Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[CH2:20](N(CC)CC)[CH3:21].C(=O)C>ClCCCl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:20][CH2:21][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: O=C1CCOCC1
Reactant: CCN(CC)CC
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: CC=O
Agent: Cl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(CNCCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1,2-dichloroethane (50 ml) were suspended p-nitrobenzylaminehydrochloride (3.77 g), 4H-tetrahydropyran-4-one (2 g) and triethylamine (2.8 ml), and to the mixture was added, under ice-cooling, triacetoxy sodium boron hydride (5.92 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours, and to the mixture were added, under ice-cooling, acetaldehyde (1.5 ml) and triacetoxy sodium boron hydride (5.92 g). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was neutralized with sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give N-(4-nitrobenzyl)-N-(tetrahydropyran-4-yl)ethylamine (4.0 g) as yellow oil.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:37][C:38]#[N:39]>>[F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:37][C:38]#[N:39])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: N#CCBr
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC#N
Yield: 3 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and bromoacetonitrile, to give the desired product as a light yellow oil (3%).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13](=O)[CH3:14])[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[NH2:22][C:23]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:24]=1[C:25]#[N:26].C(=O)(O)[O-].[Na+]>ClCCl.O>[O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](/[C:13](=[N:22]/[C:23]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:24]=2[C:25]#[N:26])/[CH3:14])[CH2:4][CH2:3]1
Reactant: Cc1ccc(N)c(C#N)c1
Reactant: CC(=O)N1CCS(=O)(=O)c2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: C/C(=N\c1ccc(C)cc1C#N)N1CCS(=O)(=O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
To a stirred solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (6.0 g, 25.0 mmol) in dry dichloromethane (100 mL) was added phosphorus oxychloride (2.5 mL, 27.3 mmol) at 10° C. After being stirred for 20 minutes at room temperature, a solution of 2-amino-5-methylbenzonitrile (3.3 g, 25.0 mmol) in dry dichloromethane (40 mL) was added and the resulting suspension was heated under reflux for 24 hours. After being cooled to room temperature, the reaction mixture was diluted with water (50 mL), basified with a saturated aqueous solution of sodium bicarbonate to about pH 8. The separated aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 16% ethyl acetate in petroleum ether) to give 1.5 g of the product as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH:21]1([C:27]([Cl:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[ClH:29].[CH:21]1([C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1ccncc1)C1CCCCC1
Yield: 68.1 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.66 ml (4.96 mmol) of cyclohexanoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 890 mg of the desired compound (free base) (77.0%, colorless prisms), mp: 93.0°-94.0° C.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([CH:16]1[CH2:18][CH:17]1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([Cl:33])[CH:20]=1)=[O:15])C1C=CC=CC=1.C(C1C[O:44]C(=O)N1)C1C=CC=CC=1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:17]2[CH2:18][CH:16]2[C:14]([OH:15])=[O:44])=[CH:20][C:21]=1[Cl:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: O=C1NC(Cc2ccccc2)CO1
Product: O=C(O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
(R)-4-Benzyl-3-[2-(4-benzyloxy-3-chloro-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (132 mg, 0.28 mmol) was reacted in the same manner as in Step A of Preparation Example 59 to obtain the mixture (85 mg) of the title compound and 4-benzyloxazolidin-2-on.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11](Cl)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][NH:27][CH2:28]2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][N:27]([C:11]1[N:10]=[C:9]3[C:14]([C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]3[CH:19]3[CH2:20][CH2:21]3)=[CH:13][C:12]=1[F:17])[CH2:28]2
Reactant: COc1cccc2c1CNC2
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 29.9 %

Procedure:
310 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 298 mg of 4-methoxyisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in the same manner as in Example 107 to produce 118 mg of 7-(4-methoxy-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]([C:10]1C=[CH:17][CH:16]=[CH:15][C:11]=1C(O)=O)[CH3:9]>C(Cl)Cl>[CH3:7][N:8]([C:10]1[CH:11]=[CH:15][CH:16]=[CH:17][C:1]=1[C:2]([Cl:4])=[O:3])[CH3:9]
Reactant: CN(C)c1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)c1ccccc1C(=O)Cl
Reaction time: 3 h

Procedure:
Oxalyl chloride (375 g) was added to a suspension prepared by adding 3.0 L of dry methylene chloride to 371.7 g of N,N-dimethylaminobenzoic acid. A vessel containing the resultant solution was dipped in an oil bath, and the solution was stirred for 3 hr while controlling the internal temperature at about 40° C. The solvent was removed by evaporation under the reduced pressure, and the residue was vacuum dried to give a crude product of N,N-dimethylaminobenzoic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[C:5]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[C:4]([F:25])[CH:3]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:11]([C:8]1[O:9][C:10]2[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([C:13]3[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=3)[C:6]=2[CH:7]=1)([OH:28])=[O:12]
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C=O)cc23)c1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
0.37 g (0.99 mmol) of 3-(7-chloro-5-fluoro-2-formylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 20 ml of acetone, and a Jones reagent (CrO3—H2SO4) was added thereto at −20° C. After stirring at −20° C. for 2 hours, the mixture was poured into water and extracted with ethyl acetate. An aqueous sodium hydroxide solution was added to make the extract alkaline, and the aqueous layer was washed with ethyl acetate and acidified by an addition of hydrochloric acid and then extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with diisopropyl ether to obtain 0.29 g (yield: 75%) of the desired product Melting point: 233-235° C.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2[O:27][CH2:28][O:29][CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:22][C:21]=2[O:27][CH2:28][O:29][CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCc1ccccn1
Reactant: COCOc1cc(O)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cc(OCc2ccccn2)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Methyl 3-cyclohexyl-2-[4-hydroxy-2-(methoxymethoxy)phenyl]-1H-indole-6-carboxylate was dissolved in DMF (0.17 M) and Cs2CO3 (1.05 eq) was added. The mixture was stirred for 20 min, then 2-bromomethylpyridine (1.05 eq) was added and the suspension was stirred at RT. After 4 h Cs2CO3 (0.3 eq) was added and the mixture was stirred overnight. Since the reaction was incomplete the mixture was warmed for 30 min to 35° C. The mixture was diluted with EtOAc and extracted with 1N aqueous HCl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The product was obtained as a beige amorphous solid (89%). (ES+) m/z 501 (M+H)+.
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][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:55][C:54](=[O:56])[NH:53][C:52]2=[O:57])[CH2:47][CH2:46]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:45]2[CH2:46][CH2:47][CH:48]([N:51]3[CH2:55][C:54](=[O:56])[NH:53][C:52]3=[O:57])[CH2:49][CH2:50]2)=[O:34])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CN(C2CCNCC2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CN(C2CCN(C(=O)N[C@@H]3CC[C@@H](c4cccc(F)c4F)Cn4c(CC(F)(F)F)cnc43)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Triethylamine (16 μL, 0.11 mmol) was added to a solution of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (38 mg, 0.11 mmol) and 4-nitrophenyl chloroformate (23 mg, 0.11 mmol) in tetrahydrofuran (2 mL) at 0° C. After 1 h, 1-piperidin-4-ylimidazolidine-2,4-dione (21 mg, 0.11 mmol) and triethylamine (47 μL, 0.33 mmol) were added and the mixture allowed to warm to ambient temperature. After 1 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→93% dichloromethane/methanol] gave the title compound (36 mg). MS 555.2126 (M+1).
Reaction SMILES: [CH:1]([O-:3])=[O:2].[K+].[C]=O.[C:7]1([O-])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[K+].C(=O)([O-])[O-:20].[K+].[K+]>>[OH:20][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:1]([OH:3])=[O:2])[CH:12]=2)[CH:7]=1
Reactant: O=C[O-]
Reactant: O=C([O-])[O-]
Reactant: [O-]c1cccc2ccccc12
Agent: [C]=O
Agent: [K+]
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 280 °C
Yield: 67 %

Procedure:
A stainless steel pressure autoclave is charged with 50 parts of kerosene and 10 parts of potassium formate and heated to 280° C. 50 bar of carbon monoxide are then injected. Using a metering pump, a mixture comprising 50 parts of potassium naphtholate and 38 parts of potassium carbonate is metered into the reactor as a suspension in kerosene over the course of 5 hours. Some of this kerosene is removed from the reaction vessel by distillation under reduced pressure, and is condensed and expelled. The reaction mixture is worked up conventionally to give 2-hydroxynaphthalene-6-carboxylic acid in a yield of 67% based on the potassium naphtholate employed. Secondary products are 15% of unreacted β-naphthol, 4% of 2-hydroxynaphthalene-3-carboxylic acid and 9% of 2-hydroxynaphthalene-3,6-dicarboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:36])([F:38])[F:37])=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (200 mg, 0.58 mmol) was dissolved in pyridine (3.0 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (132 μL, 0.88 mmol) was added, and the mixture was stirred at 70° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and washed successively with water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (145 mg, 45%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[CH3:20][N:21]([CH3:32])[C:22]1[C:27]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCOCC1>[CH3:20][N:21]([CH3:32])[C:22]1[C:27]([S:28]([NH:31][C:11]([NH:10][C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=2)=[O:13])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: CN(C)c1ncccc1S(N)(=O)=O
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2N(C)C)n1
Reaction time: 1 h
Yield: 89.6 %

Procedure:
3.28 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)phenylcarbamate are added at room temperature to a mixture of 2.41 g of 2-dimethylamino-3-pyridylsulfonamide and 1.9 ml of 1,7-diazabicyclo[5.4.0]undec-7-ene in 30 ml of absolute dioxan. The mixture is stirred for 1 hour at this temperature and then concentrated in vacuo. The residue is stirred in 10 ml of 1N aqueous HCl and filtered. The filter residue is washed with water and ether and dried, affording 3.94 g of the title urea with a melting point of 173°-175° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:14][CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1
Reactant: Cc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2c1cnn2C1CCCCO1
Temperature: 70 °C
Reaction time: 4 h
Yield: 81.5 %

Procedure:
To a solution of 2-{cis-4-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (100 mg, 0.266 mmol) in tetrahydrofuran (2.7 ml) were added 3,4-dihydro-2H-pyran (36 μl, 0.399 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.069 mmol), and the resulting mixture was stirred for 4 hours while being maintained at 70° C. The reaction solution was allowed to cool, and then was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 2-{cis-4-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (99.6 mg, 82%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)=O)[CH2:12][C:13](OCC)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:18]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)=[N:3][NH:2][C:13](=[O:14])[CH2:12]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(C(=O)c1ccc(SC)cc1)c1ccc(Cl)cc1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C2=NNC(=O)CC2c2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
Hydrazine hydrate (10.56 g, 210.9 mmol) was added to a solution of ethyl 3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate (42.54 g, 117.2 mmol) in ethanol (85 ml), followed by heating under reflux for 15 hours at a bath temperature of 100° C. A 4 N aqueous solution of sodium hydroxide (40 ml) was added to the reaction mixture. After the mixture was ice-cooled, precipitated crystals were collected by filtration, washed with water (3×100 ml), dried in air, and then dried under reduced pressure (100° C., 2 hours), whereby the title compound (31.49 g, 81.2%) was obtained as pale yellow crystalline powder.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C([N:25](CC)CC)C.[C:30]([NH:35]N)(=O)[CH:31]([CH3:33])[CH3:32]>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:25][C:30]([CH:31]([CH3:33])[CH3:32])=[N:35][N:6]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:17][CH:18]=1
Reactant: CC(C)C(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CC(C)c1nnc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a flask containing ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (106 mg, 0.37 mmol) was added absolute ethanol (2.5 mL) and triethylamine (0.15 mL, 1.11 mmol). The flask was placed on ice and to the flask was added a solution of isobutyric acid hydrazide (37.7 mg, 0.37 mmol) in absolute ethanol was heated at 60° C. for fifteen hours. An additional two equivalents of the isobutyric acid hydrazide (75 mg, 0.74 mmol) and triethylamine (0.2 mL, 1.35 mmol) was added to the reaction and allowed to stir overnight. Reaction was continuing to progress slowly, two equivalents of the isobutyric acid hydrazide (75 mg, 0.74 mmol) and triethylamine (0.2 ml, 1.35 mmol) were added to the reaction and allowed to stir overnight. The reaction was stopped. Solvent was removed by rotary evaporation and the product was purified by HPLC to yield the title compound (53 mg, 45% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 8.6 (s,1H), 8.0-8.1 (m, 3H), 7.7 (m, 1H), 7.35-7.5 (m, 2H), 1.4 (m, 7H), ES-MS (m/z) 322 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([O:30]CC4C=CC(OC)=CC=4)[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[N:13]([C@H:14]3[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[C:12]3[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:11]=3[N:10]=2)=[O:7])=[CH:40][CH:41]=1
Reactant: COc1ccc(COc2ccc3nc(NC(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(O)cc32)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of 4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-2-yl)benzamide (232 mg, 0.415 mmol) in DCM was added TFA (0.96 mL, 1.246 mmol), and the mixture was stirred at RT for 90 minutes. Additional TFA (0.96 mL, 1.246 mmol) was added, and the mixture was stirred at RT for 1 hour longer. The mixture was diluted with DCM, washed with 1 N aqueous NaOH, and the water layer back-extracted with DCM. The aqueous layer was adjusted to pH 8, and the pale green solid was collected and rinsed with 2 mL water. The solid was dissolved in ether and washed with brine, dried over Na2SO4, filtered, and evaporated. The title compound was obtained as a white sold (153 mg, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (d, J=8 Hz, 6H) 1.59 (m, 2H) 1.65-1.82 (m, 2H) 2.02-2.19 (m, 2H) 2.46-2.58 (m, 1H) 2.62-2.79 (m, 2H) 3.93-4.07 (m, 1H) 4.70-4.85 (m, 1H) 6.67 (dd, J=8.61, 2.15 Hz, 1H) 7.03 (d, J=2.05 Hz, 1H) 7.14-7.28 (m, 2H) 7.33 (d, J=8.51 Hz, 1H) 7.64 (d, J=7.82 Hz, 1H) 8.16-8.38 (m, 2H) 9.40 (s, 1H) 12.58 (s, 1H). M/Z calc'd for C24H27FN4O3: 438.50. found 439 [M+H].