Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:34]2[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: COc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(OC)nc3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 120 mg, 0.41 mmol) in dioxane (3 mL) was added K3PO4 (257 mg, 1.22 mmol), 6-methoxypyridin-3-ylboronic acid (187 mg, 1.22 mmol) and Pd(PPh3)4 (23.54 mg, 0.02 mmol) with stirring for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to get a residue, which was purified by a silica gel column with 1%-2% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(6-methoxypyridin-3-yl)quinoxaline-6-carboxylate as a light yellow solid (120 mg, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.C1C(=O)N([Br:29])C(=O)C1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Br:29])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCc2cccnc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Yield: 97.7 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (1.37 g, 5.85 mmole) in CH2Cl2 (30 mL) was added glacial HOAc (3.4 mL, 58.5 mmole) and NBS (1.09 g, 6.14 mmole). After 72 hr the mixture was washed with 2.0 M NaOH, H2O, and brine. The mixture was dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (1.79 g, 98%) which was sufficiently pure for use in the next step: 1H NMR (400 MHz, CDCl3) δ 835 (s, 1H), 7.51 (s, 1H), 3.77 (m, 2H), 2.75 (t, J=6.5 Hz, 2H), 1.93 (m, 2H), 1.54 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][C:4]([OH:8])=[N:3]1.[CH2:9](Br)[C:10]#[CH:11].C(O)C>C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([S:7][CH2:11][C:10]#[CH:9])=[N:5][C:4]([OH:8])=[N:3]1
Reactant: C#CCBr
Reactant: Cn1nc(O)nc1S
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCSc1nc(O)nn1C

Procedure:
13.1 g of 1-methyl-3-hydroxy-5-mercapto-1,2,4-triazole and 13.1 g of propargyl bromide are added to 100 ml of ethanol. To this suspension are added all at once 11.1 g of triethylamine. The exothermic reaction causes the temperature to rise to 45° C. After a short time a yellow product falls out of the clear solution and is filtered off and washed with water. The undissolved material is dried over P2O5.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1(C)C(C)=CC=CC=1.[OH-].[K+].COS(=O)(=O)OC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([N:4]([CH3:21])[C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C
Reactant: CC(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC(=O)N(C)c1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
A mixture of 1-acetylaminoanthraquinone (purity 99.9%, 26.5 g), xylene (500 g), tetra-n-butyl ammonium chloride (0.6 g) and 96% potassium hydroxide (12.0 g) was stirred for 1 hour while being maintained at 50° C. Then, dimethylsulfuric acid (25.2 g) was dropped at 50° C. over 2 hours. The mixture was stirred at 50° C. for 30 minutes, 60° C. for 2 hours and 70° C. for 4 hours, successively. After water (250 g) was added, the solution was stirred for 1 hour, while being maintained at 50° C. Then, the same procedure as in Example 3 was applied to obtain, after xylene was recovered, N-acetyl-1-methylaminoanthraquinone (27.7 g, purity 92.4%, yield 91.7%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[Br-].[CH2:26]([Zn+])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.CCOC(C)=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 57 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (800 mg, 2.06 mmol), benzylzinc bromide (10.3 mL, 5.14 mmol, 0.5 M in THF), and Pd(PPh3)4 (238 mg, 0.206 mmol) in THF (20 mL) was refluxed under nitrogen atmosphere for 16 h. After the mixture was cooled to r.t., 1 M HCl and EtOAc were added. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 470 mg of the title compound as a yellow solid. MS: (+) m/z 401.12 (M+1).
Reaction SMILES: [CH2:1]([C:12]([CH3:14])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH:15]([NH2:17])=[O:16]>C(O)=O>[CH:15]([NH:17][CH:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:14])=[O:16]
Reactant: CCCCCCCCCCCC(C)=O
Reactant: NC=O
Solvent: O=CO
Product: CCCCCCCCCCCC(C)NC=O
Temperature: 160 °C

Procedure:
70 g of methyl undecyl ketone are added to 250 ml of formamide. The mixture is heated, with constant stirring, to 160° C. Then 40 ml of formic acid are added dropwise in the course of 24 hours. The reaction mixture is cooled, poured on ice, extracted with ether and the ethereal extract is dried over Na2SO4. After distilling off the ether, the oily residue is distilled in vacuo, affording 60 g of 2-formamidotridecane. Boiling point: 145°-155° C./0.01.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][NH:5][C:6]1[C:18]2[C:17](=[O:19])[C:16]3C=CN=C[C:11]=3[C:10]=2[C:9]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:8]=2[N:7]=1.[CH3:27][NH:28][CH2:29][CH2:30]N>>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:9]2[C:10]3[C:11]4[CH:30]=[CH:29][N:28]=[CH:27][C:16]=4[C:17](=[O:19])[C:18]=3[C:6]([NH:5][CH2:4][CH2:3][NH:2][CH3:1])=[N:7][C:8]=2[CH:23]=1
Reactant: CNCCN
Reactant: COc1ccc2c3c(c(NCCN(C)C)nc2c1)C(=O)c1ccncc1-3
Product: CNCCNc1nc2cc(OC)ccc2c2c1C(=O)c1cnccc1-2

Procedure:
This compound was prepared from the compound of Example 1c-2 and N-methylethylenediamine. The desired product was obtained as a red solid. EI−MS: m/z 334 (M+); 1H-NMR (CDCl3): δ2.51 (3H, s), 2.94 (2H, t, J=6 Hz), 3.82 (2H, d, J=6 Hz), 3.97 (3H, s), 6.98 (1H, dd, J=9 Hz, 2.5 Hz), 7.10 (1H, d, J=2.5 Hz), 7.88 (1H, dd, J=5 Hz, 1 Hz), 8.05 (1H, d, J=9 Hz), 8.84 (1H, d, 5 Hz), 8.87 (1H, d, J=1 Hz).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[O:22][C:2]1[C:7]2=[C:8]([CH3:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Cc1ccn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To a mixture of 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (3.37 g, 20.11 mmol, PCT Appl.WO 2000/071129, U.S. pat. application 2003/0186982, the disclosure of which is herein incorporated by reference) and 2-fluoro-4-nitrophenol (3.48 g, 22.12 mmol) in anhydrous DMF (100 mL), stirred for 5 minutes under a nitrogen atmosphere, was added anhydrous potassium carbonate (6.11 g, 44.24 mmol). The mixture was heated at 60° C. for 15 h before 2-fluoro-4-nitrophenol (1.00 g, 6.37 mmol) was added and stirring continued at 60° C. for 4.5 h. The mixture was cooled to room temperature, diluted with dichloromethane, washed sequentially with water and 10% aqueous lithium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a tan solid. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with chloroform, afforded the title compound (4.19 g, 72%) as a pale yellow solid. 1H NMR (CDCl3) δ 8.20-8.13 (m, 2H), 7.83 (s, 1H), 7.73 (d, 1H, J=2.6 Hz); 7.58-7.53 (m, 1H), 6.69 (d, 1H, J=2.4 Hz), 2.62 (s, 3H); HRMS(ESI), 289.0737 (M+H)+ calc, 289.0733 (M+H)+ found.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CCCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Clc1nccc(N2CCCCCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloropyrimidine (3.0 g) in tetrahydrofuran (50 mL) were added triethylamine (4.2 mL) and perhydroazepine (2.5 mL) with ice cooling and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water (30 mL) and the resulting mixture was concentrated. The residue was extracted with methylene chloride three times. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1→2:1) to give the title compound (3.03 g) having the following physical data.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1.N1CCCCC1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=1
Reactant: O=C1C=C(c2ccccc2O)CC1
Reactant: BrCC1CO1
Solvent: C1CCNCC1
Product: O=C1C=C(c2ccccc2OCC2CO2)CC1

Procedure:
2.0 g 3-(2-hydroxyphenyl)-2-cyclopenten-1-one are stirred with 30 ml epibromohydrin and catalytic amounts of piperidine for 1 hour at 100° C. After concentration, the mixture of epoxy- and bromohydrin is separated by high-pressure liquid chromatography. In this manner, 2 g 3-[2-(2,3-epoxypropoxy)-phenyl]-2-cyclopenten-1-one are obtained as an oil which is then dissolved in 20 ml t-butanol. 2 ml of t-butylamine were added and the mixture is stirred at room temperature for 48 hours.
Reaction SMILES: N[C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N([O-])=[O:15].[Na+].S(=O)(=O)(O)O>Cl>[OH:15][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1C(=O)NS2(=O)=O
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1NS(=O)(=O)c2cccc(O)c21
Yield: 40 %

Procedure:
A solution of 1,2-benzoisothiazol-3(2H)-one-1,1-dioxide-4-diazonium chloride, which was prepared by diazotization of 1.98 gm (10 mmols) of 4-amino-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide with sodium nitrite in dilute hydrochloric acid, was reacted with 150 ml of aqueous 10% sulfuric acid, and the reaction mixture was heated on a water bath until the evolution of nitrogen had ceased. After cooling, the reaction mixture was strongly acidified with concentrated aqueous hydrochloric acid and extracted with ether. The organic phase was evaporated, the residue was dissolved in a little sodium hydrochloride, filtered and again acidified with hydrochloric acid. The crystals formed were recrystallized from water, yielding 0.98 gm (40% of theory) of 4-hydroxy-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[C:11]([O:14][CH2:15][CH2:16]Br)(=[O:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:11]([O:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])(=[O:13])[CH3:12]
Reactant: CC(=O)OCCBr
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
A mixture of 3-hydroxybenzamide (3.0 g, 21.9 mmol) prepared as in Example 1, 2-bromoethyl acetate (11.9 g, 70.9 mmol), and K2CO3 (5.7 g, 41.2 mmol) in 40 cc dry dimethyl formamide (DMF) was stirred at 25° C. for 48 hours and filtered. The filtrate was evaporated in vacuo and the resulting residue was recrystallized from 90% EtOH(H2O) to give 3.2 g (65%) of the desired product as a white crystalline powder, mp 121°-122° C. Here, as in the other examples, the product compound was identified by elemental analysis as well as by IR and mass spectroscopy methods.
Reaction SMILES: C(NCC[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=O)CC.[H-].[Na+].C(O[CH2:21][CH3:22])(=O)C>O1CCCC1>[C:22]1([O:14][C:11]2[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=2)[CH:21]=[CH:10][CH:9]=[CH:8][CH:13]=1
Reactant: CCOC(C)=O
Reactant: CCC(=O)NCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred solution of N-ethyl, N-propionyl tyramine (2.84 g, 12.83 mmole) in tetrahydrofuran (32.1 ml) was added 60% sodium hydride dispersion (0.56 g, 14.11 mmole). After stirring for 10 minutes, the compound of Example 42(E) (4.70 g, 12.83 mmole) was added. The reaction was allowed to stir at room temperature for 5 hours, poured into ethyl acetate, and extracted with 10% sodium sulfate, then brine. The organic layer was dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel using a hexane-ethyl acetate gradient. Further chromatography on silica gel using toluene-acetone gradients yielded the intermediate phenyl ether (2.10 g, 32%):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[CH3:36][O:37][CH2:38][C:39](O)=O>>[CH3:36][O:37][CH2:38][C:39]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: COCC(=O)O
Product: COCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 178, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and methoxyacetic acid were reacted to give 161. LCMS: M+H−=535.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.13 (d, 1H), 7.71 (d, 1H), 7.32 (m, 2H), 5.08 (s, 2H), 4.26 (s, br, 4H), 4.02 (s, 1H), 3.83 (s, 3H), 3.78 (m, 4H), 3.73 (s, 2H), 3.27 (s, 3H), 2.90 (m, 2H), 2.00 (m, 2H), 1.65 (m, 2H), 1.22 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH:1](=[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CCO.O.[Pd]>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[O:11][CH2:10][CH:9]1[NH:20][C:21](=[O:25])[O:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC1COc2ccc(OC)cc2C1=Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)NC1COc2ccc(OC)cc2C1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
3.1 g (9.1 mmol) of ethyl 4-benzylidene-6-methoxychroman-3-ylcarbamate were dissolved in 80 ml of EtOH and 910 mg (0.9 mmol) Pd/C were added. Then, 5.8 g (91 mmol) of ammonium formate dissolved in 20 ml of water were added and the mixture was warmed to 70° C. and stirred for 1.5 h. The mixture was cooled to room temperature. The catalyst was filtered off and washed with EtOH/water. The filtrate was concentrated in vacuo to remove EtOH. The aqueous concentrate was extracted with ethyl acetate (2×). The combined organic phases were dried over MgSO4 and the solvent was evaporated to yield 3.2 g (9.3 mmol, quant.) of the crude product.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]2[O:9][CH2:10][O:11][C:3]=12.[CH3:12][O:13][CH2:14][CH2:15][C:16]#[CH:17].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:12][O:13][CH2:14][CH2:15][C:16]#[C:17][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]2[O:9][CH2:10][O:11][C:3]=12
Reactant: Nc1ccc(I)c2c1OCO2
Reactant: C#CCCOC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COCCC#Cc1ccc(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A solution of 4-iodo-2,3-methylenedioxyaniline (1.32 g, 5.00 mmol) and 4-methoxybut-1-yne (0.84 g, 10.00 mmol) in ethyl acetate (25 ml) was cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (350 mg, 10 mol %) followed by copper(I) iodide (95 mg, 10 mol %) and diisopropylamine (1.40 ml, 10.0 mmol). The reaction was stirred for 2 hours in the cooling bath and then allowed to warm to room temperature over 4 hours: The mixture was filtered through Celite and the filtrate was then purified by column chromatography on silica using a gradient of methanol in dichloromethane (0–2%) as eluent to give 4-(4-methoxybut-1-yn-1-yl)-2,3-methylendioxyaniline (524 mg, 82%) as a dark oil; LCMS: M+H+ 220 (82%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.O>C(C(C)=O)C(C)C>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:11][CH:12]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCc1ccc(O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C=CC(=O)OCc1ccc(O[Si](C)(C)C)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1500 g of methyl isobutyl ketone and 100 g of 4-hydroxybenzyl acrylate werecharged into a separable flask of the same type as used in Reference Example 1, and cooled to -5° C. while replacing the flask inside gas with a nitrogen gas, and then 67 g of trimethylchlorosilane was dropwise added thereto over one hour, and then stirring was continued for 2 hours. After completion of the reaction, the reaction mixture was washedwith water and methyl isobutyl ketone was distilled off, whereby 83 g of p-trimethylsilyloxybenzyl acrylate of the following chemical formula was obtained (yield: 59%): ##STR10##
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[CH2:27]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[CH2:28][C:29]#[CH:30].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[O:41]=[C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39](=[O:40])[N:31]1[CH2:27][CH2:28][C:29]#[C:30][C:16]1[CH:17]=[CH:18][C:4]2[N:3]([CH2:1][CH3:2])[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[CH:15]=1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C#CCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 150 °C
Yield: 76.9 %

Procedure:
Trifluoromethane sulfonic acid 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-yl ester(0.59 g), 2-(but-3-ynyl)isoindol-1,3-dione(0.3 g), dichlorobis(triphenyl phosphine)palladium (II) (53 mg), copper(I) iodide(29 mg), and triethylamine(0.39 ml) were added to DMF(4 ml). The mixture was heated at 150° C. (microwave reactor) for 10 minutes. The reaction liquid was cooled to room temperature, and subjected to celite filtration. The filtrate was condensed under reduced pressure and the residue was purified by silica gel column chromatography (hexane: ethyl acetate=60:40→30:70). The purified product was condensed under reduced pressure to give the title compound(0.51 g) as a yellowish-white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][O:19]C.B(Br)(Br)Br.CO>ClCCl>[Br:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][OH:19]
Reactant: COCCOc1cc(CC2CCNCC2)ccc1Br
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: OCCOc1cc(CC2CCNCC2)ccc1Br
Reaction time: 0.5 h
Yield: 116.2 %

Procedure:
A solution of 4-[4-bromo-3-(2-methoxyethoxy)benzyl]piperidine hydrochloride (RE1) (3.00 g, 8.3 mmol) in dichloromethane (100 mL) was cooled in a salt-ice bath. A 1 M solution of boron tribromide in dichloromethane (7.8 mL, 7.8 mmol) was added dropwise thereto at 0° C. in 30 minutes, and the reaction mixture was stirred for 1.5 hours under ice cooling. Methanol (20 mL) was added thereto, and the solvent was distilled off under reduced pressure. A 5% aqueous potassium carbonate solution (50 mL) was added to the obtained concentrated residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (RE2) (3.03 g, quantitative).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Fe:7].[N+]([O-])([O-])=O.[Fe+2].[N+]([O-])([O-])=O>O>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Fe+2:7].[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: [Fe]
Agent: [Fe+2]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: C=C(C)C(=O)[O-]
Yield: 90 %

Procedure:
For example, a method has been proposed, in which methacrylic acid, an alkaline metal and an iron salt such as iron nitrate are mixed in a solvent such as water, and iron methacrylate is produced by salt exchange (Patent Literature 1). Since this method has a difficulty in securely completing salt exchange, iron methacrylate is difficult to obtain in a high yield of 90% or higher. The method has further problems such as a reduction in purity due to contamination of iron methacrylate with impurities derived from nitric acid, and a rise in the cost because of necessity of filtration and drying processes. In the case where a hydroxyalkyl methacrylate is produced by using the prepared iron methacrylate as a catalyst, there are concern about problems, such as by-production of impurities, coloration and the like derived from nitric acid contained in the catalyst raw material.