Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:33]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH3:33])[CH:23]=3)[CH2:20][CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2CCN(c3cccc(CO)c3)CC2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCc1cccc(N2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A solution of 0.4 g (1 mmol) of 4-{2-[4-(3-hydroxymethylphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester in 10 mL of dry dimethyl sulfoxyde is cooled at a temperature close to 5° C. and 40 mg (1 mmol) of sodium hydride (60% suspension) is added. The mixture is stirred for 30 minutes at room temperature then 140 mg (1 mmol) of iodomethane are added and stirring is maintained overnight at room temperature. The mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 0.3 g (73%) of crude 4-{2-[4-(3-methoxymethylphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester which is used without purification in the next step.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:20]([CH2:29][OH:30])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH2:11]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@@H:20]([CH:29]=[O:30])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 0.43 ml portion of DMSO was dissolved in 6 ml of dichloromethane, and a 3 ml dichloromethane solution of 0.26 ml of oxalyl chloride was added thereto while keeping the internal temperature at −60° C. or less. After 30 minutes of stirring, a 10 ml dichloromethane solution of 270 mg of [(3R,4S)-1-benzyl-4-phenylpyrrolidin-3-yl]methanol which had been synthesized in accordance with the technique of Ling et al. (“Tetrahedron”, 2001, vol. 57, p. 6579-6588) and the method of International Patent Publication WO 2000/59502 was added thereto while keeping the internal temperature at −60° C. or less and stirred for 30 minutes. A 1.27 ml portion of triethylamine was added to the reaction solution while keeping the internal temperature at −50° C. or less, and then the internal temperature was allowed to warm to 0° C. over 30 minutes or more, and this was stirred at 0° C. for 30 minutes. The reaction solution was mixed with water to quench the reaction and extracted with chloroform. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. This was concentrated under a reduced pressure to obtain (3R,4S)-1-benzyl-4-phenylpyrrolidine-3-carboaldehyde as a crude product.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N+:8]=2[O-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([O:18]C(C)=O)=[O:17]>>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:18][C:16](=[O:17])[CH3:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cccc(-c2ccccc2)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cccc(-c2ccccc2)n1
Yield: 70 %

Procedure:
A stirred solution of the crude 2-phenyl-6-methyl-pyridine-N-oxide (5.2 g, 28.5 mmol) in Ac2O (25 ml) was heated at reflux temperature for 2 hrs. The Ac2O was removed with the aid of an oil pump (10 mm) at 40° C. to yield a red oil which was purified by flash chromatography over silica gel with Et2O/petroleum benzine=1/1 as the eluent and yielded 2-phenyl-6-(acetoxymethyl)-pyridine (4.6 g, 70%) as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[C:6](Cl)[C:5]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH3:20]>>[CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH2:20])[C:7]([CH3:13])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCN(CC)c1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]
Reactant: N
Product: CCN(CC)c1c([N+](=O)[O-])cc(C)c(N)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a similar manner by reaction of N,N-diethyl-3-chloro-2,6-dinitro-4-methylaniline with ammonia. The crystalline product melts at 108°-109°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11](Br)=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].[CH:16]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2=[N:10][C:11]([N:24]3[CH2:25][CH2:26][N:21]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[CH2:22][CH2:23]3)=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CCOC(=O)c1cc2ccc(Br)nc2[nH]1
Product: CCOC(=O)c1cc2ccc(N3CCN(C4CCCC4)CC3)nc2[nH]1
Temperature: 140 °C
Yield: 39.5 %

Procedure:
A mixture of 1 g (3.7 mmol) 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (prepared according to the method described in WO 2003/064423 A1) and 2.8 g (18.6 mmol) 1-cyclopentyl-piperazine (commercially available) was heated to 140° C. for 1 h. The mixture was absorbed on isolute and purified by flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate (0.1% NEt3). Evaporation of the product fractions yielded 501 mg (39%) of the title compound as white solid. MS: (m/e): 343.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[C:4]([CH3:28])[CH:3]=1.O[C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][N:31]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][C:30]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:28])[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:31][CH:32]=1
Reactant: Cc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1C(CO)C1CCCCC1
Reactant: COC(=O)c1ccc(O)nc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3C)nc3cc(F)c(F)cc32)nc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a solution of 200 mg (0.494 mmol) 2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol in 5 ml tetrahydrofuran were added 83 mg (0.543 mmol) methyl 6-hydroxynicotinate (commercially available) and 120 mg (0.593 mmol) tri-n-butylphosphin. The reaction mixture was cooled down to 0° C. 102 mg (0.593 mmol) N,N,N′,N′-tetramethylazodicarboxamide were added. The reaction mixture was stirred for 18 hours at room temperature and then concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow solid (29%). MS (Turbo Spray): m/z=540.2 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:16]1(O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CO>[C:24]1([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1cccc2ccccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc3ccccc23)CC1
Reaction time: 8 h
Yield: 100.5 %

Procedure:
A solution of 5.0 g (23.2 mmol) of 1,1-dimethylethyl 4-(hydroxymethyl)-1-piperidine-carboxylate, 4.3 g (29.8 mmol) of 1-naphthalenol and 7.82 g (29.8 mmol) of triphenylphosphine in 120 ml of tetrahydrofuran, cooled under nitrogen by means of an ice bath, is admixed dropwise with a solution of 6.03 g (29.8 mmol) of diisopropyl azodicarboxylate. The reaction mixture is allowed to return to ambient temperature and stirring is continued overnight. 2 ml of methanol are added and then the mixture is evaporated to dryness. The residue is taken up in 200 ml of dichloromethane and washed in succession with a 10% aqueous potassium hydrogen sulfate solution, water and a 1M aqueous solution of sodium hydroxide. The system is dried over sodium sulfate and evaporated to dryness. The product is purified by chromatography on silica gel, eluting with an 80/20 then 70/30 and 50/50 mixture of cyclohexane and dichloromethane, to give 7.96 g of product in oil form, which solidifies.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].CC(C)([O-])C.[K+].O>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24](=[O:26])[CH:25]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2[nH]1
Temperature: 25 °C
Yield: 32 %

Procedure:
Further, in a nitrogen atmosphere, 3′,5′-bis(trifluoromethyl)-2-aminobenzophenone (1.1 g, 3.3 mmol) was dissolved in toluene (13 mL), and acetic anhydride (0.62 mL, 6.5 mL) was added to the solution at room temperature, followed by stirring while heating and refluxing. The mixture was cooled to room temperature and then concentrated using a rotary evaporator. The residue was dissolved in ethylene glycol dimethyl ether (13 mL), and potassium tert-butoxide (1.5 mL, 13 mmol) was added to the solution at room temperature, followed by stirring for 2 hours. Water was added to the reaction solution, followed by extraction with methylene chloride. The organic layer was dried and then concentrated using a rotary evaporator. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). Thus, 4-{3,5-bis(trifluoromethyl)phenyl}-2-quinolinone (372 mg, 1.04 mmol) was obtained in a yield of 32%.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[C@@H:12]2[CH2:13][C@@H:9]([CH:10]=[CH:11]2)[C@H:8]1[C:14](O)=[O:15])=[O:6])#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH:8]([CH2:14][OH:15])[CH:9]2[CH2:13][CH:12]1[CH:11]=[CH:10]2)=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@H]1[C@H](C(=O)O)[C@@H]2C=C[C@H]1C2
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CO
Product: N#CCNC(=O)C1C2C=CC(C2)C1CO
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(1S,2R,3R,4R)-3-{[(Cyanomethyl)amino]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (840 mg, 3.81 mmol) was placed in a 25 mL round bottom flask and the flask was fitted with a rubber septum. After flushing the flask with nitrogen, tetrahydrofuran (8.0 mL) was added and the solution was cooled to −78° C. 4-Methylmorpholine (0.46 mL, 4.0 mmol) and isobutyl chloroformate (0.52 mL, 4.0 mmol) were added and the reaction mixture was stirred at −78° C. for 10 min., and then warmed to ambient temperature over 1 h. After stirring for an additional 1 h, the reaction mixture was recooled to −78° C. and sodium borohydride (0.25 g, 6.5 mmol) and methanol (6.0 mL) were added. After stirring for 1 h, the reaction mixture was allowed to warm to ambient temperature over 1 hour and then quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with saturated aqueous sodium chloride solution (100 mL) and the product was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. Chromatography of the residue on a silica gel using a mixture ethyl acetate:hexanes (gradient elution 5:2 to 3:1) provided (1R/S,2R/S,3R/S,4S/R)-N-(cyanomethyl)-3-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide as a colorless solid.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:24]=[CH:23][C:13]2[N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:9].[NH4+].[Cl-].O>C1COCC1>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:14]1[C:13]2[CH:23]=[CH:24][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:11][C:12]=2[N:16]=[CH:15]1
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of EtMgBr (0.72 mL, 1 mol/L) was added to N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxamide (70 mg, 0.24 mmol) in THF at 0° C. under argon. The mixture was stirred at 0° C. for 2 h. A solution of NH4Cl was added, carefully, to quench the reaction. The mixture was poured into water and extracted with EtOAc. The organics were washed sequentially with water and brine, then dried (Na2SO4). Removal of solvent followed by SiO2 chromatography afforded 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one as a colorless oil (45 mg, 72% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:19][CH3:20]>>[N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH:15][S:27]([C:24]4[CH:25]=[CH:26][C:21]([CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=4)(=[O:29])=[O:28])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1nc2c(s1)CCc1ccc([N+](=O)[O-])cc1-2
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc3c(s2)CCc2ccc([N+](=O)[O-])cc2-3)cc1

Procedure:
The title compound was prepared from 8-nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 7-nitrotetralone) and 4-n-propylbenzenesulfonyl chloride (106 mg) as described in the synthetic METHOD A to give a yellow powder (3.5 mg) with a purity of 87%: MS-ES (neg) m/z 428.4.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:16]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C(=CC(=CC=1)C)C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(O)(C)(C)C>[CH2:16]([O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:2]2[C:15]3[C:10]([CH:9]=[C:8]4[C:3]=2[CH:4]=[CH:5][CH:6]=[CH:7]4)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1ccc(B(O)O)c2ccccc12
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1ccc(C)c(C)c1
Solvent: CC(C)(C)O
Product: CCOc1ccc(-c2c3ccccc3cc3ccccc23)c2ccccc12
Temperature: 25 °C
Yield: 85.7 %

Procedure:
9-bromoanthracene (75.0 g), (4-ethoxynaphthalen-1-yl)boronic acid (78.0 g), Pd(dba)2 (5.0 g), tricyclohexyl phosphine (4.9 g), potassium phosphate (124.0 g), and a mixture solvent (440 ml) of pseudo cumene and t-butyl alcohol (pseudo cumene/t-butyl alcohol=10/1 (volume ratio)) were added to a flask and refluxed for 8 hours. The reaction solution was cooled to room temperature and the precipitated solid were collected by suction filtration. The obtained solid was washed with aqueous solution of EDTA.4Na, water, and methanol in order. It was then dissolved in heated chlorobenzene and then subjected to suction filtration by using a Kiriyama funnel layered with silica gel. The crude product obtained by removing filtrate by distillation under reduced pressure was washed with heptane while being heated to give 9-(4-ethoxynaphthalen-1-yl)anthracene (87.1 g) as a fourteenth intermediate compound. The scheme is shown in the following “Reaction 25”.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1)=[CH2:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>ClCCl>[CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1CCC(CO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CC1CCC(C=O)CC1
Reaction time: 12 h
Yield: 39.5 %

Procedure:
Next, 15 ml of solution of 5.4 g of the crude 4-vinyl-1-hydroxymethylcyclohexane in dichloromethane was added dropwise to a mixture of 9.1 g (42.1 mmol) of pyridinium chlorochromate and 50 ml of dichloromethane while being cooled with ice and stirred for 12 hours. The reaction mixture was filtered, the solvent was distilled off under a reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (eluent: toluene) to obtain 2.1 g of a crude 4-vinylcyclohexane-carbaldehyde. As the result of analysis of this product by gas chromatography, it was found out to be a mixture of cis/trans=31/69.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[C:26](#[N:29])[CH:27]=[CH2:28]>>[C:26]([CH2:27][CH2:28][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:21])[CH2:15][CH:16]1[CH3:20])#[N:29]
Reactant: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Reactant: C=CC#N
Product: CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1CCC#N
Yield: 75.4 %

Procedure:
Analogously to Example 9, 3.45 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-methyl-1-piperazinyl)-3-quinolinecarboxylic acid (Example B) are reacted with 4.5 g of acrylonitrile to give 3 g of 7-[4-(2-cyanoethyl)-3-methyl-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 203°-206° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13](Cl)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[O:20]1[C:24]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)=[CH:23][CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]3[O:20][N:21]=[CH:22][CH:23]=3)=[CH:31][CH:30]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: Nc1ccc(-c2ccno2)cc1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reaction time: 20 h
Yield: 3.8 %

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(isoxazol-5-yl)aniline (60 mg, 0.375 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg, 0.010 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.25 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 430.4 (M+H); UV 202.3, 234.0, 274.4, 331.8 nm; t 0.483 min.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[N+:7]([C:10]1[CH:24]=[CH:23][C:13]([CH2:14][P:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl.C(Cl)(Cl)Cl>[N+:7]([C:10]1[CH:24]=[CH:23][C:13]([CH2:14][P:15]([Cl:4])(=[O:19])[O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h
Yield: 98.6 %

Procedure:
Oxalyl chloride (4.8 mL, 9.6 mmol, 2 M solution in methylene chloride) was added to a solution of diethyl 4-nitrobenzylphosphonate 298 (546 mg, 2.0 mmol) in methylene chloride (10 mL) at room temperature under nitrogen, and the mixture was stirred for 48 h. The mixture was diluted with chloroform (10 mL), and the solvent was concentrated to provide 520 mg (99% yield) of ethyl 4-nitrobenzylphosphonochloridate 299 as a thick yellow oil that was used in the next step without purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6](C)=[N:5]1)([CH3:3])[CH3:2].[CH3:25][O:26][C@H:27]1[CH2:31][NH:30][C@H:29]([C:32]([NH2:34])=[O:33])[CH2:28]1>O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:30]5[CH2:31][C@H:27]([O:26][CH3:25])[CH2:28][C@H:29]5[C:32]([NH2:34])=[O:33])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: CO[C@H]1CN[C@H](C(N)=O)C1
Solvent: O
Product: CO[C@@H]1C[C@@H](C(N)=O)N(c2cc3c(cn2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)C1
Yield: 32 %

Procedure:
Following the procedure for Examples 339 and 408, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and (2S,4R)-4-methoxy-pyrrolidine-2-carboxylic acid amide were reacted. The reaction mixture was diluted with water passed down an SCX-2 cartridge, washed with DCM, ethyl acetate and methanol and products eluted with 2M ammonia in methanol. Appropriate fractions were concentrated in vacuo and the resultant residue was triturated in diethyl ether and methanol, filtered and dried to give 407 as beige solid (45 mg, 32%). LCMS: RT=2.60 min, [M+H]+=439. 1H NMR 400 MHz (CDCl3) δ: 9.27 (1H, s), 7.83 (1H, s), 7.57 (1H, s), 6.79 (1H, br, s), 6.00 (1H, s), 5.98 (1H, m), 5.29 (1H, br, s), 4.65 (1H, dd, J=8.28, 4.87 Hz), 4.49-4.47 (2H, m), 4.39-4.34 (2H, m), 4.23 (1H, t, J=5.53 Hz), 3.74 (1H, dd, J=10.34, 5.70 Hz), 3.51-3.46 (1H, m), 3.36 (3H, s), 2.52-2.51 (1H, m), 2.24-2.23 (1H, m), 1.55-1.54 (6H, m)
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[Br:26][C:27]1[C:28]([NH2:38])=[N:29][NH:30][C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.NC1C=CNN=1>O1CCCC1>[Br:26][C:27]1[C:28]([NH:38][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[NH:5][C:4]2=[O:13])=[N:29][NH:30][C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Reactant: O=C1Nc2ccc(Cl)cc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1n[nH]c(-c2ccccc2)c1Br

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 4-bromo-5-phenyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one (0.1820 gms.) is reacted with 0.4511 gms. of 4-bromo-5-phenyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (3.0 mL).