Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:3]2[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=2.[H][H].[O-2].[O-2].[O-2].[Al+3].[Al+3]>[Pd]>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C1=CC2=C(CCCCCCCC1)O2
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Product: OC1CCCCCCCCCCC1
Yield: 20 %

Procedure:
Also, it is known that epoxidized cycloalkanes and/or epoxidized cycloalkenes can be produced by epoxidizing corresponding cycloalkenes with a high yield. If the epoxidized compounds can be converted to corresponding cycloalkanones and cycloalkanols with a high efficiency, the cycloalkanones and the cycloalkanols can be expected to be obtained at a high yield. However, only a small number of reports can be found on methods of converting an epoxidized cycloalkane and/or an epoxidized cycloalkene to a mixture of cycloalkanone with cycloalkanol. For example, J. Mol. Catal., Vol. 69, pages 69 to 103 (1991) discloses a method of hydrogenating a monoepoxycyclododecadiene with hydrogen in the presence of a catalyst comprising palladium carried on a carrier consisting of γ-alumina, under a hydrogen gas pressure of 1.3 MPa at a temperature of 90° C. In this method, cyclododecanol was produced with a yield of 20% or less and no cyclododecanone was produced. When a catalyst comprising palladium carried on a carrier consisting of titania or silica was used in place of the above-mentioned palladium catalyst carried on γ-alumina, the yield of cyclododecanol was low and unsatisfactory.
Reaction SMILES: C(OC([N:8]1[C:12]([CH3:32])([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[NH2:8][C:12]([C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:23]=2)=[CH:16][N:17]=1)([CH3:32])[CH2:11][OH:10]
Reactant: CCCCCCCCc1ccc(-c2cnc(C3(C)COC(C)(C)N3C(=O)OC(C)(C)C)[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCCCCCCCc1ccc(-c2cnc(C(C)(N)CO)[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a flame dried round bottom flask equipped with a magnetic stirbar under an inert atmosphere was added 6 (973 mg, 2.07 mmol) followed by MeOH (20 mL) and p-TsOH.H2O (1.22 g, 6.42 mmol). This mixture was then heated to reflux, stirred 3 h, cooled to 0° C., and quenched by slow addition of sat. aq. NaHCO3 (20 mL). This solution was then diluted with EtOAc (30 mL) and the aqueous layer was discarded. The organic phase washed with sat. aq. NaHCO3 (1×20 mL), washed with 1M NaOH (1×20 mL), dried over sodium sulfate, and concentrated to an orange oil. To this oil was added Et2O which produced VPC24241 (408 mg, 60%) as a white precipitate which was collected by filtration.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[Na].Cl[CH2:11][C:12]1[CH:20]=[C:18]([CH3:19])[CH:17]=[C:15]([CH3:16])[C:13]=1[CH3:14]>C(O)C>[CH3:11][C:12]1[CH:20]=[C:18]([CH3:19])[CH:17]=[C:15]([CH3:16])[C:13]=1[CH2:14][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: Cc1cc(C)c(C)c(CCl)c1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Solvent: CCO
Product: Cc1cc(C)c(CSc2cccc[n+]2[O-])c(C)c1

Procedure:
A mixture of 17 gms (0.05 mole) 2-mercaptopyridine N-oxide, sodium salt (40% aqueous solution) and 8.5 gms (0.05 mole) α 2 chloroisodurene in 50 ml of ethanol is brought to reflux for 15 minutes. The volatiles are removed and the residue extracted with 150 ml of boiling chloroform, filtered and dried over sodium sulfate. Evaporation and trituration of the residue with a few drops of acetone induced crystallization. A yield of 11.5 gms of 2-(2,4,6-trimethylphenylmethylthio)pyridine N-oxide is obtained. Melting point 137° - 138°C. Structure confirmed by IR and NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9]([C:11]1[C:12]([SH:23])=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][CH:16]=1)=[O:10].II>>[C:17]1([C:14]2[N:13]=[C:12]3[S:23][N:8]([CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:9](=[O:10])[C:11]3=[CH:16][N:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NCc1ccccn1)c1cnc(-c2ccccc2)nc1S
Agent: II
Product: O=c1c2cnc(-c3ccccc3)nc2sn1Cc1ccccn1
Yield: 81.6 %

Procedure:
Using the procedure of Example 20, 2.0 g (6.20 mmol) of 4-mercapto-2-phenyl-pyrimidine-5-carboxylic acid (pyridin-2-ylmethyl)-amide were treated with 1.73 g (6.82 mmol) of iodine to give 1.62 g of the title compound after recrystallization from isopropanol, mp 154°-156° C.
Reaction SMILES: CN(C=[O:5])C.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH2:28][O:29][CH3:30])=[C:11]([CH:26]=1)[CH:12]([C:15]1[C:20]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1)C#N.C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:27][CH2:28][O:29][CH3:30])=[C:11]([CH:26]=1)[C:12]([C:15]1[C:20]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:5]
Reactant: COCOc1ccc(Br)cc1C(C#N)c1ncccc1C1OCCO1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCOc1ccc(Br)cc1C(=O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
DMF (2 ml) was added to a mixture of 2-(5-bromo-α-cyano-2-methoxymethoxybenzyl)-3-(1,3-dioxolan-2-yl)pyridine (120 mg) and potassium carbonate (102 mg), which was stirred for 80 hours at room temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried (anhydrous sodium sulfate) and concentrated to give 2-(5-bromo-2-methoxy methoxy benzoyl)-3-(1,3-dioxolan-2-yl)pyridine (90 mg) (Compound E-1). The physical properties and spectrum data are shown in Table 16 and Table 18.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:25][C:24]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38])(=[O:22])=[O:21]>C(#N)C>[OH:10][B:7]1[C:6]2[CH:11]=[C:2]([NH:1][S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:35])[C:31]([F:32])([F:33])[F:34])=[CH:25][C:24]=3[CH2:36][C:37]([O:39][CH3:40])=[O:38])(=[O:21])=[O:22])[CH:3]=[CH:4][C:5]=2[CH2:9][O:8]1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COC(=O)Cc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To a stirred solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (3.5 g, 0.024 mol, 0.9 eq) and NMM (7.9 g, 0.079 mol, 3 eq) in acetonitrile (50 mL) was added a solution of methyl 2-(2-(chlorosulfonyl)-5-(2,2,2-trifluoroacetamido) phenyl)acetate (9.4 g, 0.026 mol) in anhydrous acetonitrile (50 mL) at 0-5° C. Then the mixture was stirred at r.t overnight, the mixture was concentrated and dissolved in DCM and then washed with brine, dried and concentrated, purified by column chromatography (PE:EA 10:1˜1.5:1) to give the title compound (7.4 g, yield 60%). 1H NMR DMSO-d6 400 MHz δ11.54 (s, 1H), 10.36 (s, 1H), 9.21 (s, 1H), 7.87-7.10 (m, 6H), 4.87 (s, 2H), 4.08 (s, 2H), 3.58 (s, 3H). ESI-MS m/z 495 (M+Na+, positive); HPLC purity: 98.23% (220 nm), 99.55% (254 nm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]2[C:13]([NH:14][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(N)c2s1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Nc1nc2c(OC)ccc(NCc3ccccn3)c2s1
Temperature: 70 °C
Yield: 36.3 %

Procedure:
To a stirred solution of 40 mg (0.16 mmol) (7-amino-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 2 ml DM F at room temperature were added 66 mg (0.47 mmol) potassium carbonate and 40 mg (0.16 mmol) 2-(bromomethyl)pyridine hydrobromide and the mixture heated at 70° C. for 16 h. The mixture was then concentrated in vacuo. Flash chromatography (2/1 ethyl acetate/hexane) afforded 20 mg (37%) {4-methoxy-7-[(pyridin-2-ylmethyl)-amino]-benzothiazol-2-yl}-carbamic acid methyl ester as a yellow solid. ES-MS m/e (%): 367 (M+Na+, 54), 345 (M+H+, 100).
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([NH:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])=[O:12])=[CH:10][CH:9]=1
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1ccc(Br)cc1
Product: CN(C)CCNC(=O)c1ccc(Br)cc1
Temperature: 150 °C

Procedure:
A microwave vial containing 4-bromo-benzoic acid ethyl ester (1 g, 4.36 mmol) and N,N-dimethylethylenediamine (2.37 g, 21.38 mmol) was heated under microwave radiation (150° C., 10 min). The volatiles were removed under rotary evaporation and the crude was used in the next step without further purification. Yield: 1.18 g, 100%. LCMS method: 2, RT: 1.93 min; MI: 271-273 [M+1].
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[C:14]([CH:16]([OH:39])[C:17]2[C:22]([NH:23][S:24]([C:27]3[CH:32]=[CH:31][C:30](C)=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:21][C:20]([Cl:38])=[CH:19][N:18]=2)[CH:13]=[CH:12][N:11]=1)(C)(C)C.O1CCOC[CH2:43]1>O=[Mn]=O>[Cl:38][C:20]1[CH:21]=[C:22]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34]([F:37])([F:36])[F:35])[C:28]=2[CH3:43])(=[O:26])=[O:25])[C:17]([C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][OH:6])[CH:15]=2)=[O:39])=[N:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(O)c2ccnc(NCCO[Si](C)(C)C(C)(C)C)c2)cc1C(F)(F)F
Reactant: C1COCCO1
Agent: O=[Mn]=O
Product: Cc1c(C(F)(F)F)cccc1S(=O)(=O)Nc1cc(Cl)cnc1C(=O)c1ccnc(NCCO)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To the dioxane (1 mL) solution of N-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide from step 1, was added MnO2 (440 mg, 5 mmol). The mixture was stirred at 80° C. for 1 hour, filtered, concentrated. The deprotection was performed in 4 M HCl in dioxane (4 mL) and water (1 mL) for 1 hour at RT. The solvent was evaporated and the residue was purified with HPLC to give N-{5-chloro-2-[2-(2-hydroxy-ethylamino)-pyridine-4-carbonyl]-pyridin-3-yl-}-methyl-3-trifluoromethyl-benzenesulfonamide: 1H NMR (400 MHz, CDCl3) δ 8.3 (s, 1 H), 8.15 (d, 2H), 8.05 (s, 1 H), 7.9 (d, 1 H), 7.4 (d, 1 H), 6.7 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2 H), 2.5 (s, 3H); MS m/z: 515 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])CCC.Cl[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=1>O1CCCC1.CCCCCC.[Cl-].[Cl-].[Zn+2]>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:22]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCS3)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 465.7 mg (2.3019 mmol) of 4,4-dimethyl-6-ethynyl-thiochroman in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.5 ml of 1.6M (2.4 mmol) n-butyllithium in hexane. This was stirred at 0° C. for 10 minutes and at room temperature for 10 minutes, cooled again to 0° C. and then treated with a solution of 330 mg (2.4215 mmol) of fused ZnCl2 in 4 ml dry tetrahydrofuran using a double ended needle. Thereafter the solution was stirred at 0° C. for 30 minutes, then at room temperature for 10 minutes. A solution of 426.3 mg (2.2967 mmol) of ethyl 6-chloronicotinoate (from Example 5) in 4 ml dry tetrahydrofuran was transferred by double ended needle into a suspension of 430 mg (0.37 mmol) of tetrakistriphenylphosphine palladium in 4 ml dry tetrahydrofuran and stirred at room temperature for 10 minutes, then treated by double ended needle with the solution of the alkynylzinc prepared above. This mixture was stirred at room temperature for 18 hours, then quenched with 100 ml water. Product was recovered by extraction with 3×75 ml ether. Ether fractions were combined and washed with saturated NaCl solutions and dried (mgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexane) followed by HPLC (Whatman Partisil M-9 10/50; 4% ethyl acetate in hexane) to give the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[NH2:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:2]=1[Cl:1]
Reactant: Nc1ncnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncnc(N)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 10-mL vial was placed 5,6-dichloropyrimidin-4-amine (250.00 mg; 1.52 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (653.40 mg; 3.05 mmol), and N,N-diisopropylethylamine (1.01 ml; 6.10 mmol) suspended in NMP (2.50 ml). The reaction mixture was run in the microwave at 150° C. for 2 hours. The reaction mixture was allowed to cool to rt. The mixture was purified using Biotage column chromatography eluting from 50-100% EtOAc/Hexanes. Fractions containing the desired product were combined and concentrated under reduced pressure to afford tert-butyl 4-{[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1-carboxylate as a yellow viscous oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:21][CH3:22])[C:5]1[CH:10]=[CH:9][C:8](/[N:11]=[N:12]/[C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Cl.[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][S:27]/[C:26]/1=[N:31]\[NH2:32].[OH-].[Na+]>C(O)(=O)C.O>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][S:27]/[C:26]/1=[N:31]\[N:32]=[CH:17][C:16]1[CH:19]=[CH:20][C:13](/[N:12]=[N:11]/[C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:3][CH2:2][Br:1])[CH2:21][CH3:22])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: CCN(CCBr)c1ccc(/N=N/c2ccc(C=O)cc2)cc1
Reactant: Cc1cs/c(=N\N)n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCN(CCBr)c1ccc(/N=N/c2ccc(C=N/N=c3\scc(C)n3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.43 g of 4-((E)-{4-[(2-bromoethyl) (ethyl)amino]phenyl}diazenyl)benzaldehyde and 0.21 g of (2Z)-3,4-dimethyl-1,3-thiazol-2(3H)-one hydrazone hydrochloride in 10% acetic acid is stirred at room temperature for 60 minutes. Next, the preparation is diluted with 50 mL of water and cooled with ice. The reaction mixture is made neutral with 2N sodium hydroxide, then the precipitate that formed is suction filtered off, washed with water, and the product obtained is dried under vacuum.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)OC)#[N:2].[C:17]1([CH2:23][CH2:24][NH2:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COC(=NC#N)c1cnc2ccccc2c1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 ml), 2-phenylethylamine (0.20 g, 1.65 mmol) was added. The mixture was stirred at room temperature for 30 minutes After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.41 g, 1.36 mmol, yield: 91%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([CH3:26])[CH:17]=1.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[C:18]([CH3:26])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)cc1Oc1ccc(Br)cc1
Temperature: 150 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
37.5 g (216.7 mmol) of 4-bromophenol and 35.4 g (256.2 mmol) of potassium carbonate are suspended in 500 ml of N,N-dimethylformamide and the suspension is stirred at room temperature for 1 h, before 36.6 g (197.0 mmol) of 4-chloro-2,5-dimethylnitrobenzene are added. The mixture is subsequently stirred at 150° C. for 14 h, water is added, and repeated extraction is carried out with ethyl acetate. The extracts are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (48.0 g, purity 91.0%, yield 68.8%, log P (pH 2.3)=4.86).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[BrH:25]>C(OCC)(=O)C.CCCCCC>[Br:25][CH2:14][C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: Br
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Temperature: 80 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
N-[4-(4-fluorophenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (50.0 g) and 48% hydrogen bromide (130.0 mL) were added to a reactor. The reaction mixture was stirred at 80° C. for 15 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:2). The reaction mixture was cooled to 20˜25° C., stirred for over 1 hour, and then filtered under reduced pressure. The resulting white solid was washed with water (500.0 mL) and then dried under reduced pressure to obtain N-[5-bromomethyl-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide as a white solid (55.3 g, yield 94%).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:29]([O:22][C:3]1[C:2]([F:1])=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1O)C(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of diethyl N-(3,4-difluoro-2-hydroxyphenyl)aminomethylenemalonate (80 mg) and anhydrous potassium carbonate (70 mg) in dry dimethylformamide (1.5 ml) was added benzyl bromide (30 μl). The mixture was stirred at room temperature for 2 hours. After removal of the solvent under reduced pressure, the residue was dissolved in dichloromethane and the precipitate was filtered off. The filtrate was washed with water, dried over anhydrous sodium sulfate and evaporated. The crystalline residue was washed with n-hexane and recrystallized from methanol to give diethyl N-(2-benzyloxy-3,4-difluorophenyl)-aminomethylenemalonate (90 mg), mp 87° C.; MS m/z 405 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]CC)=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1n[nH]c2cc(Cl)c(-c3ccc(N4CCOCC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1n[nH]c2cc(Cl)c(-c3ccc(N4CCOCC4)cc3)cc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
To a solution of ethyl 6-chloro-5-[4-(morpholin-4-yl)phenyl]-1H-indazole-3-carboxylate (72 mg, 0.19 mmol) in ethanol (2 mL) was added 6 N aqueous sodium hydroxide (0.5 mL, 3.0 mmol). The mixture was stirred for three hours at 70° C. The cooled reaction mixture was neutralized with Dowex acid resin concentrated in vacuo. The crude product was purified by reverse phase column (water/acetonitrile, 0-40%, 20CV) to give the title compound (21 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([CH2:10][CH2:11][C:12](Cl)=[O:13])[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>ClCCCl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:12](=[O:13])[CH2:11][CH2:10][CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:18][CH:17]=1
Reactant: Clc1ccccc1
Reactant: O=C(Cl)CCC1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: O=C(CCC1CCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
Aluminum chloride (4.979 g, 37.34 mmol) was added in small portions to a solution of 3-cyclopentylpropionyl chloride (3 g, 18.67 mmol) in 1,2-dichloroethane (100 mL) cooled to 0° C. After 15 min., chlorobenzene (6.304 g, 56.01 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 48 h. It was then poured into a mixture of ice and water. The product was extracted with ethyl acetate. The organic layers were washed with saturated solution of sodium bicarbonate (1×30 mL), brine (1×20 mL) and dried over anhydrous magnesium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with hexanes yielded 1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one (1.12 g, 25%) as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:20]CO.O>>[CH3:20][CH2:16][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)([CH3:17])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(C)(C)c1ccc(C(C)(C)C)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C(=O)O)c1ccc(C(C)(C)C)cc1
Yield: 73.2 %

Procedure:
A solution of methyl 4-tert-butylphenylacetate (30.00 g, 0.145 mol) and iodomethane (45.41 g, 0.320 mol) in 125 mL of dry THF was added to a slurry of NaH (8.72 g, 0.363 mol) in 200 mL of THF dropwise over 30 minutes. After completion of the addition, the reaction mixture was heated at reflux for 1.5 hr. The reaction was allowed to cool to room temperature, filtered through Celite and concentrated. The residue was diluted in ether, washed with H2O, and dried over MgSO4. Evaporation of the solvent afforded the desired product as an oil. A mixture of the crude methyl 4-tert-butylphenylisobutyrate and 4:1 EtOH/H2O containing KOH (10.07 g, 0.179 mol) were heated to reflux for 4 hr. The EtOH was evaporated in vacuo, the residual solution was acidified to pH 2 with 2N HCl, and the precipitated solid filtered. The white solid was the dried (60° C., 1 mm Hg, 24 hr) to give the desired product (23.45 g, 73.2% from methyl 4-tert-butylphenylacetate). 1H NMR (CDCl3) 1.34 (s, 9H), 1.62 (s, 6H), 7.37 (s, 4H), 11.4-12.4 (brs, 1H). 13C NMR (CDCl3) 26.16, 31.30, 34.35, 45.81, 125.31, 125.48, 140.64, 149.66, 183.57.