Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:20][C@@H:21]([CH3:38])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=2)=[N:24]1>>[C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([NH:20][C@@H:21]([CH3:38])[CH2:22][N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:35]=[C:34]([F:36])[C:31]([C:32]#[N:33])=[C:30]([Cl:37])[CH:29]=3)=[N:24]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.4 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluoro-benzonitrile (389 mg, 1.4 mmol). The product was purified with flash chromatography. Yield 260 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H), 2.61 (s, 3H), 3.48 (t, 2H), 4.33-4.48 (m, 3H), 5.66 (s, 2H), 7.02 (d, 1H), 7.84-7.87 (m, 2H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:17])[CH2:14][CH2:15]Cl)[CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH2:5].C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:3]([C:6]1[CH:7]=[C:8]([N:12]2[CH2:15][CH2:14][C:13]2=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH:4]=[CH2:5]
Reactant: C=CCc1cccc(NC(=O)CCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C=CCc1cccc(N2CCC2=O)c1
Reaction time: 8 h

Procedure:
Sodium hydride (0.1 mole; 57% dispersion in mineral oil) is charged into a glass reaction flask. The mineral oil is removed by washing the sodium hydride with benzene, and dimethyl sulfoxide (50 ml) is thereafter slowly added with stirring. The mixture is stirred until no more hydrogen gas evolves. A solution of N-(3-allylphenyl)-β-chloropropionamide (0.08 mole) in carbon tetrachloride (50 ml) is added dropwise to the reaction flask with stirring while maintaining the temperature of the reaction mixture below about 30°C. After the addition is completed the reaction mixture is allowed to stand at room temperature for a period of about 8 hours. After this time benzene is added and the reaction mixture is washed with water and aqueous sodium bicarbonate. The washed mixture is then dried over anhydrous magnesium sulfate, is filtered, and is stripped of solvents under reduced pressure to yield the desired product N-(3-allylphenyl)-2-azetidinone as the residue.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]1([C:17]2[CH:52]=[CH:51][C:20]([C:21]([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][C:29](=[O:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:22])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)=O.C(=O)=O.CO>C1(C)C=CC=CC=1>[C:11]1([C:17]2[CH:52]=[CH:51][C:20]([C:21]([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][CH:29]([OH:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:22])=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O[C@@H]1C[C@@H]2OC(O)C[C@@H]2[C@H]1CC[C@H](CCc1ccccc1)OC1CCCCO1)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A 1.5 M solution of diisobutylaluminum hydride in toluene (6.0 mL, 9.0 mmol) was added dropwise to a stirred solution of compound [9a] (4.1 g, 7.2 mmol) in toluene (60 mL) at −70-−80° C. (acetone/dry ice bath) and the resulting mixture was stirred during 1 h at the same temperature. Methanol (10 mL) was added dropwise to the stirred mixture at −70-−80° C. The mixture was stirred for 1 hour at room temperature, filtered and evaporated under reduced pressure. Dichloromethane (30 mL) was added to the residue. The resulting solution was washed with brine (2×10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 2:1 v/v) to obtain 2.0 g (49% yield) of the compound [10a]. 1H NMR (CDCl3) δ: 6.4-6.5 (m, 1H); 5.0-5.2 (m, 1H); 4.7-4.9 (m, 1H); 4.5-4.7 (m, 1H); 3.8-4.0 (m, 1H); 3.6-3.8 (m, 1H); 3.4-3.6 (m, 1H). 13C NMR (CDCl3) δ: 20.1; 25.5; 28.6; 31.3; 31.6; 36.7; 37.7; 40.3; 41.1; 46.2; 51.6; 63.0; 81.3; 82.0; 97.8; 100.2; 125.6; 127.1; 127.2; 128.1; 128.3; 128.4; 128.9; 129.2; 130.0; 130.1; 140.0; 145.7; 166.0. IR (KBr): 3500, 2945, 1712, 1605, 1278, 1117, 1026, 752 cm−1.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][N:7]=1)[CH:3]([CH3:5])[CH3:4].Br[C:38]1[CH:39]=[N:40][CH:41]=[C:42]([O:44][CH3:45])[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCO.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]>[CH3:1][C:2]([C:6]1[N:7]=[CH:8][C:9]([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([O:44][CH3:45])[CH:43]=2)=[CH:10][CH:11]=1)([C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:28]=[N:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=2)=[CH:25][CH:26]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(C)(c1ccc(-c2ccc(C(F)(F)F)nn2)cc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(F)(F)F)nn4)cc3)C(C)C)nc2)c1
Temperature: 95 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.0 mg, 0.0190 mmol) was added to a stirred solution of 8d (47.0 mg, 0.0950 mmol), 3-bromo-5-methoxypyridine (23.0 mg, 4.43 mmol) and sodium carbonate (100 μL of a 2.0 M aqueous solution, 0.200 mmol) in EtOH:toluene (500 μL of an 80:20 mixture, respectively) at rt. The resulting solution was heated to 95° C. for approximately 5 h. After cooling to rt, the reaction mixture was filtered through a short column of CELITE®, eluting with EtOAc. The filtrate was washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 20%-50% EtOAc/hexanes as eluent) to furnish the title compound 8e. m/z (ES) 479 (MH)+.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][C:11]1[C:16](N)=[CH:15][CH:14]=[C:13]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[N:12]=1.N(OC(C)(C)C)=O.[C:30]([O:33]C(=O)C)(=[O:32])[CH3:31]>CN(C)C=O.COCCOC.CCCCCC>[CH3:10][C:11]1[C:16]([O:33][C:30](=[O:32])[CH3:31])=[CH:15][CH:14]=[C:13]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[N:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(-n2cncn2)ccc1N
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=O)Oc1ccc(-n2cncn2)nc1C
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
A solution of boron trifluoride etherate (217 μL, 1.7 mmol) in dimethylformamide (1 mL) was cooled to −15° C. using an ice-acetonitrile bath, and then stirred for 15 min at this temperature. A solution of 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-ylamine (from Step 2; 200 mg, 1.14 mmol) in 1,2-dimethoxyethane (7 mL) was added dropwise to the solution at −15° C. and the stirring was continued for a further 15 min. tert-Butyl nitrite (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 90%; 157 mg, 1.4 mmol) was added dropwise, and the reaction mixture was stirred at −15° C. for 15 min and then at 0° C. for 1 h. Hexane (10 mL) was added and the solid was filtered off, washed with hexane, and air-dried. The solid was added to acetic anhydride (5 g, 49 mmol) and the mixture was heated at 100° C. for 1.5 h. The acetic anhydride was evaporated under high vacuum and then 1 M aqueous sodium carbonate solution was added. The mixture was extracted three times with dichloromethane. The dichloromethane was evaporated and the residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate/hexane to give acetic acid 2-methyl-6-[1,2,4]triazol-1-yl-pyridin-3-yl ester (125 mg, 50%). 1H NMR (CDCl3) δ 2.38 (s, 3H), 2.46 (s, 3H), 7.56 (d, 1H, J=8.8 Hz), 7.77 (d, 1H, J=8.6 Hz), 8.10 (s, 1H), 9.16 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=1)[CH2:6][C:5]2([CH3:25])[CH3:24].[CH:26]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27]1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:32][S:29]([CH:26]3[CH2:28][CH2:27]3)(=[O:31])=[O:30])=[O:14])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=1)[CH2:6][C:5]2([CH3:25])[CH3:24]
Reactant: CN(C)c1cccc(C2CC(C)(C)c3cc(Cl)cc(C(=O)O)c3N2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)c1cccc(C2CC(C)(C)c3cc(Cl)cc(C(=O)NS(=O)(=O)C4CC4)c3N2)c1
Yield: 20.1 %

Procedure:
A mixture of 6-chloro-2-(3-dimethylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.42 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (120 mg, 0.63 mmol), 4-dimethylaminopyridine (77 mg, 0.63 mmol), cyclopropane sulfonic acid amide (150 mg, 1.26 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [6-chloro-2-(3-dimethylamino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (39 mg, 20%) as a light yellow solid: MS (ESI) M+1=462.2.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])N.[F:12][C:13]([F:35])([F:34])[C:14]1[CH:33]=[CH:32][C:17]2[C:18](=NNC3C=CC=CC=3C(O)=O)[CH2:19][O:20][C:16]=2[CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.O>[F:35][C:13]([F:12])([F:34])[C:14]1[CH:33]=[CH:32][C:17]2[C:18]3[NH:1][C:3]4[C:11]([C:19]=3[O:20][C:16]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][C:4]=4[C:5]([OH:7])=[O:6]
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C(O)c1ccccc1NN=C1COc2cc(C(F)(F)F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1[nH]c1c3ccc(C(F)(F)F)cc3oc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
150 mg 6a was dissolved in ethanol (5.2 ml) and 2-hydrazino benzoic acid was dissolved in water (10.3 ml). These two homogenous mixtures were mixed together and stirred at room temperature for 4 hrs. Precipitation is filtered and first washed with water and then ethanol. The filtrate was put in vacuum oven for 4 hrs for complete evaporation. The mixture of 2-[N′-(6-trifluoromethyl-benzofuran-3-yl-idene)-hydrazino]-benzoic acid (120 mg), p-TsOH (1˜2 Eqv) and ethanol (5 ml) were refluxed for 30 hrs. Cooled to room temperature and evaporated in vacuo. Resulting mixture was purified by chromatography to afford compound 8 (CHCl3:MeOH=30:1).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][CH2:25][NH2:26])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:26][CH2:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCCO[N+](=O)[O-])c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) and sodium methoxide (0.16 g, 2.9 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (30 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). Eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.26 g, 1.0 mmol, yield: 39%) as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]3)[CH2:16]4)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>C1COCC1>[N:1]1([C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]3[O:14][C@:15]4([CH2:23][N:24]=3)[CH:20]3[CH2:21][CH2:22][N+:17]([O-:30])([CH2:18][CH2:19]3)[CH2:16]4)[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cc(-n4ccnc4)ncn3)O1)C2
Yield: 95.3 %

Procedure:
A solution of (R)—N-(6-(1H-imidazol-1-yl)pyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (52.9 mg, 0.163 mmol) and 3-chlorobenzoperoxoic acid (33.7 mg, 0.195 mmol) in 2 mL THF was stirred at room temperature for 24 h. The reaction was concentrated and the crude product was purified by flash chromatography on a 40 g silica gel cartridge with 20 to 40% [9:1 MeOH/NH4OH] in EtOAc, 40 min. Pure fractions were pooled, concentrated, and dried. The residue was dissolved in CDCl3, filtered through a 0.4μ filter, concentrated, and dried under high vacuum to yield (S)-2-(6-(1H-imidazol-1-yl)pyrimidin-4-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (53 mg, 95% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(COC1CCN(C(C)=O)CC1)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.4 %

Procedure:
N-Acetyl-4-hydroxypiperidine (57.2 g.) in dry D.M.F. (250 ml.) was added dropwise to a stirred suspension of sodium hydride (23.2 g., 50% dispersion in mineral oil) in dry D.M.F. (200 ml.) under an atmosphere of nitrogen and with external cooling in an ice/water bath. The suspension was allowed to warm to room temperature then stirred for 5 hours. Bromoacetaldehyde diethylacetal (94.7 g.) was added slowly to the stirred reaction mixture with cooling then the mixture was stirred at room temperature for 18 hours. A further quantity of sodium hydride (23.2 g.) was added portionwise and stirring continued until effervescence had ceased. A further 100 ml. dry D.M.F. was added and the mixture cooled in an ice/water bath while a second batch of bromoacetaldehyde diethylacetal (94.7 g.) was slowly added. The mixture was stirred at room temperature for 3 hours then isopropopanol (150 ml.) added to destroy excess sodium hydride. The suspension was filtered, the filtrate concentrated under reduced pressure then the residue taken up in water and extracted with chloroform. The chloroform extract was dried (Na2SO4), the solvent evaporated in vacuo and the residue distilled to give N-acetyl-4-(2,2-diethoxyethoxy)piperidine (61.5 g.), b.p. 142°-145° C./3 mm., characterized by n.m.r.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]([N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:12].[H][H]>CO.[C].[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]([N:13]([CH3:26])[CH2:14][CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:12])=[C:2]([F:1])[CH:7]=1
Reactant: [H][H]
Reactant: CN(CCCN(C)C(=O)c1ccc([N+](=O)[O-])cc1F)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCCN(C)C(=O)c1ccc(N)cc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of the compound (300 mg, 0.810 mmol) obtained in Example 12a in methanol (8 mL) was added to 10% palladium-carbon (dry; 30 mg), the atmosphere in the system was replaced with a hydrogen atmosphere, and then the mixture was stirred at room temperature for 30 minutes. The atmosphere in the system was replaced with a nitrogen atmosphere, then 10% palladium-carbon (dry; 90 mg) was further added, the atmosphere in the system was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The atmosphere in the system was replaced with a nitrogen atmosphere, and then the mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (260 mg; yield, 95%) as a light brown oily substance.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:17][O:18][C:19]1[C:20]([CH:25]=O)=[N:21][CH:22]=[CH:23][N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[C:20]([CH2:25][N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][O:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[CH3:2])[CH2:8][CH2:9]2)=[N:21][CH:22]=[CH:23][N:24]=1
Reactant: COc1nccnc1C=O
Reactant: Cc1ccccc1OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1nccnc1CN1CCC(COc2ccccc2C)CC1
Reaction time: 8 h
Yield: 87.1 %

Procedure:
After suspending 200 mg of 4-(2-methylphenoxymethyl)piperidine hydrochloride in 5 ml of dichloromethane, 137 mg of 3-methoxypyrazine-2-carboxaldehyde [CAS No. 63874-90-8] and 264 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. Aqueous sodium carbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (236 mg, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=[O:26])[CH2:21][CH2:20]2)=[O:18])[CH:9]=1.Cl.CO.[CH3:35][N:36]([CH3:43])[CH2:37][CH:38]=[CH:39]C(O)=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:26])/[CH:39]=[CH:38]/[CH2:37][N:36]([CH3:43])[CH3:35])[CH2:23][CH2:24]2)=[O:18])[CH:9]=1
Reactant: CN(C)CC=CC(=O)O
Reactant: COc1cc(Cl)c(-c2ccccc2Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1C(=O)N1CCN(C(=O)/C=C/CN(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 201 %

Procedure:
A mixture of tert-Butyl 4-(2′,6-dichloro-4-methoxy-[1,1′-biphenyl]-3-carbonyl)piperazine-1-carboxylate (550 mg, 1.18 mmol) in HCl/MeOH (20 mL, 57.2 mmol) was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to yield the crude product. The crude residue was dissolved with DMF (10 mL), 4-(dimethylamino)but-2-enoic acid (215 mg, 0.47 mmol), BOP (627 mg, 1.42 mmol) and DIEA (610 mg, 4.73 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (450 mg, 80% yield, 2 steps). ESI-MS m/z: 476.4[M+H]+.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.[C:23]1(C)[CH:28]=[CH:27][C:26](S(O)(=O)=O)=[CH:25][CH:24]=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:4][C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(Nc1cc(Br)ccc1O)c1cc([N+](=O)[O-])ccc1F
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 15c), from N-(2-hydroxy-5-bromophenyl)-2-fluoro-5-nitrobenzamide (11.0 g, 0.03 mol) and p-toluenesulfonic acid monohydrate (11.88 g, 0.06 mol) the subtitle compound was obtained (6 g, 58%). 1H NMR (DMSO) δ 8.98(dd, 1H), 8.54(m, 1H), 8.19(d, 1H), 7.97(d, 1H), 7.81(m, 4H), 7.52(t, 2H), 7.42(d, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCn1c(=O)[nH]c2ccccc21
Yield: 92.8 %

Procedure:
A solution of 22 g of the product of Step B, 22 ml of sodium hydroxide solution and 200 ml of methanol was refluxed for one hour and the methanol was evaporated. The residue was taken up in 1.5 liters of iced water and the pH was adjusted to 1 by addition of concentrated hydrochloric acid. The mixture was vacuum filtered and the product was washed with water to obtain 18.1 g of 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoic acid melting at 180° C. The product was crystallized from isopropanol to obtain 15.2 g of product melting at 185° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[C:4]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22](F)=[CH:21][C:20]=1[F:27].[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32][OH:33].[H-].[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[C:4]([NH:13][CH2:14][C:15]([F:16])([F:18])[F:17])[C:3]=1[C:19]1[C:20]([F:27])=[CH:21][C:22]([O:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:23][C:24]=1[F:25]
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2NCC(F)(F)F)c(F)c1
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2NCC(F)(F)F)c(F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 6-chloro-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine (20 mg, 0.05 mmol) and 3-dimethylamino-1-propanol (103 mg, 1.0 mmol) in 3 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol). The mixture is stirred at 60° C. for 2 h, cooled to room temperature, and partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate. Concentration provides 6-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-2-(1H-imidazol-1-yl)-N-(2,2,2-trifluoroethyl)pyrimidin-4-amine as a light tan solid (16 mg, mp 47-49° C.). MS: m/z 491.1 (M+H).