Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5](=[O:8])[N:6]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH:7]=1
Reactant: O=c1[nH]cc(Br)cc1N1CCOCC1
Reactant: C=CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CS(=O)(=O)CCn1cc(Br)cc(N2CCOCC2)c1=O
Yield: 98 %

Procedure:
Method 1 was followed using 5-bromo-3-morpholinopyridin-2(1H)-one (1.0 equiv.), (methylsulfonyl)ethene (1.2 equiv.) and cesium carbonate (1.2 equiv.) at room temperature to give 5-bromo-1-(2-(methylsulfonyl)ethyl)-3-morpholinopyridin-2(1H)-one in 98% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 2.92 (s, 3H) 3.09-3.23 (m, 4H) 3.53 (t, J=6.65 Hz, 2H) 3.78-3.96 (m, 4H) 4.32 (t, J=6.65 Hz, 2H) 6.69 (s, 1H) 7.23 (d, J=2.35 Hz, 1H). LCMS (m/z) (M+H)=365.1/366.9, Rt=0.57 min.
Reaction SMILES: Cl.[F:2][C:3]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:4]=1[CH2:5][N:6]([C:12]1[S:13][C:14]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)=[C:15]([CH2:22][N:23]([CH2:25][CH2:26][O:27][CH3:28])[CH3:24])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(OCC)C.C(O)C.[C].[Pd]>[F:2][C:3]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:4]=1[CH2:5][N:6]([C:12]1[S:13][C:14]([C:29]2[CH:30]=[CH:31][C:32]([NH2:35])=[CH:33][CH:34]=2)=[C:15]([CH2:22][N:23]([CH2:25][CH2:26][O:27][CH3:28])[CH3:24])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1c(N(Cc2c(F)cccc2F)C(=O)OCC)sc(-c2ccc([N+](=O)[O-])cc2)c1CN(C)CCOC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1c(N(Cc2c(F)cccc2F)C(=O)OCC)sc(-c2ccc(N)cc2)c1CN(C)CCOC
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A solution of 2N hydrochloride in diethyl ether (21 ml) and 10% palladium-carbon (50% wet, 3.73 g) were added to a solution of ethyl 2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-4-[N-(2-methoxyethyl)-N-methylaminomethyl]-5-(4-nitrophenyl)thiophene-3-carboxylate (12.43 g) (JP-A-2001-278884, WO 00/56739) in ethanol (315 ml). The mixture was stirred vigorously under hydrogen atmosphere for 1 hour. The catalyst was removed, and the filtrate was neutralized with sodium hydrogen carbonate solution. The solvent was distilled off, and the residue was distributed between ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to an NH-silica gel (Fuji Silysia Chemical) chromatography to give the title compound (11.44 g) as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[C:14]([O:23][CH3:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]([O:23][CH3:24])=[O:22])=[O:13])=[CH:2]1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)Cc1c[nH]c2ccccc12
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
[Route A/E modified] To a solution of 3-indoleacetic acid (5.79 g, 33.1 mmol) in 100 ml THF at room temperature was added 1,1-carbonyldiimidazole (5.36 g, 33.1 mmol). The reaction mixture was stirred for 15 minutes under nitrogen. Methyl anthranilate (5.0 g, 33.1 mmol) and PPTS (20.0 g, 80 mmol) were added to the reaction mixture which was then stirred at reflux for 24 hours, cooled, and concentrated to near dryness in vacuo. The product residue was partitioned between 1N hydrochloric acid and ethyl acetate. The two-phase mixture was heated until two clear layers were obtained. The aqueous layer was separated and the organic layer was allowed to cool, washed (water, lN NaOH, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. The resulting product was triturated with ethyl acetate/hexane and collected by vacuum-assisted filtration to give 8.85 g of 2-(3-indolyl)-N-(2-methoxycarbonylphenyl)acetamide as a pale yellow granular solid which was deesterified by refluxing it in a mixture of 100 ml of methanol and 32 ml of lM NaOH for 30 minutes. The product acid was isolated by concentrating the deesterification mixture in vacuo, acidifying with 40 ml of lN hydrochloric acid, and then extracting it into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. Trituration with ethyl acetate/hexanes and vacuum-assisted filtration provided 8.0 g of 2-(3-indolyl)-N-(2-carboxyphenyl)acetamide as an off-white solid: mp 205°-207° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1.[NH3:30].[I-].[Na+]>C(#N)C>[NH2:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Reactant: N
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: NCCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reaction time: 5 h

Procedure:
A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was left to stand with ammonia solution (1 ml) and sodium iodide (5 mg) and 24 hours. After repeated addition of the ammonia solution, the reaction was kept at 40° C. for 5 hours. The cooled reaction solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 387.44 (C24H21N3O3); MS (ESI): 388 ([M+H]+), was obtained as hydroformate in this way.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[N:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[CH:19]=[CH:18][C:17]([S:20][C:4]2[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=2)[C:8]#[N:9])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2ccncc2)cc1C#N
Reaction time: 3 h
Yield: 58.3 %

Procedure:
A mixture of 4-nitro-phthalonitrile (17.28 g), pyridine-4-thiol (10.68 g) and potassium carbonate (25.17 g) in N,N-dimethyl-formamide (160 ml) was heated to 85 C and stirred for 3 h. After cooling, the reaction mixture was filtered through a pad of celite and rinsed with ethyl acetate. Filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 15-30% of ethyl acetate in methylene chloride) to give the title compound 13.29 g. 1H NMR (200 MHz, CDCl3) δ 8.59 (d, J=6.2 Hz, 2H), 7.68 (m, 3H), 7.24 (d, J=6.3 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[CH2:8].[OH-].[Na+]>O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:7][CH2:8][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: C=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CCN2CCNCC2)nc1
Temperature: 22.5 °C
Reaction time: 0.88 h

Procedure:
A solution of piperazine:2HCl:H2O (241 g, 1332 mmol) in water (245 mL) was heated at 60-70° C. Vinyl pyridine (38.0 g, 333 mmol) was slowly added during of 45-60 min at 60-70° C. Heating was continued for 45-60 min at 60-70° C. The reaction mixture was cooled to 20-25° C. The pH was slowly adjusted to 8.0-8.5 with a solution of aqueous sodium hydroxide (40.0% w/w) during 45-60 min at 20-30° C. The reaction mixture was washed with toluene (2×175 mL). The aqueous layer was slowly adjusted to pH 12.0-12.5 with a solution of aqueous NaOH (40.0% w/w) during 45-60 min at 20-30° C. and again washed with toluene (175 mL). The aqueous layer was extracted with n-butanol (2×210 mL). n-Butanol was removed under reduced pressure until the residual volume reached 100 mL. n-Butanol was swapped completely with xylene (2×210 mL) until the residual volume reached 100 mL. Xylene (35 mL) was added at 75-85° C. and then cooled to 20-25° C. The reaction solution was maintained for 1.0 h at 20-25° C. and then filtered through celite and the celite washed with xylene (35 mL). The combined xylene solution was used in the next step without isolation of the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:10]([C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:24][CH:23]=3)=[N:19][N:18]=2)=[N:11][C:12]([CH:15]=[CH2:16])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[N-]>C1(C)C=CC=CC=1>[C:41]([O:40][C:38]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]1[N:14]=[CH:13][C:12]([CH:15]2[CH2:16][CH:47]2[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[N:11][C:10]=1[C:17]1[O:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]([C:30]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:36])[CH3:37])=[CH:24][CH:23]=2)=[N:19][N:18]=1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)o2)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)o2)n1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-vinyl-pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (850 mg, 1.4 mmol) in toluene (0.2 mL) at 110° C. was added a solution of ethyl 2-diazoacetate (637 mg, 587 μL, 5.6 mol) in toluene (0.7 mL) slowly over a period of 30 minutes. The reaction mixture showed incomplete conversion to product, when stirred at room temperature, so another 4 equivalents of ethyl 2-diazoacetate (637 mg, 587 μL, 5.6 mmol) was added and the reaction mixture was heated at 110° C. for 20 minutes. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue obtained was purified via silica gel column chromatography using 5 to 100% EtOAc in hexanes to yield ethyl 2-[5-[bis(tert-butoxycarbonyl)amino]-6-[5-[4-[[tert-butoxycarbonyl(methyl)amino]methyl]phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]cyclopropanecarboxylate (921 mg, 1.326 mmol, 94.96%). LC/MS m/z 595.6 [M+H-Boc]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:9]1[C:14]([F:15])=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:10]=1[F:25])[O:6][CH2:7][CH3:8])[CH3:2].[NH2:27][C:28]1[CH:33]=[CH:32][C:31](Br)=[CH:30][N:29]=1.[F-].[Cs+]>COCCOC>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:9]1[C:10]([F:25])=[CH:11][C:12]([C:31]2[CH:30]=[N:29][C:28]([NH2:27])=[CH:33][CH:32]=2)=[CH:13][C:14]=1[F:15])[O:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Nc1ccc(Br)cn1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C(OCC)c1c(F)cc(-c2ccc(N)nc2)cc1F
Temperature: 25 °C

Procedure:
A solution of (RS)-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethoxy-acetic acid ethyl ester in 1,2-dimethoxyethane was treated with 2-amino-5-bromopyridine and CsF. The reaction mixture was deoxygenated by passing a stream of argon through it. Tetrakis(triphenylphosphine)palladium(0) was added. The reaction mixture was heated to 80° for 2 days, then cooled to rt and concentrated. The crude product was isolated by flash chromatography (cyclohexane/EtOAc 2:1=>EtOAc) to give (RS)-[4-(6-amino-pyridin-3-yl)-2,6-difluoro-phenyl]-ethoxy-acetic acid ethyl ester as amorphous brown solid.
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:14]=1[NH:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClC(Cl)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:13]([O:12][CH3:11])=[C:14]2[C:24]=1[CH:1]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([CH3:23])=[N:15]2
Reactant: CN(C)C=O
Reactant: CCOC(=O)/C=C(/C)Nc1cc(OC)ccc1OC
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(OC)ccc(OC)c2nc1C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 127.3 %

Procedure:
To a 0° C. solution of dimethylformamide (7.5 mL, 0.097 mol) in dichloroethane (20 mL) is added dropwise phosphorous oxychloride (9.0 mL, 0.097 mol). After stirring for 3.5 hours at room temperature, a solution of ethyl 3-(2,5-dimethoxyanilino)crotonate (25.8 g, 0.097 mol) in dichloroethane (130 mL) is added dropwise at 25° C. The resulting solution is heated at reflux temperature for 3 hours. After cooling to room temperature, the reaction is quenched by the addition of an aqueous ammonium chloride solution. Methylene chloride (200 mL) is added and the layers are separated. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue. The residue is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (34 g, 100%) as a yellow solid identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16]>C(O)(=O)C.C(O)C>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:14]=2[CH3:13])[CH3:11])[N:5]=1)[CH3:2]
Reactant: Cc1cccc(C(C)C)c1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=Nc1c(C)cccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1
Yield: 35 %

Procedure:
There were supplied 325 mg of 2,6-diacetylpyridine manufactured by Aldrich Chemical Company to a 25 mL-Schlenk tube. Thereto, 5 mL of anhydrous ethanol manufactured by Kanto Chemical Co., Inc., 0.62 mL of 2-methyl-6-isopropylaniline manufactured by Tokyo Chemical Industry Co., Ltd., and a few drops of acetic acid manufactured by Kanto Chemical Co., Inc. were added. The obtained mixture was refluxed for 24 hours. Then, the solvent contained in the mixture was distilled off, and the resultant mixture was subjected to recrystallization with methanol, thereby obtaining 298 mg (yield: 35%) of 2,6-bis[1-(2-methyl-6-isopropylphenylimino)ethyl]pyridine as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:28].[OH-].[Na+].Cl>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc(O)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzaldehyde (0.18 g, 0.60 mmol, Example 28, step a) in dichloromethane (6.0 mL) at 0° C. was added m-chloroperoxybenzoic acid (0.22 g, 0.905-mmol). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate (2×10 mL) and water. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5 mL). To the solution was added 1 N NaOH (1.81 mL, 1.81 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate, acidified with 2 N HCl and washed with brine. The solvent was evaporated and the residue was purified by preparatory TLC eluting with acetone-hexanes (1:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)phenol as an oil (0.08 g, 47%): 1H NMR (200 MHz, DMSO-d6): δ 9.17 (s, 1 H), 6.82 (m, 1 H), 6.70 (m, 1 H), 6.51 (s, 2 H), 6.32 (m, 1 H), 3.71 (s, 3 H), 3.18 (m, 1 H), 1.95 (s, 6 H), 1.12 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (4:1); Rf=0.44.
Reaction SMILES: C=O.Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:37])=[C:9]([NH:11][C:12]([C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:19]([NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:30][C:24]=3[N:23]=2)=[O:20])=[O:13])[CH:10]=1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:37])=[C:9]([NH:11][C:12]([C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:19]([NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([N:31]4[CH2:32][CH2:33][N:34]([CH3:38])[CH2:35][CH2:36]4)=[CH:30][C:24]=3[N:23]=2)=[O:20])=[O:13])[CH:10]=1
Reactant: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCNCC3)ccc2[nH]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Paraformaldehyde (0.088 g, 2.0 mmol) was weighed out into a dry 25 ml round bottom flask. N4-(5-bromo-2-methylphenyl)-N5-(5-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-imidazole-4,5-dicarboxamide hydrochloride (0.0465 g, 0.1 mmol) was added, followed by sodium triacetoxyborohydride (0.106 g, 0.5 mmol) dissolved in DMF (3.0 ml). The reaction mixture was stirred at room temperature over night (16 hours). The reaction mixture was then treated with 1 mL of 1N hydrochloric acid and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC (ammonium acetate/acetonitrile) which gave N4-(5-bromo-2-methylphenyl)-N5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.45 (dd, 1H), 7.30 (m, 2H), 7.12 (m, 1H), 7.05 (m, 1H), 3.77 (d, 2H), 3.56 (d, 2H), 3.21 (d, 2H), 2.97 (m, 2H), 2.89 (s, 3H), 2.30 (s, 3H); MS (EI): 538.7 (MH+).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=1[Cl:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1c(Cl)cccc1Cl)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1c(Cl)cccc1Cl)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
138 mg (0.230 mmol) of (2R*,4S*)-2-benzyl-1-(2,6-dichlorobenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 18.4 mg (0.460 mmol) of sodium hydroxide in 1.5 ml of tetrahydrofuran and 1.5 ml of methanol. The title compound ##STR68## is obtained (56 mg, 48%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.50, FD-MS: M+ =503,505.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[N:6]1[CH:5]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:3]=[C:2]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: CN1C(=O)Cc2cc(-c3cncc(Br)c3)ccc21
Reactant: OB(O)c1cccnc1
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: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cncc(-c4cccnc4)c3)ccc21
Temperature: 120 °C

Procedure:
To 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one prepared as described in Example 21, (100 mg, 0.330 mmol) was added 3-pyridine boronic acid (52.7 mg, 0.429 mmol), 1,2-dimethoxyethane (3 mL), and 2 M aqueous sodium carbonate (0.429 mL, 0.858 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (150 mg, 0.016 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 1 to 8%) to furnish 5-[3,3′]bipyridinyl-5-yl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 302.1301 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.29 (s, 3H), 3.64 (s, 2H), 6.97 (d, J=8.1 Hz, 1H), 7.46 (dd. J=7.5, 4.9 Hz, 1H), 7.53-7.62 (m, 2H), 7.92-7.99 (m, 1H), 8.02 (t, J=2.1 Hz, 1H), 8.71 (dd, J=4.8, 1.5 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.8 Hz, 1H).
Reaction SMILES: [NH2:1][OH:2].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:28][C:29]#[N:30])[C:18]3[S:22][N:21]=[C:20]([N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)[N:19]=3)=[CH:11][C:6]=2[O:5][CH2:4]1>O.CO>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([C:18]3[S:22][N:21]=[C:20]([N:23]4[CH:27]=[CH:26][N:25]=[CH:24]4)[N:19]=3)[CH2:28][C:29]([NH:1][OH:2])=[NH:30])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: NO
Reactant: N#CCN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Solvent: O
Solvent: CO
Product: N=C(CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1)NO
Temperature: 25 °C
Reaction time: 30 h
Yield: 22 %

Procedure:
Hydroxylamine (1.0 mL of a 50 wt % in H2O, 15 mmol) was added all at once a solution of [{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetonitrile (30 mg, 75 μmol) in MeOH (1.0 mL) at r.t. The reaction mixture stirred at r.t. for 30 h prior to concentrating to a white solid. The residue was purified using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 7.0 mg (22%) of 2-[{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-N-hydroxy-acetamidine as a white solid. [M+H]+ 430.91; 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 6.76-6.70 (m, 2H), 5.89 (s, 2H), 4.19 (s, 2H), 3.65 (s, 2H), 3.58 (m, 2H), 2.63 (t, 2H), 1.94 (tt, 2H).