Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].IC.[H-].[Na+].[C:32](OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH3:32])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)=O
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.00 g) and iodomethane (0.87 mL) in N,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.95 g, 91%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:23]1[CH2:24][CH:25]=[C:26]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Fc1cccnc1Nc1ccc(Oc2nccnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cccnc1Nc1ccc(Oc2nccnc2C2=CCOCC2)cc1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added N-(4-(3-chloropyrazin-2-yloxy)phenyl)-3-fluoropyridin-2-amine (0.2824 g, 0.892 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.281 g, 1.337 mmol), trans-dichlorobis(triphenylphosphine) palladium (II) (0.050 g, 0.071 mmol), and sodium carbonate (0.473 g, 4.46 mmol) in DME (2.378 mL) and Water (0.594 mL). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 100° C. for 20 min (60 watts, Powermax feature on, ramp time 5 min). The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-3-fluoropyridin-2-amine. MS (ESI, pos. ion) m/z: 365.0 (M+1). IC50 (uM) 0.0.0217.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=1)#[CH:30].CCOC(C)=O.O>CN(C=O)C>[CH2:16]([O:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([CH:26]([CH3:28])[CH3:27])=[CH:11][C:12]=1[N:23]1[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=2)=[CH:30][N:25]=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(CO)cc1
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cc(-n2nncc2-c2ccc(CO)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 72 %

Procedure:
1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (890 mg, 2.38 mmol) was dissolved in DMF (5 ml) and (4-ethynylphenyl)-methanol (286 mg, 2.16 mmol) was added at RT. The flask was subjected to three vacuum-nitrogen cycles. [Cp*RuCl]4 was then added (116 mg, 0.11 mmol) and three further cycles were done. The reaction was left to RT until completion (monitored by TLC). AcOEt and water were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (one time) and dried over Na2SO4; the solvent was removed under reduced pressure and the mixture was purified by column chromatography (PE/AcOEt: 60:40). The title compound was obtained as an oil.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1>CO.O>[C:1]1([C:7]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][C:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NCCN=C2c2ccccc2)cc1
Reactant: COc1cccc(C=O)c1
Solvent: O
Solvent: CO
Product: COc1cccc(Cc2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-diphenyl-5,6-dihydropyrazine and m-anisaldehyde. 2,3-Diphenyl-5-(m-methoxybenzyl)pyrazine was obtained as colorless prisms, m.p. 65°-66° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (IX).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([OH:19])=O.[CH:20]([NH:23][NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=[O:26])=[O:19]
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Reactant: CC(C)NNC(=O)c1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ccccc2CCC(=O)N(NC(=O)c2ccsc2)C(C)C)c1C
Yield: 50.5 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (207 mg, 0.81 mmoles) and thiophene-3-carboxylic acid N′-isopropyl-hydrazide (150 mg, 0.81 mmoles) in DMF (8 mL) was treated with triethylamine (0.34 mL, 2.44 mmoles), HOBT (132 mg, 0.98 mmoles) and EDCI (156 mg, 0.98 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and dichloromethane. The organic layer was washed successively with 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product (172 mg, 50%). LC-MS m/e 421.46 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[N:11]3[CH2:12][CH:13]([O:15][CH3:16])[CH2:14][N:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:4][CH:3]=1.Cl[C:28]1C=CC=C(C(OO)=O)C=1.[S:38](=[O:41])(O)[O-:39].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[N:11]3[CH2:12][CH:13]([O:15][CH3:16])[CH2:14][N:10]3[C:9]=2[C:19]2[CH:24]=[CH:23][N:22]=[C:21]([S:38]([CH3:28])(=[O:41])=[O:39])[N:20]=2)=[CH:4][CH:3]=1
Reactant: O=S([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1Cn2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Agent: [Na+]
Solvent: ClCCl
Product: COC1Cn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Reaction time: 0.33 h

Procedure:
2-(4-Fluorophenyl)-6-methoxy-3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 49, (1.10 g, 2.95 mmol) is diluted with dichloromethane (60 mL). 3-Chloroperbenzoic acid (662 mg of ˜77% purity, 2.95 mmol) is added all at once to the yellow suspension. After 20 min, additional 3-chloroperbenzoic acid (240 mg, 1.07 mmol) is added. After 10 minutes, the clear, yellow reaction solution is poured in a 10% aqueous solution of sodium bisulfite (60 mL). The layers are separated and the aqueous layer extracted with dichloromethane (2×50 mL). The combined organic layers are washed with a saturated aqueous solution of sodium bicarbonate (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 948 mg of a mixture of the corresponding sulfoxide and sulfone as a yellow solid. Used as is for next step.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)[OH:2].O1CCOCC1.[OH-].[K+].[CH3:20][N:21]([S:25][N:26]([CH3:28])[CH3:27])[C:22](F)=[O:23]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.O>[CH3:27][N:26]([CH3:28])[S:25][N:21]([CH3:20])[C:22]([O:2][N:1]=[C:3]1[C:8]([CH3:9])([CH3:10])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)=[O:23]
Reactant: CN(C)SN(C)C(=O)F
Reactant: CC1(C)NC(=O)CSC1=NO
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)SN(C)C(=O)ON=C1SCC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 5.8 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, 200 ml dioxane, 2.1 g powdered potassium hydroxide and 0.1 g dicyclohexyl-18-crown-6, was charged to a stirred flask and 5.3 g of N-methyl-N-(dimethylaminosulfenyl)carbamoyl fluoride was added at 30° C over a 1-minute period. The reaction mixture was stirred overnight at room temperature and then added to cold water and stirred for 5 minutes. The resulting mixture was extracted with methylene chloride. The methylene chloride layer was washed thoroughly with water and then dried with magnesium sulfate. The methylene chloride was stripped from the product under reduced pressure and the crystalline residue was recrystallized from ethylene acetate to provide 7.0 g of 2-[O-(N-Dimethylaminosulfenyl-N-methylcarbamoyl)oximino]-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 165°-167° C. An nmr spectrum supported the proposed structure.
Reaction SMILES: ClC1C=CC2N=C([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)OC=2C=1.Cl.Cl[C:19]1[N:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([Cl:29])=[CH:24][CH:25]=2)[N:20]=1.C(OC(N1CCC(N)C1)=O)(C)(C)C>>[Cl:29][C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[N:28][C:19]([NH:9][CH:10]3[CH2:14][CH2:13][NH:12][CH2:11]3)=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2nc(NC3CCNC3)oc2c1
Reactant: Clc1ccc2cnc(Cl)nc2c1
Agent: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: Cl
Product: Clc1ccc2cnc(NC3CCNC3)nc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-yl-amine; hydrochloride (example 1, step 1) the title compound was prepared from 2,7-dichloro-quinazoline (Synthesis 1978, 5, 379-82) and 3-Amino-pyrrolidine-1-carboxylic acid tert-butyl ester (commercially available) and subsequent cleavage of the tert-butyl oxy carbonyl protecting group under acidic conditions. (MH+) 249.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1([CH3:23])[CH2:12][C:11]2[C:13]([CH3:22])=[C:14]([NH:19]C=O)[C:15]([CH3:18])=[C:16]([CH3:17])[C:10]=2[O:9]1>O>[NH2:19][C:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:10]2[O:9][C:8]([CH3:7])([CH2:23][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:12][C:11]=2[C:13]=1[CH3:22]
Reactant: Cc1c(C)c2c(c(C)c1NC=O)CC(C)(CBr)O2
Reactant: C1CCNC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCCC1)O2
Temperature: 160 °C
Yield: 83.5 %

Procedure:
Pyrrolidine (20 ml) was added to 2-bromomethyl-5-formylamino-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (3.0 g, 9.6 mmol) and the mixture was heated at 160° C. in an autoclave for 15 hours. After the reaction mixture was cooled, the mixture was diluted with water and the product was extracted with ethylacetate. The extract was washed with water and dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (chloroform-methanol, 9:1) and recrystallized from hexane to obtain the desired compound (2.2 g, yield: 83.5%), m.p. 85°-86° C. (dec.).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.[C:29]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.O>[O:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[N:6]([C:2]([C:40]4[CH:41]=[C:36]([CH:37]=[CH:38][CH:39]=4)[C:34]([O:33][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:35])=[C:3]([C:17]#[C:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: Brc1c(C#Cc2ccc3ccccc3n2)nc2c(N3CCOCC3)ccnn12
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)c1
Temperature: 80 °C

Procedure:
To a stirred solution of compound 18b (51 mg, 0.12 mmol), (3-(tert-butoxycarbonyl)phenyl)boronic acid (39 mg, 0.18 mmol), and cesium carbonate (0.12 g, 0.36 mmol) in degassed 1,4-dioxane (4 mL) and water (0.5 mL) under Argon was added dichloro(diphenylphosphinoferrocene)palladium (II) (4.3 mg, 0.0059 mmol). The resulting mixture was heated at 80° C. for 2 h, allowed to cool to rt, and treated with EtOAc (10 mL). The organic layer was washed with water (10 mL) and brine (10 mL), and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel (20-100% EtOAc/heptane) to give compound 18c as a brown oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H29N5O3: 532.2 (M+H). found: 532.5.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][C:2]2[C:7]([O:8][C:9]3[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=3[O:16][CH3:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=2)(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: COc1ccc(F)cc1Oc1c(Cl)ncnc1Cl
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Product: COc1ccc(F)cc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The 4-chloro-N-[6-chloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulfonamide (m.p. 169°-171° C.) was prepared from 4,6-dichloro-5-(5-fluoro-2-methoxy-phenoxy)-pyrimidine and 4-chlorobenzenesulfonamide K.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1.S([O-])([O-])(=O)=O.[Mg+2]>C1CCCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:9]1
Reactant: CC1CCCC(=O)C1
Reactant: C1CCNCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCCCC1
Product: CC1CCCC(N2CCCCC2)C1
Reaction time: 6 h
Yield: 76.7 %

Procedure:
A three neck 500 mL flask was charged with 20 g (0.23 mole) of piperidine, 53 g (0.47 mole) of 3-methylcyclohexanone and 200 mL of anhydrous cyclohexane. To the resulting solution, 84 g (0.70 mole) of anhydrous magnesium sulfate was added and the mixture was mechanically stirred and heated at reflux (the reaction was monitored by NMR) for 192 hours. The reaction mixture was then filtered through a fritted glass funnel. The filtrate (containing the enamine product, excess 3-methylcyclohexanone and cyclohexane) was transferred to a hydrogenation vessel. To this mixture, 3 g of 10% Pd on activated carbon was added and the vessel affixed to a hydrogenation Parr shaker at 65 psi of hydrogen. The mixture was left on the Parr shaker for 6 hours at room temperature. The mixture was then filtered through a bed of Celite® in a fitted glass filtering funnel. The filtrate was transferred to a round bottom flask and concentrated under reduced pressure on a rotary evaporator. The obtained residue, which contained 1-(3-methylcyclohexyl)piperidine and excess 3-methylcyclohexanone, was treated with 120 mL of 3M aqueous HCl solution. The mixture was stirred in an ice-water bath for 20 minutes. Then, the mixture was transferred to a reparatory funnel and extracted with 200 mL of diethyl ether. The ether layer, containing the excess 3-methylcyclohexanone, was separated from aqueous layer containing the amine in the form of its onium hydrochloride salt. The ether layer was dried over MgSO4, filtered and concentrated under reduced pressure on a rotary evaporator to recover 31 g of the excess 3-methylcyclohexanone. The aqueous layer was treated with 50 wt. % aqueous NaOH solution in an ice bath until a pH of about 11 was reached. This solution was then extracted with 300 mL of diethyl ether. The ether layer was dried over MgSO4, filtered and concentrated under reduced pressure on a rotary evaporator to give 32 g of 1-(3-methylcyclohexyl)piperidine as a yellow oil. The product was confirmed by 1H-NMR and 13C-NMR analysis. Some piperidine was also present in the oil as an impurity.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.O>CN(C=O)C>[F:23][C:22]([F:25])([F:24])[CH2:21][N:6]1[CH:5]=[C:4]([NH2:1])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cnn(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a suspension of 4-nitro-1H-pyrazole (500 mg) and potassium carbonate (1.22 g) in DMF (5 mL) was added dropwise 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.54 g). The reaction mixture was stirred at room temperature for 4 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A suspension of the obtained residue and palladium on carbon (1 g) in methanol (30 mL) was stirred at room temperature for 12 hr under a hydrogen atmosphere, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (490 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19](OC3C=CC([N+]([O-])=O)=CC=3)=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[C:33]([O:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([NH:31][C:32]3[C:33]([O:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)ccc2C1
Reactant: COc1ncccc1N
Solvent: CC#N
Product: COc1ncccc1NC(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Yield: 54.7 %

Procedure:
A mixture of 6-(4-nitro-phenoxycarbonylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.46 g) obtained in Example (24a), 3-amino-2-methoxypyridine (441 mg), and acetonitrile (20 mL) was heated to reflux for 5 hours and concentrated. The residue was diluted with ethyl acetate, then washed with a saturated aqueous solution of sodium bicarbonate (twice) and brine, and then concentrated. The residue was purified by chromatography (dichloromethane/ethyl acetate) to obtain the title compound (770 mg, 55%) as an off-white foam.
Reaction SMILES: C(N(CC)CC)C.[ClH:8].[NH2:9][OH:10].Cl[C:12]1[CH:39]=[CH:38][CH:37]=[CH:36][C:13]=1[O:14][C:15]1[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=[N:32][O:33][CH3:34])[C:29](Cl)=[O:30])[C:16]=1[F:35].Cl>O1CCCC1>[Cl:8][C:36]1[CH:37]=[CH:38][CH:39]=[CH:12][C:13]=1[O:14][C:15]1[N:20]=[CH:19][N:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28](=[N:32][O:33][CH3:34])[C:29]([NH:9][OH:10])=[O:30])[C:16]=1[F:35]
Reactant: NO
Reactant: Cl
Reactant: CON=C(C(=O)Cl)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON=C(C(=O)NO)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
1.4 g (0.014 mol) of triethylamine are initially added to a mixture of 0.8 g (0.012 mol) of hydroxylamine hydrochloride in 20 ml of tetrahydrofuran, the mixture is cooled to 0° C., and at this temperature, a solution of 1 g (0.0023 mol) of 2-{2-[6-(2-chlorophenoxy)-5-fluoro-pyrimidin-4-yloxy]-phenyl}-2-methoxyiminoacetyl chloride in 10 ml of tetrahydrofuran is then added dropwise. Without further cooling, stirring is continued for 18 hours. The reaction mixture is poured into 100 ml of 1 N hydrochloric acid and extracted 3 times with in each case 100 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (4:1). This gives 0.3 g (30% of theory) of 2-(2-{[6-(2-chlorophenoxy)-5-fluoro-4-pyrimidinyl]oxy} phenyl)-N-hydroxy-2-(methoxyimino)-acetamide.
Reaction SMILES: O1CCCC1.Br[C:7](Br)([F:9])[F:8].CN(P(N(C)C)N(C)C)C.O=[C:22]([CH3:34])[CH2:23][CH2:24][O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)C>[C:26]([O:25][CH2:24][CH2:23][C:22]([CH3:34])=[C:7]([F:9])[F:8])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(=O)CCOC(=O)c1ccccc1
Reactant: FC(F)(Br)Br
Agent: CN(C)P(N(C)C)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CCOC(=O)c1ccccc1)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
Reaction was carried out under nitrogen atmosphere. To 400 ml of tetrahydrofuran, 46.2 g (0.22 mol) of dibromodifluoromethane was dissolved, followed by drop-wise adding 70.2 g (0.43 mol) of tris (dimethylamino)phosphine at −10° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature for 1 hour, and 150 ml tetrahydrofuran solution dissolving with 19.2 g (0.10 mol) of 3-oxobutylbenzoate was further added drop-wise at −20° C. After the end of the drop-wise addition, the reaction liquid was stirred at room temperature overnight. To this mixture, diethyl ether was added, followed by washing with dilute hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (diisopropyl ether:hexane=1:8) to obtain 16.4 g (yield: 72%) of 4,4-difluoro-3-methyl-3-butenyl benzoate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33](C3CC(=O)N(O)C3=O)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.Cl>O1CCOCC1>[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([NH:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=3)=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 40 °C
Yield: 99 %

Procedure:
To 4-aminomethyl-benzoic acid (10.6 g, 70.1 mmol) in dioxane (130 mL) was added 9% aqueous Na2CO3 (150 mL) followed by 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide (26 g, 77 mmol). The solution was heated to 40° C. for 12 h and then cooled to room temperature. The reaction was acidified with 1 M HCl (500 mL), and extracted with ether (300 mL) to obtain acid S23 as a fluffy white solid (25.9 g, 69.4 mmol, 99%). 1H NMR (500 MHz, d6-DMSO): δ 12.85 (broad s, 1H), 7.90 (m, 4H), 7.70 (m, 2H), 7.39 (m, 2H), 7.31 (m, 4H), 4.37 (d, 2H, J=6.8 Hz), 4.24 (d, 2H, J=5.8 Hz), 4.23 (t, 1H, J=6.8 Hz). APCI/MS: 372 (M+H+).