Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:26]1[N:31]([CH3:32])[C:30](=[O:33])[CH:29]=[C:28]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:27]=1>O1CCCC1>[CH3:32][N:31]1[C:30](=[O:33])[CH:29]=[C:28]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:27]=[C:26]1[N:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:10]=2)[CH2:13][CH2:14]1
Reactant: c1cc(N2CCCC2)ccc1C1CCNCC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCC(c3ccc(N4CCCC4)cc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 81 %

Procedure:
A solution of 4-(4-pyrrolidin-1-yl-phenyl)-piperidine (215 mg, 0.933 mmol) and triethylamine (391 mg, 3.86 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (187 mg, 0.844 mmol) in tetrahydrofuran (10 mL) was refluxed for 5 hr. The resulting solution was diluted with tetrahydrofuran and filtrated. After removal of the solvents under reduced pressure and the purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting dichloromethane/ethanol (15/1, v/v) and wash with ethyl acetate afforded 3-methyl-6-pyridin-4-yl-2-(4-(4-pyrrolidin-1-yl-phenyl)-piperidin-1-yl)-3H-pyrimidin-4-one (284 mg, 81%) as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]([OH:8])[C@H:5]([OH:7])[CH3:6].F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1>C1COCC1>[CH3:3][C@H:4]([O:8][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:21])[F:20])[CH:11]=1)[C@@H:5]([O:7][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1)[CH3:6]
Reactant: C[C@@H](O)[C@@H](C)O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(C#N)c(C(F)(F)F)c1)[C@H](C)Oc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The NaH was suspended in 15 ml of dry THF at 0° C. under N2 gas, then (2R,3R)-2,3-butanediol (0.23 g, 2.46 mmol) was added, this mixture was stirred at 0° C. under N2 for 10 min before adding 4-fluoro-2-(trifluoromethyl)-benzonitrile (1.0 g, 5.18 mmol) The reaction mixture was stirred at 0° C. for 2 hours, then RT(room temperature) for 1 hour. It was quenched with 50 ml of distilled water, extracted with ethyl acetate (3×30 ml), the organic layer was washed with saturated NaHCO3 (three times), the solvent was removed to yield the crude product, it was purified by silica gel column with hexane:ethyl acetate=5:1 as the elute.
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[N:5][CH:4]=1.CCOCC>C(O)(=O)C>[Br:1][C:11]1[C:12](=[O:15])[NH:13][CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][N:5]=2)[CH:10]=1
Reactant: O=c1ccc(-c2ccncn2)c[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=c1[nH]cc(-c2ccncn2)cc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.7 g of bromine are added over a period of one minute to a solution of 4.5 g of 5-(4-pyrimidyl)-2(1H)-pyridone in 60 ml glacial acetic acid. The mixture is allowed to cool, stirred at RT for 1 hour and then poured into 100 ml of anhydrous ether and stirred for 30 minutes. The slurry is filtered and the filtered solid washed with ether and dried. The solid is suspended in 100 ml of H2O and the pH adjusted to about 6 with anhydrous K2CO3. The mixture is stirred for 15 minutes, filtered, the solid washed with H2O and briefly dried. The moist solid is added to 40 ml of 5% aqueous hydrochloric acid and the resultant mixture stirred for 30 minutes, diluted with an equal volume of isopropyl alcohol, stirred for an additional 10 minutes and filtered. The resulting solid is washed with isopropyl alcohol ether and dried, giving 3-bromo-5-(4-pyrimidyl)-2 (1H)-pyridone as a green powder, M.P>250° C.
Reaction SMILES: [CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccncc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccncc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 10-mL sealed tube, was placed a solution of methyl 3-(isopropyl(methyl)amino)-2-(pyridin-4-yl)quinoxaline-6-carboxylate (50 mg, 0.15 mmol, 1.00 equiv) in methanol (15 mL), sodium hydroxide (30 mg, 0.75 mmol, 5.04 equiv), water (2 mL). The resulting solution was stirred for 2 hr at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (2 mol/L). The resulting solids were collected by filtration. This resulted in 22 mg (44%) of 3-(isopropyl(methyl)amino)-2-(pyridin-4-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:18]([OH:20])=[O:19])=[N:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[O:21]1[CH2:24][C:23](=[O:25])[CH2:22]1>C1COCC1>[CH:15]1([CH2:14][O:13][C:12]2[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:7]=2[C:23]2([OH:25])[CH2:24][O:21][CH2:22]2)[CH2:17][CH2:16]1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)COC2)c(OCC2CC2)n1
Reaction time: 1 h
Yield: 12.3 %

Procedure:
Under a nitrogen atmosphere, n-BuLi (3.23 mL, 5.6 mmol) was added dropwise to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d, 1.1 g, 4.0 mmol) in THF (50 mL) at −78° C. and stirred for 1 h at this temperature. Then a solution of oxetan-3-one (CAN 6704-31-0, 0.73 g, 10 mmol) in THF (5 mL) was added at −78° C. The reaction mixture was stirred for 1 h at room temperature and quenched with aq. NH4Cl solution. The pH was adjusted to 2 with conc. HCl. The mixture was extracted with ethyl acetate (3×50 mL), the organic layers were combined, washed with brine (2×50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by chromatography over silica gel using petroleum ether/ethyl acetate=1/1 to give the title compound (0.13 g, 30.8%) as a yellow solid; MS (EI): m/e=266.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[C:16]([S:28][CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=[O:40])CCC1=O>ClCCCl.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:23])([F:25])[F:24])=[O:19])=[C:16]([S:28]([CH3:29])=[O:40])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Solvent: O
Product: CS(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 43.4 %

Procedure:
In a solution of 0.38 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylthio-N-(2,2,2-trifluoroethyl)benzoic acid amide (Compound of the present invention No. 5-322) synthesized similarly to Synthetic Example 13 in 6 ml of 1,2-dichloroethane, 0.10 g of N-chlorosuccinic acid imide was added with stirring at room temperature, and stirred at the same temperature for 11 hours. After the completion of the reaction, the reaction mixture was poured in 30 ml of water, and extracted with ethyl acetate (20 ml×3). The organic phase was washed with 30 ml of saturated sodium hydrogen carbonate, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2), and 0.17 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[N:10]([CH3:11])[N:9]=[CH:8][C:6]=2[N:7]=1.[CH3:13]N1C2C(=O)NC(=O)NC=2C(C)=N1>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[N:10]([CH3:11])[N:9]=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cn1ncc2nc(Cl)nc(Cl)c21
Reactant: Cc1nn(C)c2c(=O)[nH]c(=O)[nH]c12
Product: Cc1nn(C)c2c(Cl)nc(Cl)nc12

Procedure:
This compound was prepared in an analogous fashion to 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine, using 1,3-dimethyl-1H-pyrazolo[4,3-d]-pyrimidine-5,7(4H,6H)-dione as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 4.32 (s, 3H), 2.60 (s, 3H); LC-MS m/z (method B2)=217.2/219.2 [M+H]+, RT=1.688 min.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Product: CC(=O)NCC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 100 %

Procedure:
The title compound (1.16 g, 100%) was prepared using 1-{4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanamine and acetic anhydride similarly to the procedure used for example 140. 1H NMR (400 MHz, CDCl3) δ 1.82-1.86 (m, 2H), 1.87 (s, 3H), 2.00-2.04 (m, 4H), 2.58-2.85 (m, 10H), 3.45 (d, 2H), 3.56-3.61 (m, 2H), 3.79-3.84 (m, 2H), 4.02 (t, 2H), 4.97 (brs, 1H), 6.91 (d, 2H), 7.19 (d, 2H). LRMS APCI+ m/z 393 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([OH:45])=O)=[C:18]3[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:49]=C=NCCCN(C)C)C.C(N(CC)CC)C.N>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([NH2:49])=[O:45])=[C:18]3[N:17]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1ccc(C(=O)N(OC(C)(C)C)c2c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c(C(=O)O)cnn23)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)N(OC(C)(C)C)c2c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c(C(N)=O)cnn23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.25 g) in N,N-dimethylformamide (20 mL) were added ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g), N-hydoroxybenzotriazole monohydrate (0.31 g), triethylamine (2.8 mL) and ammonia (5.0 mL, 2.0 mol/L in methanol). The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH2Cl2, the combined organic layer was washed with water, dried over MgSO4, and the solvent was removed in vacuo to give the crude title compound (1.25 g) as a white solid. This crude product was used in the next reaction without further purification. ESI/MS data for this compound are shown below.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].[OH-].[Na+]>[Zn].C1C=CC=CC=1>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[CH:2][N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: c1ccccc1
Product: Clc1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Into a 5-liter fluted 3-neck flask fitted with a reflux condenser, a heater, thermometer and a stirrer was added 251.0 grams (1.0 mole) of pentachloropyridine, 500 milliliters of benzene and 1.25 liters of 8N sodium hydroxide (10 moles). The mixture was heated to ~75° C., with stirring. At this time, 260.0 grams (4.0 gram atoms) of zinc dust was added and the mixture refluxed at ~79° C. for a total reaction time of 5 hours. The pH of the reaction mixture was 14-15. At the completion of the reaction, the reaction mixture was cooled to room temperature and filtered to remove insolubles. The filter cake was washed with benzene and the benzene wash was combined with the filtrate. Gas-liquid chromatography indicated a 2,3,5-trichloropyridine content of 140.9 grams (77 percent of theoretical).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].S([O-])([O-])=[O:12].[Na+].[Na+]>>[CH:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=1
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(O)cc1

Procedure:
The pH of the aqueous distillation residue can be adjusted by addition of acid or alkali. According to a preferred procedure, the slightly acid organic solution containing the nitrophenol isomers is neutralised by means of an aqueous solution of sodium sulphite the solvent followed by the o-nitrophenol are then removed to leave a slightly alkaline aqueous distillation residue of p-nitrophenol, to which a suitable amount of acid is added to adjust the pH. The acid may be a strong inorganic acid such as sulphuric acid or phosphoric acid or an organic acid such as acetic acid. The pH is preferably adjusted to 5.8 to 6.1 but in practice, it is very particularly recommended to adjust the pH of the aqueous solution of para-nitrophenol to pH 6.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:3]([O:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(OC)cc3)cc2OC1C(F)(F)F
Temperature: 105 °C
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A 50 mL flask was charged with the substituted ethyl 2H-1-benzopyran-3-carboxylate from Step 2 (1.44 g, 4.43 mmol), 4-methoxyphenol (0.62 g, 4.99 mmol), K2CO3 (0.84 g, 6.07 mmol), and DMSO (10 mL). The reaction was stirred at 105° C. for 18 hours, poured into water extracted with ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated in vacuo, to give a brown oil which was passed through a column of silica gel with 5% ethyl acetate/hexanes to give a yellow solid (0.78 g, 41%): mp 115.8–117.0° C. 1H NMR (CDCl3/300 MHz) 7.66 (s, 1H), 7.32 (s, 1H), 7.04 (d, 2H, J=9.3 Hz), 6.98 (d, 2H, J=9.1 Hz), 6.38 (s, 1H), 5.65 (q, 1H, J=6.8 Hz), 4.33 (m, 2H), 3.86 (s, 3H), 1.37 (t, 3H, J=7.2 Hz). 19F NMR (CDCl3/282 MHz) −78.9 (d, J=6.5 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])=[S:18])[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C>C(O)C.Cl.O>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])=[S:18])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cc(C)c(NC(=S)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)c(C)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(NC(=S)Nc2cccc(CO)c2)c(C)c1
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To 0.56 g (0.1.4 mmol) of 1-[3-(tert-butyldimethylsilyloxymethyl)phenyl]-3-mesitylthiourea in 10 mL of ethanol was added 10 drops of concentrated hydrochloric acid. After 30 min, the reaction was diluted with water and the precipitate that formed was collected to give 0.35 g (86%) of the title compound as a white powder.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]3([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11][CH2:10]3)=[N:7][N:6]=[C:5]2[C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21]([O:23]C)=[O:22])[CH2:3][CH2:2]1.[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[CH:1]1([N:4]2[C:8]([C:9]3([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[CH2:10][CH2:11][CH2:12]3)=[N:7][N:6]=[C:5]2[C:18]2[CH:19]=[C:20]([C:21]([OH:23])=[O:22])[CH:25]=[CH:26][CH:27]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc(-c2nnc(C3(c4cccs4)CCC3)n2C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2nnc(C3(c4cccs4)CCC3)n2C2CC2)c1
Reaction time: 12 h
Yield: 78.1 %

Procedure:
Methyl 3-{4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazol-3-yl}benzoate (206 mg) was dissolved in dioxane (4 ml) and a 1M aqueous sodium hydroxide solution (1.1 ml) was added thereto at room temperature, followed by stirring at the same temperature for 12 hours. The solvent was removed by evaporation and pH was adjusted to 4 by adding an aqueous citric acid solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure to obtain an amorphous. Furthermore, ethyl acetate was added thereto and the whole was heated under stirring to obtain 155 mg of 3-{4-cyclopropyl-5-[1-(2-thienyl)cyclobutyl]-4H-1,2,4-triazol-3-yl}benzenecarboxylic acid (white crystals).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[N+:11]([O-])([OH:13])=[O:12]>O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH2:2][CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CCCc1ccc(O)cc1
Solvent: O
Product: CCCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 10.0 g of 4-n-propylphenol in 50 ml of water was added dropwise 11.0 ml of 61% nitric acid while cooling with ice, the temperature of mixture was raised to room temperature and the reaction was carried out for 2 hours. The reaction mixture was extracted with 300 ml of ethyl acetate, washed with a brine and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform]to give 8.69 g of 4-n-propyl-2-nitrophenol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([OH:20])=O)=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]([OH:32])[CH2:29][NH:30][CH3:31])[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:8][C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[N:12][NH:11][C:10]=1[C:18]([N:30]([CH2:29][CH:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=1)[OH:32])[CH3:31])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(O)c1cccc(Br)c1
Reactant: COC(=O)c1[nH]nc(C(=O)O)c1OCc1ccccc1
Product: COC(=O)c1n[nH]c(C(=O)N(C)CC(O)c2cccc(Br)c2)c1OCc1ccccc1

Procedure:
The title compound was prepared from methyl 4-benzyloxy-3-carboxy-1H-pyrazole-5-carboxylate (prepared as in Example 31, Step 1) using a procedure similar to that described in Example 31, Step 2, except that 1-(3-bromophenyl)-2-(methylamino)ethanol (prepared as described in Tsushima, S., et al., EP 278621 and Cudahy, M. M., et al., WO 2003059911) was used in place of (1R)-2-(methylamino)-1-phenylethanol. ES MS (M+2)=490.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][C:14]1([CH3:26])[CH2:23][C:22](=O)[C:21]2[C:16](=[CH:17][C:18]([OH:25])=[CH:19][CH:20]=2)[O:15]1.[Cl-].[NH4+]>CCOCC>[CH3:13][C:14]1([CH3:26])[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[C:21]2[C:16](=[CH:17][C:18]([OH:25])=[CH:19][CH:20]=2)[O:15]1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Yield: 86.2 %

Procedure:
3-Bromobenzotrifluoride (61 g) in dry ether (100 ml) was added to magnesium (6.6 g) in ether (50 ml). 2,2-Dimethylchroman-4-one-7-ol (17.4 g) suspended in ether (500 ml) was added and the mixture refluxed for 16 hourss. The reaction mixture was poured into ammonium chloride solution and extracted with ether. The combined ether layers were washed with 2 N HCl (2×100 ml) and dried (MgSO4). Removal of the solvent under reduced pressure gave the title compound (25 g), m.p. 102°-106° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].CCN(C(C)C)C(C)C.Cl.[CH3:18][NH:19][O:20][CH3:21]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([N:19]([O:20][CH3:21])[CH3:18])=[O:6]
Reactant: CNOC
Reactant: O=C(Cl)CCCBr
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)CCCBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromobutanoyl chloride (5.62 ml, 48.5 mmol) in DCM (64 ml) was added slowly to a solution of DIPEA (17.80 ml, 102 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.97 g, 51.0 mmol) in DCM (32 ml) at 0° C. The mixture was stirred at room temperature for 16 hours then diluted with DCM (50 ml). The mixture was washed with 1M HCl(aq) (2×50 ml) and saturated NaHCO3(aq) (2×50 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 30% EtOAc/hexane afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8](OC)=[O:9])[O:5][N:4]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH2:8][OH:9])[O:5][N:4]=1
Reactant: COC(=O)c1cc(OC)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(CO)on1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
2.23 g of methyl 3-methoxyisoxazole-5-carboxylate was dissolved in 30 ml of ethanol, and 0.60 g of sodium borohydride was then added ice-cooling. The mixture was stirred for 8 hours under ice-cooling. After water was added under ice-cooling, the reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.55 g of (3-methoxyisoxazol-5-yl)methanol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[O:31]C(C)(C)[NH:29][C:28](=[O:34])[C:27]=2[CH:35]=1>>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([OH:18])[CH2:2][NH:1][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([OH:31])=[C:27]([C:28](=[O:34])[NH2:29])[CH:35]=2)=[CH:5][CH:6]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)NC(=O)c2cc(OCCBr)ccc2O1
Product: NC(=O)c1cc(OCCNCC(O)c2ccc(OCc3ccccc3)cc2)ccc1O
Reaction time: 1 h

Procedure:
A mixture of 21 g of α-(aminomethyl)-4-benzyloxybenzyl alcohol and 12 g of 6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-4H-1,3-benzoxazin-4-one is stirred in an oil bath at 130° for 1 hour. The reaction mixture is partitioned between 500 ml of ethyl acetate and 50 ml of 2N aqueous ammonia solution, the organic phase is separated off and evaporated and the residue is recrystallised from isopropanol. 4-Benzyloxy-α-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol with a melting point of 160°-162° is obtained.