g, 7.94 mmol), potassium carbonate (5.5 g, 39.74 mmol) and Aliquat 336 (2 drops) in dimethyl formamide (25 ml) was stirred at 65° C. for 8 h. Water (50 ml) was added to reaction mixture and extracted with ethyl acetate (2×50 ml). The extracts were washed with water (50 ml), brine (50 ml) and dried (Na2SO4). The solvent was evaporated to dryness and the residue was chromatographed over silica gel using a mixture of ethyl acetate pet. ether (3:7) as an eluent to afford the title compound (2.1 g, 91%) as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:26]([O-])=O)[C:18]([NH:19][CH:20]4[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[NH2:26][C:17]1[C:18]([NH:19][CH:20]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol (6 g, 15 mmol) in methanol (250 mL) was added palladium on carbon (1 g, 10%), then the reaction mixture was stirred at room temperature under hydrogen (45 psi) for 3 hours. The catalyst was filtered off, and the organic solution was concentrated under reduce pressure to give 4.6 g (83%) of 3-(5-Amino-1-benzene sulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclopentanol. 1H NMR (400 MHz, CDCl3) δ: 8.12-8.05 (s, 1H), 7.74 (s, 1H), 7.52-7.32 (m, 5H), 6.64-6.53 (m, 1H), 4.43-4.40 (s, 1H), 4.30-4.29 (m, 1H), 2.94-2.84 (m, 3H), 2.02-1.90 (m, 1H), 1.90-1.73 (m, 6H).
Reaction SMILES: [CH2:1]([N:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:4]([N:8](Cl)[Cl:9])[C:5]([O-:7])=[O:6])[CH3:2].C(C(N)(C([O-])=O)N(C(=O)C(C)C)C=O)C>Cl.O1CCCC1.[Pd]>[ClH:9].[CH2:1]([N:3]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[CH:4]([NH2:8])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN(C(=O)C(C)C)C(C(=O)[O-])N(Cl)Cl
Agent: [Pd]
Agent: CCC(N)(C(=O)[O-])N(C=O)C(=O)C(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCN(C(=O)C(C)C)C(N)C(=O)O
Temperature: 25 °C

Procedure:
Preparation of ethyl-α-N,N-dichloroaminoisobutyrylglycinate: To a solution of 2.16 g (0.01 mol) of ethyl-N-formyl-α-aminoisobutyrylglycinate in 50 ml of dry hydrogen chloride in tetrahydrofuran (1 M), there was added 1 g of 10% palladium-on-charcoal. The mixture was shaken at room temperature under an atmosphere of hydrogen at 50 psi for several days. Following filtration, the solvent was removed under reduced pressure to afford 1.18 g (0.005 mol), 50%, ethyl-α-aminoisobutyrylglycinate hydrochloride, pmr (D2O) δ 4.43 (s, 2H), 4.33 (q, 2H), 1.70 (s, 6H) and 1.23 (t, 3H) ppm.
Reaction SMILES: C(OC([N:11]1[CH:23]([C:24]2[NH:28][N:27]=[N:26][N:25]=2)[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.Br.CCOCC>C(O)(=O)C>[NH:28]1[C:24]([CH:23]2[CH2:22][C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH2:12][NH:11]2)=[N:25][N:26]=[N:27]1
Reactant: O=C(OCc1ccccc1)N1Cc2[nH]c3ccccc3c2CC1c1nnn[nH]1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: c1ccc2c3c([nH]c2c1)CNC(c1nnn[nH]1)C3
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3RS)-2-Benzyloxycarbonyl-3-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydro-β-carboline (0.3 g) is dissolved in acetic acid (1 ml) and thereto is added dropwise a 25% solution of HBr in acetic acid (2 ml). The mixture is stirred at room temperature for 20 minutes, and thereto is added ether. The precipitates are collected by filtration, washed with ether and dried to give the title compound (0.257 g, quantitatively) as pale yellow powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2C=CC=CN=2)=[CH:4][CH:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](B(O)O)=[C:39]2[C:34]=1[CH:35]=[CH:36][CH:37]=[CH:38]2.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=[C:9]3[CH3:17])=[CH:6][CH:7]=2)=[C:41]2[C:46]=1[CH:45]=[CH:44][CH:43]=[CH:42]2
Reactant: Brc1ccc(-n2c(-c3ccccn3)nc3ccccc32)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1-c1ccc(-c2c3ccccc3c(-c3ccc4ccccc4c3)c3ccccc23)cc1
Yield: 69.1 %

Procedure:
Dissolving 1.2 g (3.4 mmol) of 1-(4-bromophenyl)-2-pyridine-2-yl-1H-benzimidazole, 1.2 g (3.4 mmol) of 10-naphthalene-2-yl-anthracene-9-boronic acid and 0.10 g of tetrakis (triphenylphosphine) palladium into 15 milliliter of 1,2-dimethoxyethane, adding 6 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed with heating for 7 hours. After completion of the reaction, the precipitated solids were dissolved into the dichloro-methane, washed with water and dried with sodium sulfate. Removing the solvent by distillation and by refining the resultant product with the use of a silicagel column chromatography (dichloro methane-ethyl acetate), 1.2 g of an yellowish white solids were obtained (yield: 61%). As a result of MS analysis, it was recognized that the yellowish white solids were identified as the aimed substance and that m/e=573 for molecular weight of 573.22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:25])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[C:10](=O)[CH2:9]1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:11](=[C:12]([CH3:25])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=2)[C:10](=[N:31][NH:30][C:27]([NH2:29])=[NH:28])[CH2:9]1
Reactant: Cc1c2c(nn1CCc1ccccc1)CC(c1ccccc1Cl)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c2c(nn1CCc1ccccc1)CC(c1ccccc1Cl)CC2=NNC(=N)N
Yield: 135.6 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-2-(2-phenylethyl)-4,5,6,7-tetrahydroindazol-4-one (0.20 g), aminoguanidine hydrochloride (0.073 g), concentrated hydrochloric acid (0.14 ml), water (0.14 ml) and ethanol (15 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-2-(2-phenylethyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 152) (0.17 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccccc1F
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1F
Yield: 76.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. The crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.053 g (77%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([OH:5])=O.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1>>[O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[C:3]([NH:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[NH:27][C:23]=2[CH:22]=1)=[O:5]
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: Cc1ccc(OC2CCN(C(=O)C(=O)O)CC2)cc1
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)[nH]c4c3)CC2)cc1

Procedure:
The title compound is prepared from oxo-(4-p-tolyloxy-piperidin-1-yl)-acetic acid (Example 26b) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 294° C. (isopropanol)