Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]([N:8]([CH2:28][CH2:29][CH2:30][S:31]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32])[C:9]1[C:10]([C:23](OCC)=[O:24])=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].[O-]CC.[Na+]>C(O)C.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:13]2[CH:14]=[C:9]3[C:10]([C:23]([OH:24])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:39])[C:6](=[O:7])[N:8]3[CH2:28][CH2:29][CH2:30][S:31]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)(=[O:32])=[O:33])=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)N(CCCS(=O)(=O)N1CCCC1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) solution of ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][3-(1-pyrrolidinylsulfonyl)propyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (275 mg, 0.488 mmol) in ethanol (5 mL) was added sodium ethoxide (347 μL, 3.09 M in ethanol, 1.07 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred 10 minutes, then poured onto ice. Once the ice had melted, the mixture was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1 H), 7.73 (s, 1 H), 7.23 (dd, J=8.3, 5.4 Hz, 2 H), 7.02 (t, J=8.7 Hz, 2 H), 4.51 (q, J=7.1 Hz, 2 H), 4.38 (t, J=7.8 Hz, 2 H), 4.12 (s, 2 H), 3.37-3.33 (m, 4 H), 3.05 (t, J=6.5 Hz, 2 H), 2.18 (m, 2 H), 1.96-1.93 (m, 4 H), 1.48 (t, J=7.2 Hz, 3 H); MS m/z 518 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11]C)[CH:5]([NH2:9])[CH2:6][CH2:7]C)C.COC(OC)C(C#N)C>CO.[Ni]>[CH3:1][O:3][CH:4]([O:10][CH3:11])[CH:5]([NH2:9])[CH2:6][CH3:7]
Reactant: CCCC(N)C(OCC)OCC
Agent: [Ni]
Agent: COC(OC)C(C)C#N
Solvent: CO
Product: CCC(N)C(OC)OC
Reaction time: 0.06 h
Yield: 77.5 %

Procedure:
This reaction was run as for aminopentanal diethyl acetal [Example 15(c)(ii)] using MeOH as solvent (160 mL), 7.8 g of Raney nickel and 25 g (0.194 mol) of cyanopropionaldehyde dimethyl acetal. (H2 consumption 113% of theoretical after 3.5 hr. ) The product after concentration at reduced pressure analyzed as an essentially pure single component at 3.40 min by gc (20 g, 77.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:18]1([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:28][C:27]([C:26]3[CH:25]=[CH:24][C:23]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:30][CH:29]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NCc1ccc(N2CCCC2)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate and 4-(1-pyrrolidinyl)benzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid is reacted and treated in the same manner as in Example 1 to give 5-(4-chlorophenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH:1](=[N:3]/[OH:4])\[CH3:2].[CH3:5][C:6]([NH2:10])([C:8]#[CH:9])[CH3:7].C(N(CC)CC)C.Cl[O-].[Na+]>C(Cl)Cl>[CH3:5][C:6]([NH2:10])([C:8]1[O:4][N:3]=[C:1]([CH3:2])[CH:9]=1)[CH3:7]
Reactant: C#CC(C)(C)N
Reactant: C/C=N/O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(C)N)on1
Temperature: 4 °C
Reaction time: 5 h
Yield: 4.2 %

Procedure:
To a solution of (E)-acetaldehyde oxime (CAN 107-29-9, 1.0 g, 16.9 mmol), 2-methylbut-3-yn-2-amine (CAN 2978-58-7, 1.4 g, 16.9 mmol) and triethylamine (CAN 121-44-8, 0.17 g, 1.69 mmol) in methylene chloride (25 mL) at 0° C. was added a 5% aqueous solution of sodium hypochlorite (5%, 42.6 g) over 3 h. The reaction was allowed to warm to 4° C. and stirring continued for 5 h. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (50 mL). The combined methylene chloride extracts were washed with saturated aqueous sodium chloride (60 mL) and dried over anhydrous magnesium sulfate. The solvent was removed to give a yellow oil. The crude product was purified by column chromatography (silica gel 30 g, eluting with 30% ethyl acetate in petroleum ether) to yield the product as yellow solid (0.1 g, 4.2%); MS (EI): m/e=141.2 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])(=O)=O.[NH3:28].O.O>CN(C=O)C>[NH2:28][CH2:6][CH2:7]/[CH:8]=[CH:9]/[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:12]
Reactant: N
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCOS(C)(=O)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCN
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (E)-6-(2-(tert-butoxycarbonylamino)phenylamino)-6-oxohex-3-enyl methanesulfonate (358 mg, 0.9 mmol) in DMF (5 mL) was added NH3.H2O (20 mL) at 0° C. and stirred at the same temperature for 0.5 hour, then the reaction mixture was stirred at room temperature for 12 hr, then water (100 mL) was added, the mixture was extracted with DCM (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-tert-butyl 2-(6-aminohex-3-enamido)phenylcarbamate (100 mg, 88%) as a white solid after purification by column chromatography (eluent: DCM:MeOH=50:1).
Reaction SMILES: [N+:1]([C:4]1[CH:51]=[CH:50][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:49])([CH3:48])[O:14][Si:15]([CH3:47])([CH3:46])[O:16][Si:17]([CH3:45])([CH3:44])[O:18][Si:19]([CH3:43])([CH3:42])[O:20][Si:21]([CH3:41])([CH3:40])[O:22][Si:23]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=2)([CH3:25])[CH3:24])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:51]=[CH:50][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:48])([CH3:49])[O:14][Si:15]([CH3:47])([CH3:46])[O:16][Si:17]([CH3:45])([CH3:44])[O:18][Si:19]([CH3:43])([CH3:42])[O:20][Si:21]([CH3:41])([CH3:40])[O:22][Si:23]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[CH:35][CH:36]=2)([CH3:24])[CH3:25])=[CH:6][CH:5]=1
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1
Yield: 99.6 %

Procedure:
1.02 g of the above (2A) (1.25 mmol) and 10 mL of a 10 wt % Pd/C (0.0203 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,11-bis[4-(4-aminophenoxy)butyl]-1,1,3,3,5,5,7,7,9,9,11,11-dodecamethylhexasiloxane (3A) (0.943 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained (3A), and results are shown below.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:16][CH2:17]C(OCC)=O)=[C:4]([O:14]C)[C:5]2[C:10]([C:11]=1[O:12]C)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+]([O-])(O)=O.CC(C)=O.[CH3:31][CH2:32][O:33][C:34](C)=[O:35]>CC(O)=O>[Br:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[C:3]=1[CH:16]([CH3:17])[C:34]([O:33][CH2:32][CH3:31])=[O:35]
Reactant: CCOC(=O)CCc1c(Br)c(OC)c2ccccc2c1OC
Reactant: CCOC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C1=C(Br)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Following the general procedures by Shinkawa et al. and Flader et al.,16,22 67a (0.361 g, 0.983 mmol) was dissolved in EtOAc (10.0 mL) and then AcOH (6 drops) and HNO3 (1.0 mL) were added at room temperature. Then Ag(II)O (0.473 g, 3.82 mmol) was added in one portion at room temperature and stirred for 30 minutes at room temperature, the reaction was monitored by TLC (1:4 acetone:hexanes). After 30 minutes another addition of Ag(II)O (0.147 g, 1.19 mmol) was required, and the reaction stirred at room temperature for another 30 minutes. TLC showed the reaction to be complete, and the solvent was then separated from the silver solid by passing the reaction through a pipette with cotton plug, the solid was rinsed with EtOAc (4×5.0 mL), and then the solution was diluted with EtOAc (50.0 mL). The solution was then washed 2 times with saturated brine, dried over MgSO4, filtered, and condensed. The crude yellow solid was recrystallized from acetone/hexane to provide 68a (0.135 g, 0.400 mmol, 41%) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1.[OH-].[Na+]>[Fe].O>[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1
Reactant: CSc1ccc([N+](=O)[O-])cn1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CSc1ccc(N)cn1
Yield: 91.7 %

Procedure:
Iron powder (3 g), water (20 mL) and concentrated hydrochloric acid (3 mL) were mixed, and 2-(methylthio)-5-nitropyridine (2 g, 12 mmol) was added portionwise. After reflux reaction for 2 hours, the reaction mixture was basified with 1N sodium hydroxide and extracted with 20 mL ethyl acetate for three times. The combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to yield the target compound (1.54 g, 11 mmol).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1([F:37])[CH2:8][CH:7]([CH2:9][O:10][CH2:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[N:27][CH:26]=4)=[C:21]([O:32][CH3:33])[CH:20]=3)[N:15]=[C:14]([C:34](=[O:36])[CH3:35])[CH:13]=2)[CH2:6]1>C1COCC1>[F:37][C:5]1([F:4])[CH2:8][CH:7]([CH2:9][O:10][CH2:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[N:27][CH:26]=4)=[C:21]([O:32][CH3:33])[CH:20]=3)[N:15]=[C:14]([C:34]([OH:36])([CH3:1])[CH3:35])[CH:13]=2)[CH2:6]1
Reactant: C[Mg]Br
Reactant: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)=O)n2)ccc1-c1cnnc(C)c1
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC3CC(F)(F)C3)cc(C(C)(C)O)n2)ccc1-c1cnnc(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of methylmagnesium bromide (1.430 mL, 2.00 mmol) in THF (6 mL) a solution of 1-(6-(((3,3-difluorocyclobutyl)methoxy)methyl)-2-(3-methoxy-4-(6-methylpyridazin-4-yl)phenylamino)pyrimidin-4-yl)ethanone (94 mg, 0.20 mmol) in THF (3 mL) was added over 5 min. The mixture was stirred on ice-bath for 30 minutes before it was quenched with ammonium chloride (aq, sat). The solvent volume was reduced by evaporation. The mixture was extracted with dichloromethane and the organic phase was passed through a phase separator. The residue was purified by preparative HPLC to give the title compound as a dry film 38 mg (39%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2c(cc(CCc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (53 mg, 0.13 mmol), glycine (2.06 g, 27.5 mmol) and NaOMe solution (41 mL, 20.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 53 mg of the title compound. MS: (+) m/z 458.10 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][NH:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[N:56]([CH3:60])[CH:57]=[CH:58][N:59]=2)=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:47]([CH3:46])[CH2:48][C:49]3[CH:50]=[CH:51][C:52]([C:55]4[N:56]([CH3:60])[CH:57]=[CH:58][N:59]=4)=[CH:53][CH:54]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(-c2nccn2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-c4nccn4C)cc3)co2)c(C)c1
Reaction time: 1 h

Procedure:
5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (50 mg, 0.14 mmol) was dissolved in DMF (3 mL) and EDCI (32 mg, 0.17 mmol) and HOBt (23 mg, 0.17 mmol) were added. The resulting solution was stirred for 60 min prior to the addition of N-methyl-1-[4-(1-methyl-1H-imidazol-2-yl)phenyl]methanamine (31 mg, 0.17 mmol) dissolved in DMF (2 mL) and stirred at ambient temperature for 18 h. The reaction was diluted with EtOAc (20 mL) and washed with water, saturated aqueous NaHCO3, saturated brine, dried over Na2SO4 and concentrated in vacuo. The resulting oil was purified using prep method C.
Reaction SMILES: [NH2:1][C:2]1[C:6](Br)=[C:5]([CH3:8])[O:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>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].O1CCOCC1>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:18]2[C:17]([C:6]3[C:2]([NH2:1])=[N:3][O:4][C:5]=3[CH3:8])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:25][CH:26]=1
Reactant: CC1(C)OB(c2cccnc2Oc2ccc(N)cc2)OC1(C)C
Reactant: Cc1onc(N)c1Br
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Product: Cc1onc(N)c1-c1cccnc1Oc1ccc(N)cc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
In a 20 mL sealed tube was added dioxane (1.0 mL), which was purged with nitrogen for 5 minutes and the tube sealed. To this was added 3-amino-4-bromo-5-methylisoxazole (0.100 g, 0.565 mmol), 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine (0.265 g, 0.847 mmol), 2.0M aqueous sodium carbonate (0.565 mL, 1.13 mmol) and the tube was purged with nitrogen and sealed. To the mixture was added tri-t-butylphosphonium tetrafluoroborate (0.037 g, 0.13 mmol), tris(dibenzylideneacetone)dipalladium (0)(0.039 g, 0.042 mmol) and the tube was purged with nitrogen, sealed and heated to 100° C. with stirring for 5 hours. The mixture was cooled to RT, passed through pad of silica, which was washed with 100% CH2Cl2:MeOH:NH4OH (90:10: 1)/CH2Cl2. The eluent was concentrated and purified on a Gilson reverse phase chromatography system. The product fractions were extracted into CH2Cl2, washed 1× saturated NaHCO3, 1×H2O, dried with Na2SO4, filtered through fritted funnel and concentrated to yield 4-(2-(4-aminophenoxy)pyridin-3-yl)-5-methylisoxazol-3-amine as light yellow solid. MS m/z=283 [M+1]+. Calc'd for C15H14N4O2: 282.30.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.Br[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.C(#N)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:26][C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Reactant: O=C(CBr)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3cc(OCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A mixture of 4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (prepared as described above, 750 mg, 2.27 mmol), 4-(bromoacetyl)morpholine (565 mg, 2.72 mmol), and cesium carbonate (2.22 g, 6.81 mmol) in DMF (30 mL) was heated at 75° C. overnight. The reaction mixture was allowed to cool and was poured into water (300 mL). After 30 minutes, the solution was extracted with chloroform (6×75 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The resulting solid was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-35% methanol/dichloromethane (1:10) in dichloromethane) The appropriate fractions were combined and concentrated to yield an off white solid that was slurried in boiling acetonitrile for 15 minutes. The slurry was allowed to cool with stirring. The solid was isolated by filtration and dried to yield 797 mg of 1-[4-amino-2-(ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid, mp 209-211° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>[Cu]I.[Pd](Cl)Cl.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.C(N(CC)CC)C>[Cl:10][C:4]1[C:5]([S:8][CH3:9])=[N:6][CH:7]=[C:2]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:3]=1
Reactant: CSc1ncc(Br)cc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CSc1ncc(C#C[Si](C)(C)C)cc1Cl
Temperature: 80 °C
Reaction time: 17 h
Yield: 70.6 %

Procedure:
A mixture of 5-bromo-3-chloro-2-methylthio-pyridine (7.5 g, 0.031 mol), trimethylsilylacetylene (5.3 g, 0.053 mol), copper (I) iodide (60 mg, 0.32 mmol), bis(triphenylphosphine) palladium (II) chloride (0.42 g, 0.6 mmol) and triethylamine (100 mL) was sealed in a 300 mL Hastelloy steel bomb and heated with stirring at 80° C. for 17 hours. The mixture was cooled, filtered, and the precipitate washed with ethyl acetate (100 mL). The combined organic solutions were evaporated to dryness under reduced pressure. The resultant dark oil was dissolved in hexane (100 mL) and washed with water and brine, and evaporated under reduced pressure. Purification of the residue by chromatography over silica (0-2% ethyl acetate:hexane) gave the desired product (5.6 g, 71%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH2:12][CH2:13][C:7]=2[C:6]([O:25]C)=[C:5]([O:27][CH3:28])[C:4]=1[O:29][CH3:30].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(=O)(O)[O-].[Na+].O>[N:16]1([CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][C:8]3[C:3](=[O:2])[C:4]([O:29][CH3:30])=[C:5]([O:27][CH3:28])[C:6](=[O:25])[C:7]=3[CH2:13][CH2:12]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[CH:17]1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCn1cnc3ccccc31)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCn3cnc4ccccc43)CC2)C1=O
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To a mixture of 1-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethyl]-1H-benzo[d]imidazole (380 mg), pyridine-2,6-dicarboxylic acid (465 mg), THF (8 ml), and water (4 ml) was added an water (4 ml) solution of CAN (2.03 g) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was recrystallized from ethyl acetate to obtain the entitled compound (240 mg).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:19][CH3:20])=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[C:12]3O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:25]>C1(C)C=CC=C(C)C=1>[NH2:25][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([O:19][CH3:20])=[CH:9][CH:10]=2)[NH:15][C:14](=[O:17])[CH:13]=1
Reactant: COc1ccc2c(O)cc(=O)[nH]c2c1OC1CCCC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1cccc(C)c1
Product: COc1ccc2c(N)cc(=O)[nH]c2c1OC1CCCC1
Temperature: 150 °C
Reaction time: 0.03 h

Procedure:
A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one (350 mg, 1.3 mmol), ammonium acetate (4.0 g, 52 mmol), and anhydrous m-xylene (10 mL) was heated at 150° C. under N2 for 48 h and then allowed to cool to rt. The mixture was concentrated to dryness, diluted with water (25 mL), stirred for 2 min, sonicated for 1 min, and then stirred for 5 min. The free-flowing solid was filtered, washed with water (25 mL), and pumped to dryness to give 4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one: MS (ESI): 274.9.