Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[CH3:7].Cl.Cl[CH2:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH3:35])=[CH:29][CH:28]=2>C(O)C>[CH3:35][O:34][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][C:24]([CH2:23][C:10]([NH:9][C:6](=[O:8])[CH3:7])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:33]2
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COc1ccc2ncc(CCl)cc2c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cnc2ccc(OC)cc2c1)(NC(C)=O)C(=O)OCC
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of sodium ethoxide prepared from 0.3 g (13.1 mmol) of sodium and 30 mL of ethanol were added, in one portion, 2.85 g (13.1 mmol) of diethyl acetamidomalonate. After 30 minutes, 1.52 g (6.24 mmol) of 3-chloromethyl-6-methoxyquinoline hydrochloride were added and the resultant mixture was refluxed overnight. The reaction mixture was evaporated and the residue was dissolved in 25 mL of 1N hydrochloric acid and extracted twice with ethyl ether. The aqueous layer was neutralized with solid sodium bicarbonate and extracted twice with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel, using first 4:1 methylene chloride/ethyl acetate and then 1:1 methylene chloride/ethyl acetate as eluents, to give 1.82 g (75.2%) of the desired product as a white solid, which melted at 151°-152° C. after crystallization from a mixture of ethyl acetate and isopropyl ether. TLC Rf =0.34 (ethyl acetate); NMR (CDCl3) δ 8.4 (1H, d), 7.9 (1H, d), 7.7 (1H, bs), 7.35 (1H, d), 7.0 (1H, d), 6.6 (1H, bs), 4.3 (4H, q), 3.9 (3H, s), 3.85 (2H, s), 2.05 (3H, s), 1.3 (6H, t); IR (KBr) ν 3400, 3230, 1740, 1640, 1300 cm-1. The product has the formula ##STR84##
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[C:29]([CH3:40])[C:28]=1[CH3:41]>>[CH3:40][C:29]1[C:28]([CH3:41])=[C:27]([O:5][CH2:6][C:7]2[C:8]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:9][S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:32]=[CH:31][C:30]=1[CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: CS(=O)(=O)OCc1c(-c2ccc(C(F)(F)F)cc2)nsc1C(F)(F)F
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2c(-c3ccc(C(F)(F)F)cc3)nsc2C(F)(F)F)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(4-trifluoromethylphenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ7.89 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 5.14 (s, 2H), 3.89 (s, 3H), 2.88 (t, J=7.2 Hz, 2H), 2.48 (t, J=7.5 Hz, 2H), 2.22 (s, 3H), 1.76 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H19F6NO3S, 502.1 (M−H). found 502.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[N:10]=[CH:9][C:8]=1[C:16]([OH:18])=O.[CH3:19][CH:20]([CH3:44])[CH2:21][NH:22][C@H:23]1[CH2:28][C@@H:27]([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:24]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[N:10]=[CH:9][C:8]=1[C:16]([N:22]([CH2:21][CH:20]([CH3:44])[CH3:19])[C@H:23]1[CH2:28][C@@H:27]([C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])[CH2:26][N:25]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:24]1)=[O:18]
Reactant: COCCCNc1cc(C(C)C)ncc1C(=O)O
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1cc(C(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
4-[(3-Methoxypropyl)amino]-6-(1-methylethyl)pyridine-3-carboxylic acid (160 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (185 mg) and diisopropylethylamine (431 μl) were dissolved in methylene chloride (10 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (168 mg) was added and the mixture was stirred at room temperature for 15 hr. Aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (7:3) was concentrated under reduced pressure to give the object compound (268 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7].Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl.O>[CH3:39][Si:2]([CH3:38])([CH3:1])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([N:27]=[C:41]=[O:43])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(N=C=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (from EXAMPLE 3.2B, 90 mg in a mixture of 1 mL chloroform and 1 mL water containing 47 mg calcium carbonate) at 0° C. was added 46 mg triphosgene and the mixture allowed to warm slowly to room temperature. After 2 hours, the reaction was quenched by the addition of 2N hydrochloric acid, extracted with methylene chloride and the organics dried over sodium sulfate to give the crude title compound (94 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.I[CH3:23]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:23])[N:21]=4)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Fc1ccc(-n2ccc3cc(-c4nnn[nH]4)ccc32)cc1
Solvent: CN1CCCC1=O
Product: Cn1nnc(-c2ccc3c(ccn3-c3ccc(F)cc3)c2)n1
Reaction time: 2 h

Procedure:
To a solution of 1-(4-fluorophenyl)-5-tetrazol-5-yl-1H-indole (8a) (19 g) in NMP (200 mL) potassium t-butoxide (8.5 g) was added cautiously at 10° C. followed by dropwise addition of iodomethane (22 g) during 20 minutes. The mixture was allowed to reach room temperature and stirred for another 2 hours. Crude title compound was worked up according to the general procedure above. Purification was performed by column chromatography on silica gel using dichloromethane as eluent. Yield 15 g, mp 131-133° C.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][NH2:44]>>[CH2:36]([O:35][C:33]([NH:32][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:40]=[CH:41][C:9]([C:1](=[N:44][O:43][CH3:42])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:34])[CH2:37][CH2:38][CH3:39]
Reactant: CON
Reactant: CCCCOC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Product: CCCCOC(=O)NC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
Starting from the compound obtained in Step B, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]([CH3:43])[C:10](=[O:42])[NH:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23](C2CCCCO2)[N:22]=[C:21]3[C:33]([NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:34])[CH:15]=[N:16][CH:17]=1.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:8][N:9]([CH3:43])[C:10](=[O:42])[NH:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:33]([NH:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:34])[CH:15]=[N:16][CH:17]=1
Reactant: CN(C)C(=O)Nc1cncc(-c2ccc3c(c2)c(C(=O)Nc2cccnc2)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cncc(-c2ccc3[nH]nc(C(=O)Nc4cccnc4)c3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
TFA (5 mL) was added to a solution of 5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXVI) (0.134 g, 0.27 mmol) and triethylsilane (0.110 mL, 0.69 mmol) in DCM (5 mL) and stirred 3 h at room temperature. The solvent was removed under vacuum. The residue was treated with water, sonicated briefly to disperse the solids, basified to pH 9.0 with 5 N NH4OH and sonicated again. The solids were filtered, washed with cold water and purified by column chromatography (100% DCM→5:95 MeOH[7N NH3]:DCM) to afford 5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (1) as a white solid (35.8 mg, 0.09 mmol, 33% yield). 1H NMR (DMSO-d6) δ ppm 13.99 (s, 1H), 10.69 (s, 1H), 9.08 (d, J=1.2 Hz, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.47 (s, 1H), 8.33-8.30 (m, 2H), 8.26 (m, 1H), 7.80 (s, 2H), 7.41 (dd, J=6.6, 3.6 Hz, 1H), 2.98 (s, 6H); ESIMS found for C21H19N7O2 m/z 402.3 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([NH:27][C:28](=[O:40])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH:39]=[N:38][N:37]=[N:36]4)[CH:30]=3)[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:27][C:28](=[O:40])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N:35]4[CH:39]=[N:38][N:37]=[N:36]4)[CH:30]=3)[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cccc(-n2cnnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cccc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
1.0 mL of trifluoroacetic acid was added to 1.0 mL of methylene chloride solution containing 20 mg of tert-butyl 4-phenyl-2-(3-(1H-tetrazol-1-yl)benzamido)benzoate and stirred an room temperature for 1 hour. The solvent was evaporated under reduced pressure and ethyl acetate and tetrahydrofuran were added to the obtained residue and headed to 50° C., Insoluble were removed by filtration at the same temperature, and the solvent was evaporated under reduced pressure. Tetrahydrofuran was added to the obtained residue and a solid substance was separated by filtration to obtain 5.0 mg of 4-phenyl-2-(3-(1H-tetrazol-1-yl)benzamido)benzoic acid as white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>O1CCCC1>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Solvent: C1CCOC1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.33 h
Yield: 57.9 %

Procedure:
Under a nitrogen atmosphere, phenyl isocyanate (52 μL, 0.48 mmol) was added to a suspension of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) in anhydrous tetrahydrofuran (60 mL). The reaction mixture was stirred for 20 minutes at which time it had turned homogeneous and thin layer chromatography indicated no starting material remained. Aminomethyl resin (280 mg of 1% cross linked, 100-200 mesh available from BACHEM, Torrance, Calif.) was added and the reaction mixture was allowed to stir for 0.5 hr. Silica gel (0.4 g) was added and the mixture was concentrated under vacuum to provide a solid. The solid was purified by flash chromatography eluting with 95/5 dichloromethane/methanol to give a white solid which was dried under vacuum at 60° C. to provide 0.12 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-phenylurea. Analysis: Calculated for C24H29N7O+⅕H2O: % C, 66.25; % H, 6.81; % N, 22.53; Found: % C, 66.27; % H, 6.63; % N, 22.83
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH3:36])([CH3:35])[C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:17][CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[CH:27]=[CH:28][CH:29]=[CH:30][C:12]=2[C:11]2[CH:31]=[CH:32][CH:33]=[CH:34][C:10]1=2)=[O:7])C.[OH-].[Li+]>C1COCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:20]([O:19][CH2:18][CH2:17][N:14]1[C:15](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[C:5]([CH3:36])([CH3:35])[C:4]([OH:37])=[O:3])[C:10]2[CH:34]=[CH:33][CH:32]=[CH:31][C:11]=2[C:12]2[CH:30]=[CH:29][CH:28]=[CH:27][C:13]1=2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
N—[(S)-5-(2-Benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2,2-dimethyl-malonamic acid ethyl ester (127 mg, 0.25 mmol) were dissolved in THF (4.5 ml) and water (1.1 ml), treated with lithium hydroxide (25 mg, 1 mmol) and stirred for 18 h at ambient temperature. The mixture is diluted with aqueous saturated sodium carbonate and extracted twice with ethyl acetate. The aqueous phase is acidified with concentrated aqueous hydrogen chloride to pH 0 and extracted twice with ethyl acetate. The acidic organic layers were combined, dried over magnesium sulfate and evaporated to afford 112 mg (93%) of white foam. MS: m/e=472(M−H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7]Cl.[N+:9]([C:12]1[O:16][C:15]([CH:17]=[CH:18][C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:23]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:18]=[CH:17][C:15]1[O:16][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ncc[nH]2)o1
Reactant: ClCc1ccccn1
Product: O=[N+]([O-])c1ccc(C=Cc2nccn2Cc2ccccn2)o1

Procedure:
Using the same general procedure of Example 1, the captioned compound was prepared using 2-picolyl chloride and 2-[2-(5-nitro-2-furyl)vinyl]imidazole. The resulting yellow product was recrystallized from benzene-petroleum ether and melted at 141°-142°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([F:17])[CH:11]=2)[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[CH:11][C:12]=1[F:17]
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 103.1 %

Procedure:
5-(4-Bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (830.0 mg, 2.0 mmol) prepared in Step 3 and a solution of potassium hydroxide (226.0 mg, 4.0 mmol) in distilled water (10.0 mL) were added to methanol (10.0 mL). The reaction mixture was stirred at 70° C. for 4 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 820.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[NH:13][CH:14]1[CH2:19][CH2:18][N:17](C(OCC)=O)[CH2:16][CH2:15]1.[OH-].[K+]>CC(O)C>[NH:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:5]2[N:4]([CH2:3][CH2:2][OH:1])[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:7]3[N:6]=2)[CH2:19][CH2:18]1
Reactant: CCOC(=O)N1CCC(Nc2nc3cccnc3n2CCO)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: OCCn1c(NC2CCNCC2)nc2cccnc21
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A mixture of 14 parts of ethyl 4-[[3-(2-hydroxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate, 22 parts of potassium hydroxide and 160 parts of 2-propanol was stirred overnight at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The aqueous layer was salted out with potassium carbonate and the product was extracted with tetrahydrofuran. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5.5 parts (52.3%) of 2-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridine-3-ethanol; mp. 156.9° C. (compound 20).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].OO.C(O)C>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]1[NH:13][C:11](=[O:12])[C:10]2[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(OC)cccc1C(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCOc1ccccc1-c1nc2c(OC)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(2-ethoxybenzamido)-3-methoxybenzamide (2.6 g, 0.0083 mol), anhydrous potassium carbonate (2.33 g, 0.017 mol), hydrogen peroxide (30%, 4 ml), ethanol (40 ml) and water (80 ml) was heated under reflux for 1 hour. The mixture was allowed to cool and poured into a mixture of water (200 ml) and dichloromethane (100 ml), then the aqueous phase separated, acidified to pH 4 by the addition of 2N hydrochloric acid and extracted with dichloromethane (2×100 ml). The organic solutions were combined, dried (MgSO4) and evaporated under vacuum to give the title compound, which crystallized from ethyl acetate as a colourless solid (2.8 g, 83%), m.p. 198-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([N:30]=[C:31]=[O:32])=[O:29])[CH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:31]([NH:30][C:28](=[O:29])[O:27][CH2:25][CH3:26])=[O:32])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)N=C=O
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine (540 mg, 1.57 mmol) in 30 ml of freshly distilled tetrahydrofuran at 0° C. is added dropwise 194 μl (1.88 mmol) of ethoxycarbonyl isocyanate. The reaction mixture is stirred for 10 minutes at 0° C. and concentrated in vacuo. The residue is purified by column chromatography on silica using an ethyl acetate:methylene chloride gradient (15:85 to 1:1). Recrystallization from methylene chloride:hexane gives pure [[[[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]methyl]hydroxyamino]carbonyl]carbamic acid, ethyl ester (68%); mp 147.5°-148° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:7]([Cl:21])[C:6]=1[Cl:22])=O.[C:23]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[S:25])[NH2:24].N>>[Cl:22][C:6]1[C:7]([Cl:21])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]1[N:24]=[C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[S:25][CH:2]=1
Reactant: NC(=S)N1CCCCC1
Reactant: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Agent: N
Product: CC(C)c1ccccc1Sc1ccc(-c2csc(N3CCCCC3)n2)c(Cl)c1Cl

Procedure:
The title compound 42 was prepared according to the procedure of Example 11 from compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl piperidine. Yield: 21 mg, 65.6%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 1.65 (m, 6H), 3.44-3.52 (m, 5H),), 6.48 (d, J=8.4 Hz, 1H), 7.01 (s, 1H), 7.21 (m, 1H), 7.44-7.51 (m, 3H), 7.61 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 463 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:10]=[C:4]2[CH:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([C:2]3[CH:7]=[CH:6][N:5]4[C:8]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:9][N:10]=[C:4]4[CH:3]=3)[CH:21]=2)[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nnc2cc(Br)ccn12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccn2c(NC(C)C)nnc2c1
Temperature: 150 °C
Yield: 141.7 %

Procedure:
In a microwave tube was placed 7-bromo-N-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-amine (0.105 g, 0.41 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.16 g, 0.54 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.024 g, 0.034 mmol) and sodium carbonate monohydrate (0.29 g, 2.3 mmol) in 2.8 mL of DME and 1.1 mL of water. The mixture was heated in the microwave at 150° C. for 15 min. Water was then added and the mixture was extracted with DCM (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 203 mg of a black solid. The crude material was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound as a pale yellow solid. MS (ESI, pos. ion) m/z: 350.4 (M+1).