Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]1[CH:21]=O.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:21][C:13]1[NH:12][C:20]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2C1=Cc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2-oxindole (212 mg), indole-2-carbaldehyde (174 mg) (prepared according to Synthetic Communications, 1993, 23, 3109) and piperidine (10 mg) in ethanol was held in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in a vacuum oven to give 5-bromo-3-(1H-indol-2-ylmethylene)-1,3-dihydroindol-2-one.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][OH:30].O>O1CCCC1.N1C=CC=CC=1>[OH:30][CH2:29][C:28]1[CH:27]=[C:26]([NH:25][C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)=[O:24])[CH:33]=[CH:32][CH:31]=1
Reactant: Nc1cccc(CO)c1
Reactant: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CO)c2)cc1
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a 0° C. solution of 13 g of p-(tetradecyloxy)phenyl isocyanate in 70 ml of tetrahydrofuran and 30 ml of pyridine is added over 10 minutes a solution of 7.24 g of 3-aminobenzyl alcohol in 70 ml of tetrahydrofuran with continued stirring for one hour. The mixture is heated until all the solids dissolve then allowed to stand at ambient temperature overnight. The mixture is poured into water and the solid collected. The solid is washed with dilute hydrochloric acid and water then crystallized from ethyl alcohol to give 13.1 g of the desired product as a light pink solid, m.p. 150°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1/[CH:15]=[C:16](\[CH2:22][CH2:23][CH3:24])/[C:17]([O:19]CC)=[O:18].COC1C2C(=CC=CC=2)C(OC)=CC=1/C=C(\C)/C(O)=O>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1/[CH:15]=[C:16](\[CH2:22][CH2:23][CH3:24])/[C:17]([OH:19])=[O:18]
Reactant: CCC/C(=C\c1cc(OC)c2ccccc2c1OC)C(=O)OCC
Agent: COc1cc(/C=C(\C)C(=O)O)c(OC)c2ccccc12
Solvent: CCOC(C)=O
Product: CCC/C(=C\c1cc(OC)c2ccccc2c1OC)C(=O)O

Procedure:
Compound 29b was prepared from 28b (0.215 g, 0.656 mmol) as described above for 29a to give 0.193 g (0.642 mmol, 99%) of the product as a white solid following flash chromatography (1:3 EtOAc:hexanes 0.5% AcOH) and recrystallization from Et2O/hexanes.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[C:7](/[CH:19]=[CH:20]/[C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)=[CH:6][CH:5]=[CH:4][C:3]1=2.ClC1C=C(C=CC=1)C(OO)=[O:38].[OH2:44]>C(Cl)Cl>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([S:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:38])=[O:44])[C:8]2[C:7](/[CH:19]=[CH:20]/[C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O
Reactant: CCOC(=O)c1ccc(/C=C/c2cccc3c2C(Sc2ccccc2)=CCC3(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(/C=C/c2cccc3c2C(S(=O)(=O)c2ccccc2)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 0.090 g (0.2 mmol) of ethyl (E)-4-[2-(5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalenyl)ethenyl]benzoate (Compound A16) in 2.0 mL of methylene chloride was added dropwise a solution of 140 mg (0.45 mmol, 50-60%) of m-chloroperoxybenzoic acid in 2.0 mL of methylene chloride and the reaction stirred at room temperature for 3.5 h. The mixture was diluted with water and extracted with methylene chloride (2×). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica, 30% ethyl acetate in hexanes) followed by recrystallization in EtOH to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16]O)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.CS(Cl)(=O)=O.[OH-].[K+]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:16][O:18]1
Reactant: OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CO
Product: Clc1ccc(C2(Cn3ccnc3)CO2)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To an ice-cooled solution of (-)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2,3-propanediol (5.4 g) in pyridine (50 ml) was added dropwise methanesulfonyl chloride (2.15 g). The reaction mixture was stirred at 0°-10° C. for 2 hours. An ice-cooled solution of 85.5% potassium hydroxide (3.7 g) in methanol (60 ml) was added dropwise thereto, and then the mixture was stirred at 0°-10° C. for 1 hour. The solvent was removed in vacuo, and the residue was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and evaporated to give a red oil. The oily residue was purified by chromatography on silica gel (60 g) with chloroform as a solvent and recrystallized from ether-hexane to give (-)-2-(2,4-dichlorophenyl)-2-(imidazol-1-yl)methyloxirane (4.3 g) as colorless needles. Yield, 84.6%. M.P., 107°-108.5° C. [α]D21.5, -8.4° (C=1.0, MeOH).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[S:5])[NH2:4].[P].[S].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=O>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]1[S:5][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:4]=1
Reactant: NC(=S)C(F)(F)F
Reactant: O=C(CBr)c1ccccc1O
Agent: [P]
Agent: [S]
Solvent: CCO
Product: Oc1ccccc1-c1csc(C(F)(F)F)n1

Procedure:
2,2,2-Trifluoroethanethioamide (which may be prepared by the method of J. H. Hillhouse et al., Phosphorus, Sulfur Relat. Elem. 1986, 26, 169-84) (157 mg, 1.22 mmol) in ethanol (1.3 mL) was added drop-wise to a solution of 2-bromo-1-(2-hydroxyphenyl)ethanone (119 mg, 0.55 mmol) in ethanol (1.3 mL) and the reaction was refluxed overnight. The reaction was concentrated in vacuo and purified via silica gel chromatography (Gradient: 5% to 20% ethyl acetate in heptane) to afford the title compound. Yield: 67 mg, 0.27 mmol, 49%. LCMS m/z 246.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 6.95 (ddd, J=8, 7, 1 Hz, 1H), 7.07 (dd, J=8.2, 1.2 Hz, 1H), 7.33 (ddd, J=8, 7, 2 Hz, 1H), 7.64 (dd, J=7.8, 1.6 Hz, 1H), 7.81 (s, 1H), 10.47 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[CH3:39][OH:40]>O1CCOCC1.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:13]2[C:12]([N:8]3[C:9]4[C:4](=[CH:3][C:2]([C:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:40])=[CH:11][CH:10]=4)[CH2:5][CH2:6][CH2:7]3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=3)[N:14]=2)=[CH:31][CH:30]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)nc2c1
Reactant: CO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C(=O)N5CCOCC5)ccc43)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of methyl 3-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (130 mg, 0.26 mmol) in dioxane (25 ml) was added morpholine (35 mg, 0.40 mmol) and Pd(dppf)2Cl2 (6.7 mg, 0.05 mmol) with stirring overnight maintained with atmosphere of CO (g) at 100° C. under 5 Atm. The reaction mixture was concentrated under vacuum to give a residue, which was applied onto a silica gel column with 1% methanol in dichloromethane to afford methyl 2-(4-fluorophenyl)-3-[6-[(morpholin-4-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-1-yl]quinoxaline-6-carboxylate as a yellow solid (107 mg, 77%).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH3:22])[CH:6]1[O:23]C(=O)C)(=O)C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[OH-].[Na+]>COC(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:23])[CH:7]([CH3:22])[CH2:8]3)[C:11]([NH:30][CH:27]3[CH2:29][CH2:28]3)=[N:12][C:13]=2[CH:18]=1
Reactant: NC1CC1
Reactant: CC(=O)OC1C(C)CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1OC(C)=O
Agent: COC(C)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Yield: 64 %

Procedure:
(±)-(1R*, 2S*, 3R*, 5S*)-5-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-methyl-1,2-cyclopentanediyl diacetate (Part D, 350 mg, 0.75 mmole) and cyclopropylamine (Aldrich, 0.53 mL) were refluxed in methoxyethanol (5 mL) for 5 hours. 1 N sodium hydroxide (0.75 mL) was added to the cooled reaction mixture and volatiles were evaporated in vacuo. The residue was chromatographed on silica gel. Product was eluted with 5% methanol-chloroform. Recrystallization from methanol-ethyl acetate gave (±)-(1R*, 2S*, 3R*, 5S*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-methyl-1,2-cyclopentanediol as white crystals (170 mg, 64%); m.p. 231-233 ° C.; 1H-NMR(DMSO-d6)δ: 7.48 and 7.39 (both s, 1 each, 2 benzimidazole CH), 7.10 (m, 1, NH), 4.83 (d, J=5.9 Hz, 1, OH), 4.74 (d, J=5.1 Hz, 1, OH), 4.5-4.3 (m, 2, NCH and OCH), 3.7-3.6 (m, 1, OCH), 2.85-2.7 (m, 1, Ce), 2.1-1.8 (m, 2, CH2 and CH), 1.7-1.5 (m, 1, CH), 1.16 (d, J=5.4 Hz, 3, CHCH3), 0.8-0.5 (m, 4, 2 CH2 of cyclopropyl); mass spectrum (CI): 356 (M+1). [See Examples 1 and 2]
Reaction SMILES: Cl[C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[OH-].[NH4+:12].O>C(O)C>[NH2:12][C:2]([CH:8]([CH3:10])[CH3:9])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: [NH4+]
Reactant: CC(C)C(Cl)=C(C#N)C#N
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(N)=C(C#N)C#N
Temperature: 0 °C
Reaction time: 3.75 h

Procedure:
A solution of 530.5 g of 3-chloro-2-cyano-4-methyl-2-pentenenitrile in 515 ml of ethanol was added dropwise during one hour to a stirred solution of 2,400 ml of concentrated ammonium hydroxide in 1,560 ml of ethanol while maintaining the reaction mixture at 35°-40° with an ice-water bath. The reaction mixture was stirred for 3.5-4 hours and was poured into 6.5 liters of ice and water. The mixture was stirred until all the ice had melted (approximately thirty minutes). The precipitate was collected by filtration. The filter cake was washed with two 1500-ml portions of water and air-dried on the filter. After the drying the 400 g of 3-amino-2-cyano-4-methyl-2-pentenenitrile, mp 182°-184°, was used in the next synthesis step without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:15][C:16](OC(C)=O)=[O:17]>CC(O)=O>[F:14][C:2]([F:13])([F:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:16](=[O:17])[CH3:15])=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Reflux 4-trifluoromethylsulfonyl-phenylamine (5 g) and Ac2O (2.2 mL) for 1.5 hours in HOAc (20 mL). Evaporate the solvent in vacuo, then crystallize the residue in EtOAc/EtOH to obtain N-(4-trifluoromethylsulfonyl-phenyl)-acetamide.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C12BC(CCC1)CCC2.O1CCCC1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C@H:31]([O:33][CH2:34][C@H:35]1[CH2:37][O:36]1)[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.ClCCl.O1CCCC1>[O:36]1[CH2:37][C@@H:35]1[CH2:34][O:33][C@@H:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[CH3:32]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CCCCC(=O)OC
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCCc1ccccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To methyl 5-hexenoate (608 mg) was added 0.5 M 9-bora bicyclo[3.3.1]nonane-tetrahydrofuran solution (9.5 ml) under ice-cooling and the mixture was stirred overnight at room temperature. The reaction mixture was added dropwise to a suspension of tetrahydrofuran (10 ml), (2R)-2-[[(1R)-1-(2-bromophenyl)ethoxy]methyl]oxirane (1.06 g) obtained in Example 1, Step 1, tri-potassium phosphate (1.32 g), [bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (170 mg) and the mixture was heated under reflux for 7 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give the title compound (621 mg).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10](=[O:12])[CH:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]2[CH2:11][C:10]([O:12][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)c(C2C(=O)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(C2=C(OC(=O)C(C)(C)C)CC(Cc3ccc(F)cc3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of 4-(4-fluoro-benzyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (30 mg, 0.09 mmol) in dichloromethane (1 ml) and triethylamine (52 μl, 0.37 mmol) is added the pivaloyl chloride (34 μl, 0.37 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethyl-propionic acid 4-(4-fluoro-benzyl)-3-oxo-2-(2,4,6-trimethyl-phenyl)-cyclopent-1-enyl ester (31 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C)c21
Temperature: 97.5 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (20.4 g, 96.55 mmol) in DMA (117 mL) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (26.0 g, 96.55 mmol) and potassium tert-butoxide (11.4 g) in DMA (96 mL) at room temperature. The mixture was stirred at 95-100° C. for 1.5 h. Water (221 mL) was added at 80-100° C. The precipitate was collected at room temperature and dried over under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (35.8 g) as crude product. The obtained crude 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (10.0 g) was dissolved in DMSO (150 mL) at 90-100° C. The solution was filtered through filter paper and washed with DMSO (10 mL). The combined filtrate was slowly added to a mixture of crystals (Form G: 100 mg) obtained in 120p) (as seed crystals) in AcOEt (100 mL) at 5-30° C. After stirring at room temperature for 17 h, the mixture was stirred at 70° C. for 1 h. The mixture was gradually cooled to 25° C. and stirred for 2 h. The mixture was stirred at 0-10° C. for 1 h and at room temperature for 1 h. The solids were collected by filtration and dried at 50° C. under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8.0 g) as white crystals (Form G).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6]([C:8]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=2[Cl:26])=[C:16]([F:27])[C:11]2[N:12]=[CH:13][N:14]([CH3:15])[C:10]=2[CH:9]=1)=[O:7].N1C=NN=N1.C(N(C(C)C)[P:37]([O:43]C(C)(C)C)[O:38]C(C)(C)C)(C)C.C([O:55]O)(C)(C)C>CN(C=O)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:17]2[C:8]([C:6]([NH:5][O:4][CH2:3][CH2:2][O:1][P:37](=[O:43])([OH:55])[OH:38])=[O:7])=[CH:9][C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]=2[F:27])=[C:20]([Cl:26])[CH:21]=1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc21
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: CC(C)(C)OO
Agent: c1nnn[nH]1
Solvent: CN(C)C=O
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCOP(=O)(O)O)cc21
Temperature: -78 °C
Reaction time: 3 h

Procedure:
3.000 g of 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide, 660 mg of tetrazole and 2.80 mL of di-tertbutyl diisopropyl-phosphoramidite were dissolved/suspended in 30 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was stirred for about 3 hrs after which time the reaction was cooled to −78° C. and 2.50 mL of 70% tert-butyl hydrogen peroxide was added. The cooling bath was then taken away and the reaction was slowly warmed up to room temperature and reacted over night. The reaction was then partitioned between a solution of ethyl ether/ethyl acetate (5:1) and saturated aqueous NaHCO3. The organic layer was saved and successively washed with 10% aqueous sodium sulfite, 3 times with water and finally with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated under vacuum. The residue was dissolved in 45 mL of a solution for about 2 hours after which time it was concentrated under vacuum and the resulting residue was stirred in methanol for about 1 hours. The off-white solid was collected via suction filtration, washed with methanol followed by ethyl ether and then air-dried to give 2.717 g of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.94 (brs, 1H), 8.40 (s, 1H), 7.96 (brs, 1H), 7.75 (s, 1H), 7.60 (s, 1H), 7.25 (dd, 1H), 6.37 (dd, 1H), 4.02 (brs, 4H); 19F NMR (376 MHz, DMSO-d6)−132.9 (s, 1F).
Reaction SMILES: [F:1]C1C=C(OC)C(OC)=CC=1C(NC1C=CC(C2N=C(C)ON=2)=CC=1)C1NC(=O)N(C2C=CC=CC=2C(O)=O)N=1.CO[C:43](=[O:75])[N:44]=[C:45](SC)[C:46]([C:60]1[CH:70]=[C:69]([O:71][CH3:72])[C:63]2[O:64][CH2:65][CH2:66][CH2:67][O:68][C:62]=2[CH:61]=1)=[N:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[N:58]=[C:57]([CH3:59])[O:56][N:55]=2)=[CH:50][CH:49]=1.Cl.Cl.[CH2:78]([O:80][C:81]([C:83]1[C:84]([NH:88][NH2:89])=[N:85][NH:86][CH:87]=1)=[O:82])[CH3:79].COC(=O)N=C(SC)C(C1C=C(OC)C(OC)=CC=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.Cl.N(C1C=CC=CC=1C(O)=O)N>>[CH2:78]([O:80][C:81]([C:83]1[CH:87]=[N:86][NH:85][C:84]=1[N:88]1[C:43](=[O:75])[NH:44][C:45]([CH:46]([C:60]2[CH:70]=[C:69]([O:71][CH3:72])[C:63]3[O:64][CH2:65][CH2:66][CH2:67][O:68][C:62]=3[C:61]=2[F:1])[NH:47][C:48]2[CH:49]=[CH:50][C:51]([C:54]3[N:58]=[C:57]([CH3:59])[O:56][N:55]=3)=[CH:52][CH:53]=2)=[N:89]1)=[O:82])[CH3:79]
Reactant: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c2c(c1)OCCCO2
Reactant: CCOC(=O)c1c[nH]nc1NN
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Agent: Cl
Agent: NNc1ccccc1C(=O)O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c3c(c2F)OCCCO3)[nH]c1=O

Procedure:
The same procedure was carried out as in Examples (1e) to (1f), except that {2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (30c)) and 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)) were used instead of respectively the [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester and 2-hydrazinobenzoic acid hydrochloride in Example (1e), to give the title compound.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[N:16]=3)[CH:11]=[CH:10][C:9]2=[O:20])C(=O)C2=CC=CC=C12.NN.[ClH:29].C(NN)(=O)C1C(=CC=CC=1)C(NN)=O>C(O)C.O>[ClH:29].[NH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[C:13]([CH3:19])[CH:14]=[C:15]([CH3:18])[N:16]=2)[CH:11]=[CH:10][C:9]1=[O:20]
Reactant: Cc1cc(C)c2ccc(=O)n(CCN3C(=O)c4ccccc4C3=O)c2n1
Agent: Cl
Agent: NN
Agent: NNC(=O)c1ccccc1C(=O)NN
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2ccc(=O)n(CCN)c2n1

Procedure:
A mixture of 1-(2-phthalimidoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (5.2 gm., 0.015 mole) and 95% hydrazine (1.8 ml., 0.053 mole) in absolute ethanol (50 ml.) is refluxed for one hour. The reaction is cooled, water (37.8 ml.) and concentrated hydrochloric acid (37.5 ml.) are added. After refluxing for one half hour, the mixture is cooled in an ice bath and phthalhydrazide (2.85 gm., 0.0125 mole) is filtered off. The filtrate is concentrated and the residue is dissolved in water, made basic with saturated sodium carbonate and extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and evaporated. The residue containing the free base of the title compound is dissolved in a minimum amount of methanol and treated with ethereal hydrogen chloride. Recrystallization of the product from isopropanol gives 1-(2-aminoethyl)-5,7-dimethyl-1,8-naphthyridine-2(1H)-one hydrochloride melting at 253.5-254.5° C.