Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:31])([F:30])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)([OH:18])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1.[CH2:32]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Cl)=[CH:38][CH:37]=1)[C:33]#[CH:34].[F-].[K+]>>[CH2:32]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][N:15]2[CH2:16][CH2:17][CH:12]([C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:30])([F:2])[F:31])=[CH:10][CH:9]=3)([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=3)[OH:18])[CH2:13][CH2:14]2)=[CH:40][CH:41]=1)[C:33]#[CH:34]
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: C#CCOc1ccc(CCl)cc1
Agent: Cl
Agent: [F-]
Agent: [K+]
Product: C#CCOc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 64.7 %

Procedure:
A stirred mixture of 0.8 gram (0.0016 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine hydrochloride, 0.3 gram (0.0016 mole) of 4-(2-propyn-1-yloxy)phenylmethyl chloride and 0.5 gram (0.0079 mole) of potassium fluoride on Celite® filter aid in 50 mL of acetonitrile was heated at reflux for about 1.3 hours. After this time 0.5 mL (excess) of triethylamine was added, and the reaction mixture became homogeneous. Upon completion of addition, the reaction mixture was heated at reflux for an additional 18 hours. After this time the reaction mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of 10-70% diethyl ether in hexane as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.6 gram of N-[4-(2-propyn-1-yloxy)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.500 g, 0.0014 mol) in dimethoxyethane (15 mL) and water (30 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.631 g, 0.00155 mol), sodium carbonate (0.374 g, 0.0035 mol) and tetrakis(triphenylphosphine)palladium (0) (0.163 g, 0.00014 mol) at 80° C. for 18 hours. The solid was filtered and washed with water. The solid was slurried in ethyl acetate for 18 hours and filtered, washing with ethyl acetate. The solid was dried in vacuo to give crude 4-[4-amino-3-(3-methoxy-4-[(1-methyl-1H-2-indolyl)-carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.523 g, 0.0010 mol) as a brown solid:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:19][CH2:18][CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCC1CCOCC1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (6.5 g, 29.5 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (4.25 g, 36.9 mmol) and potassium carbonate (16.33 g, 118 mmol) in N,N-dimethylformamide (130 mL) was heated at 80° C. for 1 hour. After cooling, the mixture was diluted with 400 mL ethyl acetate. The mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].O[N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:5][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C:8]1=[O:13])=[O:4]
Reactant: O=C(O)CBr
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CBr)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
Bromoacetic acid (4.30 g) and N-hydroxysuccinimide (4.03 g) were dissolved in DCM (25 ml). The mixture was stirred on a magnetic stirrer at room temperature. DCC was added (7.42 g) in one portion and the mixture was reacted overnight. The reaction mixture was filtered to remove dicyclohexylurea. The filter cake washed several times with DCM. The combined filtrates were washed three times with saturated aqueous sodium chloride solution (30 mL/each wash), dried over anhydrous magnesium sulfate, and filtered. The title compound was obtained as a white solid (5 g) after rotary evaporation in vacuo.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1OC.[OH-].[Na+]>CCO.O>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: COc1cccc(N)c1N
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanogen bromide (7.05 mmol, 0.74 g) was added to a solution of 2,3-diaminoanisole (4.7 mmol, 0.65 g) in EtOH (10 mL) and the reaction was stirred at room temperature for 14 h. The reaction was diluted with H2O and then basified (pH>12) using 4 M NaOH. The aqueous layer was extracted with CH2Cl2. The organic phase was then separated and washed with brine and then dried over MgSO4 and then concentrated to provide 2-aminobenzimidazole 37b.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: OB(O)c1ccc(F)cc1
Product: COC(=O)c1c(O)c2ccc(-c3ccc(F)cc3)cc2sc1=O

Procedure:
7-(4-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 4-fluorophenylboronic acid under conditions analogous to Example 7(a). 1H NMR (200 MHz, CDCl3): δ (ppm)=15.27 (s, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.60-7.50 (m, 4H), 7.21-7.17 (m, 2H), 4.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:26])[C:10]([O:24][CH3:25])=[C:11]([C:20]([O:22][CH3:23])=[O:21])[N:12]([CH2:14][CH:15]([O:18]C)[O:16]C)[CH:13]=1)=[O:7].CS(O)(=O)=O>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:26])[C:10]([O:24][CH3:25])=[C:11]([C:20]([O:22][CH3:23])=[O:21])[N:12]([CH2:14][CH:15]([OH:18])[OH:16])[CH:13]=1)=[O:7]
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)NCc2ccc(F)cc2F)cn1CC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1c(OC)c(=O)c(C(=O)NCc2ccc(F)cc2F)cn1CC(O)O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-B, 0.106 g, 0.24 mmol) in acetonitrile (0.9 mL) and acetic acid (0.1 mL) was treated with methanesulfonic acid (0.005 mL, 0.072 mmol), sealed with a yellow cap, and heated to 70° C. After 16 hours, the mixture was cooled to afford a crude solution of methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxy late, 1-C. LCMS-ESI+ (m/z): [M+H]+ calculated for C18H19F2N2O7: 413.12; found: 413.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].I[CH3:12].O>O1CCCC1>[CH3:12][O:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-hydroxymethylpyridine (10 g, 92 mmol) in anhydrous tetrahydrofuran (200 ml), under an atmosphere of nitrogen, was treated with sodium hydride (4 g of a 55% oil dispersion, 92 mmol) in portions. After stirring for 15 minutes iodomethane (5.7 ml, 92 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 hours. Water (20 ml) was added and the tetrahydrofuran evaporated. The residue was partitioned between water (50 ml) and dichloromethane (70 ml). The organic layer was separated, dried (sodium sulphate) then evaporated. The crude product was purified by column chromatography on silica using ethyl acetate. The title compound was obtained (11 g, 93%) as an oil, δH (250 MHz, CDCl3) 3.42 (3H, s), 4.48 (2H, s), 7.27-7.32 (1H, m), 7.66-7.71 (1H, m), 8.53-8.60 (2H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[H-].[Na+].[CH2:14]([O:18]CC1C=CC(C(O)=O)=CC=1)[CH2:15]C=C>C(O)C>[CH2:14]([O:18][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:15]
Reactant: C=CCCOCc1ccc(C(=O)O)cc1
Reactant: O=C(O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOCc1cccc(C(=O)O)c1

Procedure:
The reaction of ethanol and 3-Chloromethyl-benzoic acid in the presence of sodium hydride was performed as described for Compound 33 to give 3-ethoxymethyl-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 7.89 (m, 1 arom.H); 7.84 (m, 1 arom.H); 7.54 (m, 1 arom.H); 7.46 (m, 1 arom.H); 4.49 (s, OCH2C6H4—); 3.48 (q, J=6.9, CH3CH2); 1.15 (t, J=6.9, CH3CH2). 13C-NMR (100 MHz, d6-DMSO): 167.24 (—C═O); 139.26; 131.67; 130.76; 128.51; 128.23; 128.06; 71.01; 65.14; 15.07.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18]C)=[O:17])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]([OH:18])=[O:17])[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1snc(-c2ccccc2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1snc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of methyl 3-phenyl-4-(trifluoromethyl)isothiazole-5-carboxylate (50 mg, 0.174 mmol) in THF (0.5 mL) was added a 1M LiOH solution (0.2mL). The resulting mixture was stirred at room temperature overnight. The pH of the reaction mixture was made acidic using 1N HCl and the solid that separates out was collected by filtration and dried in vacuo to yield 3-phenyl-4-(trifluoromethyl)isothiazole-5-carboxylic acid (42 mg, 0.154 mmol, 88% yield) as a pale yellow solid. LC/MS M+1=274.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([O:23][CH3:24])[N:10]=1.[CH2:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:26]1[O:28][CH2:27]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:27][CH:26]([OH:28])[CH2:25][O:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:27][CH:26]([OH:28])[CH2:25][O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([O:23][CH3:24])[N:10]=1
Reactant: COc1nc(-c2ccc(O)cc2O)nc(-c2ccc(O)cc2O)n1
Reactant: CCCCOCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Product: CCCCOCC(O)COc1ccc(-c2nc(OC)nc(-c3ccc(OCC(O)COCCCC)cc3O)n2)c(O)c1
Temperature: 80 °C

Procedure:
10 g of 2,4-di(2,4-dihydroxyphenyl)-6-methoxy-1,3,5-triazine are stirred for 3 hours at 130° C. with 100 ml of butyl glycidyl ether and 0.20 g of tetrabutylammonium bromide. The mixture is subsequently allowed to cool to 80° C., 100 ml of ethyl acetate and 2.0 g of Prolith Rapid are added, the mixture is filtered through kieselguhr, and the solvent is removed under reduced pressure. The excess butyl glycidyl ether is then removed by vacuum distillation, giving 2,4-di[2-hydroxy-4-(3-butoxy-2-hydroxypropoxy)phenyl]-6-methoxy-1,3,5-triazine, which, after recrystallisation from ethanol, has a melting point of 108°-109° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].C1(S(O[CH2:41][CH2:42][O:43][CH3:44])(=O)=O)C=CC=CC=1>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:41][CH2:42][O:43][CH3:44])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COCCOS(=O)(=O)c1ccccc1
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(OCCOC)cccc2c1Nc1ccccc1C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
A solution of 3-butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.20 g, 10 mmol) and potassium t-butoxide (1.47 g, 12 mmol) in dry tetrahydrofuran (100 ml) was heated at reflux for 5 minutes, then 2-methoxyethyl benzenesulphonate (4.33 g, 20 mmol) added and hearing continued for 18 hours. Evaporation of the solvent, chromatography (silica gel, 1-2% methanol in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(2-methoxy-ethoxy)quinoline (1.42 g, 38%), m.p. 75°-77°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:22]([N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1)[CH2:23][CH2:24][CH3:25]
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1

Procedure:
A solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (6.1 g, 0.023 mole), 1-chlorobutane (2.42 g, 0.026 mole), K2CO3 (10 g) and KI (0.1 g) in 100 ml dimethylformamide was heated at 70° C. for a total of 7 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:20]([NH-])([CH3:22])[CH3:21].O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:20]([CH3:22])[CH3:21])=[C:7]([OH:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CC(C)[NH-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(OC(C)C)c(O)c1
Yield: 25 %

Procedure:
To a solution of 3,4-dihydroxybenzoic acid ethyl ester (2.0 g, 11 mmol) in acetone (450 l) were added potassium carbonate (2.28 g, 16.5 mmol) and isopropylamide (1.03 ml, 11 mmol), and the resultant mixture was stirred at room temperature for 2 days. The reaction mixture was poured into chilled water and extracted with ethyl acetate under acidic conditions. The organic layer was concentrated, and the residue was chromatographed On a silica gel column to give a mixture (617 mg) of 3-hydroxy-4-isopropyloxybenzoic acid ethyl ester and its position isomer, 4-hydroxy-3-isopropyloxybenzoic acid ethyl ester (6:1). There was observed NOE of protons at 1'-position of the isopropyl group and 5-position. The reaction was effected using this mixture (617 mg) in the same manner as in Reference Example 18, and the resultant product was recrystallized from hexane to give the titled compound (370 mg, yield 12%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH2:31])[CH3:27]>N1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)[NH:31][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[CH3:27]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cccnc1
Reaction time: 8 h

Procedure:
Nicotinic acid (12.3 g, 0.1 mol) was dissolved in dry pyridine (300 mL). The solution was cooled and dicyclohexylcarbodiimide (20.6 g, 0.1 mol) was added. After dissolution, tyrosine ethyl ester hydrochloride (24.6 g, 0.1 mol) was added and the solution was stirred overnight. The precipitated dicyclohexylurea (DCU) was removed by filtration. Additional DCU was removed by triturating the oil with hot water. The product was purified with acetone. Calculated for C17H18N2O4.1/2H2O: C, 63.16; H, 5.88; N, 8.66. Found: C, 63.10; H, 5.96; N, 8.59. The product can also be named N-[1-ethoxycarbonyl-2-(4'-hydroxyphenyl)ethyl]nicotinamide.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:12][C:11]=1[O:21][CH3:22])[CH2:4][CH3:5])[CH3:2].S(OC)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9](=[O:23])[C:10]1[CH:15]=[C:14]([N:16]([CH3:28])[S:17]([CH3:20])(=[O:18])=[O:19])[CH:13]=[CH:12][C:11]=1[O:21][CH3:22])[CH2:4][CH3:5])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCN(CC)CCNC(=O)c1cc(NS(C)(=O)=O)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)CCNC(=O)c1cc(N(C)S(C)(=O)=O)ccc1OC

Procedure:
To a solution of N-(diethylaminoethyl)-5-methanesulfonamido-2-methoxybenzamide in acetone are added dimethyl sulfate and potassium carbonate. The resultant mixture is refluxed for 2 hours. After evaporating the solvent, the residue is mixed with water and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue is washed with isopropyl ether to give N-(diethylaminoethyl)-2-methoxy-5-(N-methyl-methanesulfonamido)benzamide as crystals melting at 48°-50° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][S:4]/[C:3]/1=[N:21]\[CH3:22].C([Li])CCC.CCCCCC.[Cl-].[NH4+].C1C[O:39][CH2:38]C1>CN(C=O)C>[CH:38]([C:5]1[S:4]/[C:3](=[N:21]\[CH3:22])/[N:2]([CH3:1])[C:6]=1[CH2:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1)=[O:39]
Reactant: C1CCOC1
Reactant: C/N=c1\scc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C/N=c1\sc(C=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)n1C

Procedure:
tert-Butyl 4-(((2Z)-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate (1.0 g) obtained in Example 11a) was dissolved in THF (20 mL), n-butyllithium (4.6 mL; a 1.6 M hexane solution) was added thereto at −70° C., and the mixture was mixed for 30 minutes. To the reaction solution was added DMF (1.0 mL), mixed at −70° C. for 1 hour, and then an aqueous ammonium chloride solution was added thereto at 0° C. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound (1.1 g) as a pale brown oily matter.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH:16]([OH:25])[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCOC(C)=O.[ClH:32]>O1CCOCC1>[ClH:32].[ClH:32].[CH3:24][S:23][C:19]1[N:18]=[C:17]([CH:16]([OH:25])[CH2:15][NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: CSc1nccc(C(O)CNC2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1nccc(C(O)CNC2CCNCC2)n1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
4-[2-Hydroxy-2-(2-methylsulfanyl-pyrimidin-4-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester (510.0 mg, 1.387 mmol) was dissolved into 3 mL of EtOAc and 3 mL of 4.0 M HCl in dioxane was added. The mixture was allowed to stir overnight with a white precipitate forming. The precipitate was triturated with 3×10 mL of EtOAc and dried under vacuum to give 441.4 mg, 93.2% of crude 1-(2-methylsulfanyl-pyrimidin-4-yl)-2-(piperidin-4-ylamino)-ethanol dihydrochloride salt. The material was carried on without further purification.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COCCCOc1ccnc(CCl)c1C
Yield: 112.6 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in toluene (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise into the solution in a temperature that did not exceed 25° C. Stirring was carried out at room temperature, and then after it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.13 g (yield: 97.3%)).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1

Procedure:
The product is prepared according to the procedure described in Example 9, using 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 1.254 ml of 3-methoxyaniline in place of the 2-fluoroaniline. 56 mg of N-(3-methoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-di hydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following: