Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=2)=[C:21]([CH3:27])[CH:20]=1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cc(Cl)cc(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To a mixture of (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)-amine (850 mg, 3.30 mmol) and 4-chloro-2,6-dimethylphenol (516 mg, 3.30 mmol) in 25 ml of dry THF was added potassium tert-butoxide (370 mg, 3.30 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid (1.31 g). The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 1.10 g (88%) of the title compound as yellow solid, mp 152-154° C. 1H NMR (CDCl3) δ 7.65 (d, 1H), 7.05 (s, 2H), 6.21 (s, 1H), 3.41 (m, 1H), 2.15 (s, 3H), 2.11 (s, 6H), 1.5-1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:22]#[N:23])=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1cccc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A mixture of 4.00 g (10.8 mmol) of 4-[(3-bromophenyl)amino]-6-nitro-3-quinolinecarbonitrile and 12.2 g (54.2 mmol) of SnCl2 dihydrate in 160 mL of ethanol was refluxed under N2 for 1.3 h. After cooling to 25° C., ice water and sodium bicarbonate were added and the mixture was stirred for 2 h. Extraction with chloroform, treatment with Darco, drying (magnesium sulfate) and solvent removal gave 3.9 g of brown crystals: mass spectrum (electrospray, m/e): M+H 339.
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12]1[S:13][C:14]([S:18](Cl)(=[O:20])=[O:19])=[C:15]([CH3:17])[N:16]=1)(=[O:10])[CH3:9].[CH:22]([O:35][C:36]1[C:37]2[C:49](=[O:50])[N:48]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[CH2:47][C:38]=2[C:39]([OH:46])=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOC(C)=O.CCCCCC>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:22]([O:35][C:36]1[C:37]2[C:49](=[O:50])[N:48]([CH2:51][C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[CH2:47][C:38]=2[C:39]([O:46][S:18]([C:14]2[S:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[N:16][C:15]=2[CH3:17])(=[O:19])=[O:20])=[C:40]2[C:45]=1[N:44]=[CH:43][CH:42]=[CH:41]2)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: O=C1c2c(c(O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)Oc2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.4 %

Procedure:
Triethylamine (50 g), DMAP (catalytic amount) and 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride (25.5 mg, 0.10 mmol) were added to 0.034 mmol 45. The reaction mixture was stirred at room temperature for 18 hours under an inert atmosphere. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 44=0.5, Rf 45=0, Rf 272=0.2) and LC/MS. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethylacetate/hexane—3/7) to afford 2-acetylamino-4-methyl-thiazole-5-sulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 272 (18.9 mg, 79%).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].[CH2:7]([OH:10])[CH2:8][CH3:9]>>[CH2:1]([NH:4][C:5](=[S:6])[O:10][CH2:7][CH2:8][CH3:9])[CH2:2][CH3:3]
Reactant: CCCN=C=S
Reactant: CCCO
Product: CCCNC(=S)OCCC
Temperature: 25 °C

Procedure:
To 10 g (0.099 g) of propyl isothiocyanate was added 50 mL of n-propanol. The reaction mixture was heated to reflux for 3 h and cooled to room temperature. An aliquot was removed and concentrated under reduced pressure to give the title compound, 1H NMR (300 MHz, CDCl3): δ0.94-1.02 (m,6H); 1.49-1.83 (m,4H); 3.22 (q), 3.51 (q,2H total); 4.37 (t), 4.45 (t,2H total), 6.25 (br s), 6.78 (br s,1H total). The remaining reaction mixture was concentrated under reduced pressure as above to provide 13.5 g of oil which was used without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)#[N:13]>CCOCC>[NH2:13][CH2:12][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: NCc1ccc(CO)cc1
Yield: 70.6 %

Procedure:
Adapting the procedure described by Keppler et al., Nature Biotechnology 21, 86-89 (2003), 1.5 L of 0.5 M LiAlH4 were chilled on ice and 22 mL of concentrated H2SO4 were added dropwise. 4-Cyanobenzoic acid (10) 20 g (136 mmol) was suspended in 120 mL of ether and this was added dropwise to the sulfuric acid. The reaction was heated to reflux for 4 hours. The reaction was quenched on ice with 215 mL of water followed by the addition of 80 g of NaOH in 650 mL of water. The ether was decanted off the resulting gel and the gel was extracted twice with 600 mL portions of ether. The combined ether fractions were dried over MgSO4 and evaporated under vacuum to give 13.1 g (96 mmol) of 4-(aminomethyl)benzyl alcohol (11) as a clear oil. 1H NMR (CDCL3/TMS) δ=1.95 (broad s, 3H, —OH and —NH2, exchangeable with D2O), 3.86 (s, 2H, —CH2—NH2), 4.68 (s, 2H, —CH2—OH), 7.30 (m, 4H, aromatic).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1)=[O:7].[F-].[Cs+].C(O[Si](OCC)(OCC)OCC)C.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[CH:50]=[CH2:51]>C1COCC1>[CH2:54]([O:53][C:49](=[O:52])[CH2:50][CH2:51][N:13]1[C:12](=[O:22])[C:11]2([CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH2:24][CH2:23]2)[N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14]1)[CH3:55]
Reactant: C=CC(=O)OCC
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: CCO[Si](OCC)(OCC)OCC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCN1CN(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a mixture of 8-(3,5-bis-trifluoromethyl-benzoyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (1.0 g, 2.1 mmol), cesium fluoride (32 mg, 0.21 mmol) and tetraethoxysilane (475 μL, 2.1 mmol) in THF (10 mL) was added ethyl acrylate (254 μL, 2.3 mmol). The mixture was stirred for 1 d at room temperature. Evaporation of the solvent yielded a residue which was purified by chromatography on silica gel (ethyl acetate/n-hexane 1:2) to yield the desired product (0.9 g, 75%), MS: m/e=572.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3)c2[N+](=O)[O-])CC1
Temperature: 120 °C
Yield: 54.2 %

Procedure:
4-(3-Fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.300 g, 0.923 mmol) and benzylamine (0.110 mL, 1.015 mmol) were combined in 1 mL dimethylsulfoxide with potassium carbonate (0.318 g, 2.308 mmol), and the reaction mixture was heated to 120° C. for 2 hours. The reaction mixture was poured onto 100 g icewater and extracted twice with 100 mL ethyl acetate. The combined organic phases were washed twice with 50 mL water, once with 50 mL brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash chromatography (1% to 15% ethyl acetate in hexanes) to afford 0.208 g (0.50 mmol, 54%) of 4-(3-benzylamino-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: 413 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][N:27]=[CH:26]3)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[N:11]1([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][N:27]=[CH:26]3)=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: O=C(c1ccccc1Nc1ccc2[nH]ncc2c1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(c1ccccc1Nc1ccc2[nH]ncc2c1)N1CCNCC1
Yield: 56.4 %

Procedure:
To a solution of the N-{2-[(4-benzylpiperazin-1-yl)carbonyl]phenyl}-1H-indazol-5-amine (127 mg, 0.309 mmol) obtained in Example 515 in ethanol (5 ml) were added 10% Pd-C (20 mg) and ammonium formate (98 mg, 1.55 mmol), and the resulting mixture was heated under reflux for 2 hours. The solid was removed by filtration using Celite, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby N-[2-(piperazin-1-ylcarbonyl)phenyl]-1H-indazol-5-amine (56 mg, 57%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:9][C:8]([CH:26]=C)=[CH:7][N:6]=1)=[O:4].C(=O)(O)[O-:29].[Na+].CSC>C(Cl)Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[N:9][C:8]([CH:26]=[O:29])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: C=Cc1cnc(C(=O)OC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Solvent: CO
Product: COC(=O)c1ncc(C=O)nc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -78 °C

Procedure:
A mixture of 3-(di-tert-butoxycarbonyl-amino)-5-vinyl-pyrazine-2-carboxylic acid methyl ester (1 g, 2.64 mmol) and sodium bicarbonate (0.332 g, 3.95 mmol) in DCM (45 ml) and MeOH (15 ml) was cooled to −78° C. and purged with oxygen for 5 min. The reaction mixture was treated with ozone for 40 min until the mixture turned blue. The reaction mixture was purged with oxygen for 10 min and with nitrogen for 10 min, then dimethyl sulfide (0.487 ml, 6.59 mmol) was added at −78° C. and the mixture was allowed to warm to room temperature. The mixture was diluted with DCM and washed with 10% aq. sodium thiosulfate. The aq. layer was extracted with DCM and the combined organic layers were dried with Na2SO4 and evaporated to provide the title compound as yellow oil. The compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH3:2].Br[C:32]1[N:36]=[C:35]([C:37]2[CH:38]=[CH:39][C:40]([CH2:45][CH:46]([CH3:48])[CH3:47])=[C:41]([CH:44]=2)[C:42]#[N:43])[S:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.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>[C:42]([C:41]1[CH:44]=[C:37]([C:35]2[S:34][N:33]=[C:32]([C:8]3[C:3]([CH2:1][CH3:2])=[C:4]([CH:18]4[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:22][CH2:23]4)[CH:5]=[CH:6][CH:7]=3)[N:36]=2)[CH:38]=[CH:39][C:40]=1[CH2:45][CH:46]([CH3:48])[CH3:47])#[N:43]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)Cc1ccc(-c2nc(Br)ns2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(-c2nsc(-c3ccc(CC(C)C)c(C#N)c3)n2)cccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Yield: 99.2 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinecarboxylate (70 mg, 0.169 mmol), 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-(2-methylpropyl)benzonitrile (D60) (81 mg, 0.253 mmol) and Pd(Ph3P)4 (19.47 mg, 0.017 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (1 mL) was added tripotassium phosphate (107 mg, 0.506 mmol). This solution was stirred in MW irradiation at 120° C. for 20 Min. The solution was dried directly with silica gel and purified on column chromatography to afford 1,1-dimethylethyl 4-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,2,4-thiadiazol-3-yl}-2-ethylphenyl)-1-piperidinecarboxylate (D124) (89 mg). MS (ES): C31H38N4O2S requires 530.3. found 531.3 (M+H+).
Reaction SMILES: N=C=N.[C:4]([OH:8])(=O)[CH2:5][OH:6].ON1C2C=CC=CC=2N=N1.Cl.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:30]([Br:42])[C:29]2=[O:43])=[CH:24][CH:23]=1.CN=C=O>CN(C)C(=O)C.CN1CCOCC1.ClCCCl>[CH2:35]([O:34][C:31]1[CH:32]=[CH:33][N:28]([C:25]2[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:4](=[O:8])[CH2:5][OH:6])=[CH:27][CH:26]=2)[C:29](=[O:43])[C:30]=1[Br:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)CO
Reactant: NCc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Agent: CN=C=O
Agent: Cl
Agent: N=C=N
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: O=C(CO)NCc1ccc(-n2ccc(OCc3ccccc3)c(Br)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a reaction vessel (borosilicate culture tube) was added approximately 1.95 g of polymer bound carbodiimide resin (0.96 mmol/g) followed by a stock solution of glycolic acid (5.8 mL, 0.10 M) in N,N-dimethylacetamide. A stock solution of 1-hydroxybenzotriazole in N,N-dimethylacetamide (0.4 mL, 0.10 M) and N-methylmorpholine in 1,2-dichloroethane (3.9 mL, 0.10 M) were added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 2 hours. A stock solution of 1-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(1H)-one hydrochloride in N,N-dimethylacetamide (0.05 M, 7.8 mL) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with 1,2-dichloroethane (8 mL) and treated with approximately 1.17 g of polyamine resin (2.63 mmol/g) and approximately 0.58 g of methylisocyanate functionalized polystyrene (1.50 mmol/9) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with N,N-dimethylacetamide (2×5 mL) and combined with the partially concentrated filtrate. The filtrate was concentrated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.081 g, 21%). 1H NMR (400 MHz, CD3OD) δ 7.55-7.30 (m, 10H), 6.51 (d, J=7.85 Hz, 1H), 5.37 (s, 2H), 4.52 (s, 2H), 4.08 (s, 2H). ES-HRMS m/z 443.0605 (M+H C21H19BrN2O4 requires 443.0601).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH2:16][NH:17][C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][Si](C(C)(C)C)(C)C)[N:23]=2)=[O:19])[CH:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:29][CH2:28][C:24]1[N:23]=[C:22]([CH2:21][NH:20][C:18]([NH:17][CH2:16][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][OH:8])[N:15]=2)=[O:19])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CNC(=O)NCc2cccc(CO[Si](C)(C)C(C)(C)C)n2)n1
Solvent: C1CCOC1
Product: O=C(NCc1cccc(CO)n1)NCc1cccc(CO)n1
Temperature: 25 °C
Yield: 166.8 %

Procedure:
N,N′-Bis{[6-(tert-butyldimethylsilyloxy)methylpyridin-2-yl]methyl}urea (27) (855 mg, 1.61 mmol) was suspended in THF (8.1 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The suspension was stirred at a room temperature. To the suspension was added dropwise 1.0M TBAF in THF (3.7 mL), and further stirred for 5 hours. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was suction-filtered to give N,N′-bis{[6-(hydroxymethyl)pyridin-2-yl]methyl}urea (28) (812 mg) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][CH:16]=[C:17]([CH:20]=1)[C:18]#[N:19]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C#N)cnc1N1CCNCC1
Product: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C#N)cc2C)CC1
Yield: 106.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 4-bromo-2-methylbenzoic acid (215 mg) and 5-methyl-6-piperazin-1-ylnicotinonitrile (202 mg), the title compound (426 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][C:23]([O:25]C)=[O:24])[C:10]3=[N:9][C:8]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[CH2:22][C:23]([OH:25])=[O:24])[C:10]3=[N:9][C:8]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C/C=C/CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C/C=C/CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C

Procedure:
To a solution of (E)-methyl 7-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)hept-3-enoate (step 2) (30 mg, 0.070 mmol) in THF (3 ml):MeOH (1 ml) was added LiOH (10.08 mg, 0.421 mmol) in water (1 ml). The reaction mixture was heated at reflux for 1.5 h. After cooling to RT, 2M HCl was added until the pH of the mixture was below pH 5. The volatile solvent was removed in vacuo and the resulting mixture was extracted with EtOAc (2×15 ml). The combined organic extracts were washed with water, dried over MgSO4 and concentrated in vacuo to afford the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O>[N:11]([CH2:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])=[N+:12]=[N-:13]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1c(Cl)cccc1Cl
Temperature: 55 °C
Yield: 87.9 %

Procedure:
To a solution of 2,6-dichlorobenzylbromide (0.50 g) in dimethylformamide (5 mL) is added sodium azide (0.41 g). The reaction is heated to 55° C. overnight. The resulting solution is cooled to room temperature and is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.37 g). 1H NMR (400 MHz, CDCl3) δ 7.45-7.40 (d, 2H), 7.30-7.25 (t, 1H), 4.73 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][NH:21][C:20](=[N:23][NH2:24])[C@H:19]([NH:25][C:26]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[C:42]4[C:37](=[N:38][CH:39]=[CH:40][CH:41]=4)[NH:36][C:35]3=[O:43])[CH2:30][CH2:29]2)=[O:27])[CH2:18][CH2:17]1.[CH:44]1([C:47](Cl)=O)[CH2:46][CH2:45]1>ClCCl>[CH:44]1([C:47]2[N:21]3[CH2:22][C@H:16]([C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=4[F:8])[CH2:17][CH2:18][C@@H:19]([NH:25][C:26]([N:28]4[CH2:29][CH2:30][CH:31]([N:34]5[C:42]6[C:37](=[N:38][CH:39]=[CH:40][CH:41]=6)[NH:36][C:35]5=[O:43])[CH2:32][CH2:33]4)=[O:27])[C:20]3=[N:23][N:24]=2)[CH2:46][CH2:45]1
Reactant: NN=C1NC[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C3CC3)nnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 45 °C
Reaction time: 20 h
Yield: 88.1 %

Procedure:
Triethylamine (20 μL, 0.142 mmol) was added to a solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-hydrazonoazepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide (59 mg, 0.118 mmol) and cyclopropanecarbonyl chloride (11 μL, 0.124 mmol) in dichloromethane (1 mL) and the mixture heated to 45° C. After 20 h, the reaction was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the title compound (57 mg). MS 549.2524 (M+1).