Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[N:9]=[C:10]([CH:16]4[CH2:18][CH2:17]4)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=3[C:6]([CH3:19])=[N:5]2)[CH2:3][CH2:2]1.[NH2:20][CH2:21][C:22]1[C:23](=[O:32])[NH:24][C:25]([CH3:31])=[CH:26][C:27]=1[CH2:28][CH2:29][CH3:30].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O.O>[CH:1]1([N:4]2[C:8]3[N:9]=[C:10]([CH:16]4[CH2:18][CH2:17]4)[CH:11]=[C:12]([C:13]([NH:20][CH2:21][C:22]4[C:23](=[O:32])[NH:24][C:25]([CH3:31])=[CH:26][C:27]=4[CH2:28][CH2:29][CH3:30])=[O:15])[C:7]=3[C:6]([CH3:19])=[N:5]2)[CH2:2][CH2:3]1
Reactant: Cc1nn(C2CC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,6-dicyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (125 mg, 0.486 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (126 mg, 0.583 mmol), 1-hydroxy-7-azabenzotriazole (132 mg, 0.972 mmol), EDC (186 mg, 0.972 mmol) and N-methylmorpholine (0.214 mL, 1.943 mmol) were suspended in Dimethyl Sulfoxide (DMSO) (10 mL) and stirred at room temperature for 16 hours. Added 25 mL of water and let stir for 10 minutes. The contents were filtered and dried. The product was collected as 200 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.07 Hz, 3 H), 1.04 (d, J=6.06 Hz, 8 H), 1.45-1.73 (m, 2 H), 2.12 (s, 3 H), 2.24 (br. s., 1 H), 2.33 (s, 3 H), 3.79 (br. s., 1 H), 4.34 (d, J=3.79 Hz, 2 H), 5.89 (br. s., 1 H), 6.99 (s, 1 H), 8.57 (br. s., 1 H), 11.51 (br. s., 1 H). MS(ES) [M+H]+ 420.2
Reaction SMILES: [C:1]([C@H:4]([C@@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5])([O-:3])=[O:2].C([C@H]([C@@H](C([O-])=O)O)O)([O-])=O.[Na+].[Na+].C([C@H]([C@@H](C([O-])=O)O)O)([O-])=O.[Ca+2].S(=O)(=O)(O)O>[O-][W]([O-])(=O)=O>[C:8]([OH:10])(=[O:9])[C@H:6]([C@@H:4]([C:1]([OH:3])=[O:2])[OH:5])[OH:7]
Reactant: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Agent: O=[W](=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O

Procedure:
Three samples of disodium cis-epoxysuccinate solution containing different amount of tungstate were separately converted to d-tartrate by treatment with a microbiorganism (FERM-P 2507) which has the ability to convert cis-epoxysuccinate to d-tartrate selectively. Disodium d-tartrate enzymatically prepared was converted to calcium d-tartrate, followed by acid-treatment with sulfuric acid to afford d-tartaric acid. The tungstate contents in the product and the starting material are compared in Table 3.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[C:8]2[C:7](=[CH:20][CH:19]=1)[NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[C:9]2([OH:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCN=C=O
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: CCN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Yield: 83.8 %

Procedure:
A solution of 28.4 g (31.7 ml, 0.4 mole) of ethyl isocyanate and 46.3 g (0.2 mole) of 2-amino-5-chlorobenzophenone in 100 ml of methylene chloride was refluxed for 20 hr. The reaction mixture was cooled, and the solid portion was collected on a filter and washed with methylene chloride to give 50.72 g (84%) of 6-chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-phenyl-2(1H)-quinazolinone as colorless crystals: mp 182°-184°; 13C nmr (DMSO-d6) δ 86.9 ppm (for COH) and δ 151.0 ppm (for NHCO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Na+].O.C(O)(=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=C([O-])c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Reaction time: 5 h

Procedure:
Sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (3.0 g) was suspended in ethyl acetate (100 ml) and water (100 ml) with stirring. Acetic acid (1.0 ml) was added to give two clear phases which were separated. The ethyl acetate layer was dried over magnesium sulfate and concentrated to give an oil which crystallised after a few minutes. Toluene (100 ml) was added and the solution was re-evaporated to give a white solid. Left at 20 mBar for 5 hours at 45° C. 2.69 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]([S:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])(=[O:28])=[O:27])[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[S:26]([N:19]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:23]=2[O:22][C:21]([CH3:25])([CH3:24])[CH2:20]1)(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OC(C)(C)CN3S(=O)(=O)c2ccccc2F)CC1
Agent: Cl
Solvent: CCO
Product: CC1(C)CN(S(=O)(=O)c2ccccc2F)c2cccc(N3CCNCC3)c2O1
Temperature: 100 °C
Yield: 42.4 %

Procedure:
4-[4-(2-Fluoro-benzenesulfonyl)-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylic acid tert-butyl ester (470 mg, 0.93 mmol) was dissolved in 3 ml ethanol. To this solution was added 1 ml of 10% ethanolic hydrochloric acid solution. The mixture was heated at 100° C. (steam bath) for 15 minutes, and then cooled to room temperature at which time a white crystalline solid formed. The solid was collected by filtration and dried at 70° C. under vacuum to provide 160 mg of 4-(2-fluoro-benzenesulfonyl)-2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo[1,4]oxazine as a hydrochloride salt. MP: 222.9–227.1° C. MS: (M+H) 479.
Reaction SMILES: [CH3:1][N:2]([S:6]([CH3:9])(=[O:8])=[O:7])[C:3](Cl)=[O:4].C(N(CC)CC)C.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>O1CCCC1>[CH3:1][N:2]([S:6]([CH3:9])(=[O:8])=[O:7])[C:3]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([C:18]([F:17])([F:26])[F:27])[CH:20]=1)=[O:4]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CN(C(=O)Cl)S(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1cccc(C(F)(F)F)c1)S(C)(=O)=O
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A solution OF 11.4 g of N-methyl-N-methylsulfonyl-carbamoyl chloride in 100 ml of tetrahydrofuran was slowly added at 10° C. to a mixture of 60 ml of tetrahydrofuran, 10.1 g of triethylamine and 16.1 g of 3-trifluoromethylaniline, and after stirring for 16 hours, the mixture was filtered. The filtrate was distilled to dryness under reduced pressure. The residue was added to isopropyl ether and the precipitate formed was recovered by vacuum filtration and was washed and dried to obtain 8 g of N-methyl-N-methylsulfonyl-N'-(3-trifluoromethylphenyl)-urea melting at 72° C. The melting point was unchanged after crystallization from isopropyl ether.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:15]=[CH:16]/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)/C=C/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCc1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a solution of 0.52 g (1.58 mmol) of methyl 7-(3-cyclopentoxy-4-methoxyphenyl)-2,4,6-E,E,E-heptatrienoate in 100 mL of methanol is added 0.05 g of 5% palladium on carbon black. The suspension is shaken under a 50 psi atmosphere of hydrogen for 16 hours after which time the excess gas is dissociated and the solution is filtered over Celite 545. The mixture is concentrated to dryness followed by liquid chromatography of the crude product over 100 g of silica gel eluting with 7.5% ethyl acetate in hexane. The final product is dried in vacuo and is found to be as analytically pure as an oil.
Reaction SMILES: CC1[N:3]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH3:21])[C:17]([OH:22])=[CH:16][C:15]=3[O:23][CH3:24])[CH:11]=[CH:10][CH:9]=2)C(C)=CC=1.Cl.NO.C(OCC)(=O)C.CCCCCC>C(O)C.O>[NH2:3][C:8]1[N:13]=[C:12]([C:14]2[C:15]([O:23][CH3:24])=[CH:16][C:17]([OH:22])=[C:18]([CH2:20][CH3:21])[CH:19]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCc1cc(-c2cccc(-n3c(C)ccc3C)n2)c(OC)cc1O
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(-c2cccc(N)n2)c(OC)cc1O
Temperature: 25 °C
Yield: 54.5 %

Procedure:
Under a nitrogen atmosphere, 4.50 g (13.96 mmol) of 4-[6-(2,5-Dimethyl-pyrrol-1-yl)-pyridin-2-yl]-6-ethyl-3-methoxyphenol (7) and 11.64 g (167.5 mmol) of hydroxylamine hydrochloride were combined in 84 mL of ethanol and 14 mL of water. The resultant mixture was allowed to reflux for 16 hours. The reaction mixture was then allowed to cool to ambient temperature and concentrated in vacuo. The resultant yellow residue was partitioned between ethyl acetate (200 mL) and dilute sodium bicarbonate (200 mL). The aqueous layer was extracted again with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine (1×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield crude product as a brown solid. Chromatography of the crude product on 250 g of silica gel 60 (EM Science) using 4:1 ethyl acetate: hexane yielded 1.86 g (55%) of 4-(6-Amino-pyridin-2-yl)-2-ethyl-5-methoxyphenol (8) as a salmon colored solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[O:17])[C:13]([CH3:29])=[CH:12][C:11]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1>CN1CCCC1=O>[Cl:1][C:2]1[N:6]=[CH:5][N:4]([C:10]2[N:15]=[C:14]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:20][CH2:19]3)=[O:17])[C:13]([CH3:29])=[CH:12][C:11]=2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)[N:3]=1
Reactant: Clc1nc[nH]n1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-n2cnc(Cl)n2)nc1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A well stirred solution of 0.17 g (1.59 mmol) of 3-chloro-1H-[1,2,4]triazole in 1.0 ml of 1-methyl-pyrrolidin-2-one was treated at RT with 0.058 g (1.32 mmol) of a sodium hydride (55% in mineral oil). After 30 min, 0.20 g (0.44 mmol) of [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was added and the reaction mixture was heated up to 150° C. After 24 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.11 g (48%) of the title compound as yellow oil. MS: 519.3 (MH+, 1Cl).
Reaction SMILES: [I:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[C:11]([O:25][CH3:26])[CH:10]=2)[CH3:8])=[C:4]([N+:29]([O-])=O)[CH:3]=1.[Cl-].[NH4+].CO.O>O1CCCC1.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].[Zn]>[I:1][C:2]1[CH:3]=[C:4]([NH2:29])[C:5]([NH:6][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[C:11]([O:25][CH3:26])[CH:10]=2)[CH3:8])=[CH:27][CH:28]=1
Reactant: COc1ccc(COc2ccc(C(C)Nc3ccc(I)cc3[N+](=O)[O-])cc2OC)cn1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COc2ccc(C(C)Nc3ccc(I)cc3N)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a stirred suspension of 4-iodo-N-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-2-nitroaniline (3.17 g, 5.92 mmol) and ammonium chloride (2.53 g, 47.37 mmol) in tetrahydrofuran (50 mL)/methanol (20 mL)/water (10 mL) was added iron(II) sulfate heptahydrate (5.76 g, 20.73 mmol) and zinc dust (1.35 g, 20.73 mmol). The resulting mixture was heated to reflux. After 1 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtercake was washed with methanol (50 mL). The filtrate was concentrated, and the residue was diluted with 3N ammonium hydroxide solution (100 mL). The basic mixture was extracted with chloroform (3×50 mL), and the combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 2.02 g (68%) of 4-iodo-N1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)benzene-1,2-diamine as a brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 83 %

Procedure:
To a suspension of N-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.383 g, 5.005 mmol) in anhydrous dichloromethane (60 ml) were added carbon tetrachloride (5.8 ml, 60 mmol) and triphenylphosphine (1.574 g, 6.000 mmol), and the mixture was stirred at room temperature for 22.5 hr. Triphenylphosphine (786.0 mg, 2.997 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g, ethyl acetate:hexane=2:3) to give N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.224 g, 4.153 mmol, yield 83.0%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[CH2:22]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:19][C@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Cc2ccccc2)CC1
Temperature: 85 °C
Yield: 70 %

Procedure:
Combine (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (150 mg, 0.526 mmol) dissolved in dimethylformamide (˜2 mL) and add 0.13 M solution of 4-benzylpiperidine in ethanol (˜4 mL) and heat for 10 hours at 85° C. Concentrate and purify the reaction mixture by flash (silica) chromatography on a Water's Sep-Pak 5 g silica cartridge using a graded solvent mixture of dichloromethane to 10% methanol in dichloromethane to give the title compound (169.9 mg, 70% Yield). Purity by LC/MS=99%, [M+H]+=461.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18](Cl)=[O:19])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[O:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH2:36])=[C:31]([F:37])[CH:30]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[O:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH:36][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:19])=[C:31]([F:37])[CH:30]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Reactant: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A suspension of 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (freshly prepared from Example B2 (0.207 g, 0.747 mmol) using the method of Example 4) in THF (5 ml) was added to a 0° C. solution of Example A2 (0.15 g, 0.498 mmol) and N,N-diisopropylethylamine (0.870 ml, 4.98 mmol) in THF (5 ml). The mixture was allowed to warm to room temperature and stir overnight. Additional 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride [freshly prepared from Example B2 (0.207 g, 0.747 mmol)] was added and the mixture was stirred overnight at RT. Additional 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride [freshly prepared from Example B2 (414 mg, 0.996 mmol)] was added to the reaction mixture. After stirring for 3 h, the mixture was partitioned between CH2Cl2 and sat. Na2CO3 (aq) and extracted with sat. Na2CO3 (aq) (2×). The organic extract was dried and evaporated. The crude product was purified by silica gel chromatography (hexanes/EtOAc) to yield N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 44.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 8.74 (s, 1H), 8.37 (m, 2H). 7.92 (d, J=7.8 Hz, 1H), 7.59 (dd. J=10.9, 7.4 Hz, 1H), 7.48 (dd, J=8.8, 4.9 Hz, 2H), 7.36 (t, J=8.7 Hz, 2H), 6.88 (d, J=5.6 Hz, 1H); 6.55 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.33 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 560.1 (M+H+).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[C:11](=[O:22])[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:13]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O>C1COCC1>[OH:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:23][CH2:24][CH3:25])[C:11](=[O:22])[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:13]=1
Reactant: CCCn1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn(Cc2ccc(C)cc2)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCn1c(CCO)cn(Cc2ccc(C)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
The 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-one (16.79 g, assumed 27.8 mmol) was dissolved in THF (160 mL) and then treated with a 1 M solution of tetrabutylammonium fluoride in THF (55.6 mL, 55.5 mmol) and the reaction stirred at room temperature under N2 for 20 minutes. The reaction was worked up extractively with EtOAc and water and the organic layer dried (MgSO4) and the solvent removed in vacuo to give crude product that was purified by flash chromatography using 3% of MeOH in CH2Cl2 to afford 4.65 g (61%) 4-(2-hydroxy-ethyl)-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-one. MS (ES+) Calc'd for C16H23N2O2 (M+1) 275. Found m/z 275 (100%). 1H NMR.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46]1(=O)[O:50][CH2:49][CH2:48][CH2:47]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[OH:50][CH2:49][CH2:48][CH2:47][C:46]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: O=C1CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CCCO)nc12
Yield: 42 %

Procedure:
A solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (150 mg), butyrolactone (628 mg) and p-toluenesulfonic acid (139 mg) was heated at 100° C. for 4 hours. The reaction mixture was diluted with chloroform and washed with aqueous sodium hydrogen carbonate. The extract was dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (10% methanol in chloroform) and then preparative thin-layer chromatography (chloroform/methanol=20/3) to give 4-[2-(3-hydroxypropyl)-1H-benzimidazol-4-yl]carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (70 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.[Cl:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2([C:37](=N)OCC)[CH2:36][CH2:35]2)[CH:33]=1.C(N(CC)CC)C>C(O)C>[Cl:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2([C:37]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH2:36][CH2:35]2)[CH:33]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (5.5 g, 15.2 mmol) and acetic acid (17.4 mL, 305 mmol) in ethanol (20 mL) was added a solution of ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (3.25 g, 15.2 mmol) in ethanol (30 mL) followed by triethylamine (12.7 mL, 91.2 mmol). The resulting mixture was purged with nitrogen. The reaction mixture was stirred for 18 h at 100° C. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between a saturated aqueous solution of ammonium chloride (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL). The combined organics were washed with a saturated aqueous solution of sodium bicarbonate and the resulting aqueous layer was extracted with dichloromethane (50 mL). The organics were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-5% methanol in dichloromethane) to afford (R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (6.33 g, 94%). 1H NMR (500 MHz, CDCl3) δ 1.55-1.70 (m, 1H), 1.72-2.05 (m, 11H), 2.60-2.70 (m, 1H), 2.90-2.95 (m, 1H), 3.03-3.10 (m, 1H), 3.42-3.50 (m, 3H), 3.56-3.62 (m, 1H), 4.20-4.25 (m, 1H), 4.38-4.44 (m, 1H), 6.62-6.68 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 1H); MS (ES+) (M+H) 440; UPLC retention time 0.47 min (Method N).