Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[O:29][C:30]([C:33]([F:36])([F:35])[F:34])=[N:31][N:32]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:17].[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[O:29][C:30]([C:33]([F:36])([F:34])[F:35])=[N:31][N:32]=4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2F)cc1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Product: Cl
Product: Fc1ccccc1COc1ccc(Nc2ncnc3ccc(-c4nnc(C(F)(F)F)o4)cc23)cc1

Procedure:
The title compound was prepared according to Procedure A from 4-(2-fluoro-benzyloxy)aniline and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.80(1H,bs), 9.54(1H,s), 8.93(1H,s), 8.67(1H,dd), 8.14(1H,d), 7.67(2H,d), 7.59(1H,m), 7.46(1H,m), 7.29(2H,m), 7.19(2H,d), 5.23(2H,s); m/z (M+1+) 482.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:49]=[CH:48][C:12]([CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])=[CH:22]4)[CH:15]=2)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:29])[N:24]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]([CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:22]4)[CH:15]=2)=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(-c3cc(Cc4ccc(F)cc4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCc1cc2cc(-c3cc(Cc4ccc(F)cc4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (100 mg, 0.175 mmol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH=10:1 to give 5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (75 mg, 0.146 mmol) as a yellow solid. LCMS [M+H]+=515. 1H NMR (500 MHz, CDCl3) δ ppm: 8.42 (d, J=8.51 Hz, 1H), 7.93 (d, J=1.26 Hz, 1H), 7.81 (d, J=1.58 Hz, 1H), 7.17-7.37 (m, 6H), 7.09 (t, J=8.51 Hz, 2H), 6.49 (s, 1H), 6.33 (s, 1H), 4.17 (s, 2H), 2.22-2.39 (m, 4H), 1.38-1.65 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]O)[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:30])[N:16]([CH3:31])[C:15]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:13][N:14]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:12][C:4]3[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH2:22][CH2:21]2)=[CH:18][C:17](=[O:30])[N:16]([CH3:31])[C:15]1=[O:32]
Reactant: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Yield: 87.9 %

Procedure:
In 20 ml of anhydrous tetrahydrofuran were suspended 0.68 g of 2-methoxy-4-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3 -hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound a) and 1.1 g of triphenylphosphine, and 0.71 ml of diethyl azodicarboxylate was added to the resultant suspension. Afterward, the mixture was treated in the same manner as in Reference Example 4, followed by recrystallizing from methanol to obtain 1.35 g of oily 1,3-dimethyl-6-[4-(3-[2-methoxy-4-nitrophenyloxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound w).
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11]OS(C)(=O)=O)[O:8][C:7](=[O:17])[NH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:18]([SH:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+].C(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][S:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][C:7](=[O:17])[NH:6]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H]1NC(=O)O[C@H]1CCOS(C)(=O)=O
Reactant: SCCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H]1NC(=O)O[C@H]1CCSCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a 0° C. solution of 4(S)-isobutyl-5(S)-(2-mesyloxyethyl)-2-oxazolidinone (500 mg, 1.88 mmol) and phenethyl mercaptan (273 mg, 1.98 mmol) in THF (6 mL) was added NaH (95 mg, 1.98 mmol of a 50% dispersion) all at once. The reaction was stirred for 3 hours at room temperature and then distributed between methylene chloride and brine solution. The organic layer was washed with brine solution, dried over MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with 65/35 hexane=ethyl acetate to give 570 mg (98%) of product as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[C:4]([CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31].O>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([CH:12]([OH:17])[C:13]([F:15])([F:16])[F:14])[C:3]([O:18][CH3:19])=[C:2]([NH:1][C:30](=[O:31])[O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(NC(=O)OCC(Cl)(Cl)Cl)cc(C(C)(C)C)cc1C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A solution of crude product (0.397 g) containing 1-(3-amino-5-tert-butyl-2-methoxyphenyl)-2,2,2-trifluoroethanol and N,N-diisopropylethylamine (0.374 mL, 2.14 mmol) in THF (4.77 mL) was cooled to 0° C., and 2,2,2-trichloroethyl chloroformate (0.217 mL, 1.57 mmol) was added thereto, followed by stirring the mixture for 10 minutes. Water was added to the reaction solution and the aqueous layer was extracted with ethyl acetate and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=100/0-75/25) to obtain 0.622 g of the captioned compound (96% yield in 2 steps).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([OH:26])=O)=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:69][C:70]1[S:74][N:73]=[C:72]([CH3:75])[N:71]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:69][C:70]3[S:74][N:73]=[C:72]([CH3:75])[N:71]=3)=[O:26])=[C:18]([F:44])[CH:17]=2)=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2F)cc(C(=O)O)c1
Reactant: Cc1nsc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3F)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
DIPEA (0.8 mL, 4.77 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)-2-fluorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (800 mg, 1.59 mmol), HATU (787 mg, 2.07 mmol) and 5-amino-3-methyl-1,2,4 thiadiazole (549 mg, 4.77 mmol) in DMF (110 mL). The resulting mixture was stirred at ambient temperature for 16 hours, water (150 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (950 mg).
Reaction SMILES: [Mg:1].ClCCl.C[OH:6].[CH3:7][C:8]1[CH:9]=[N:10][C:11]([CH2:17][S+:18]([O-:30])[C:19]2[NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=3[N:27]=2)=[C:12]([CH3:16])[C:13]=1[O:14][CH3:15]>O>[CH3:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([CH3:16])[C:11]([CH2:17][S:18]([C:19]2[N-:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=3[N:27]=2)=[O:30])=[N:10][CH:9]=1.[CH3:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([CH3:16])[C:11]([CH2:17][S:18]([C:19]2[N-:20][C:21]3[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=3[N:27]=2)=[O:30])=[N:10][CH:9]=1.[OH2:6].[OH2:14].[OH2:14].[Mg+2:1]
Reactant: CO
Reactant: [Mg]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2[n-]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Product: [Mg+2]

Procedure:
Magnesium metal (1.33 grams) and Dichloromethane (3.7 ml) were added to methanol (111 ml) and stirred for 1–2 hours. The mass was cooled to a temperature of 5–10° C., esomeprazole obtained in Example 2 (37.0 grams) and methanol (111.0 ml) were added accompanied by stirring for 15–30 minutes. The reaction mass was decomposed into water (666 ml) at a temperature of 5–10° C. over a period of 45–60 minutes, and then further stirred for 30–45 minutes to separate the solid mass. The solid mass was filtered, and washed with water (222 ml). The thus obtained compound was dissolved in methanol (222 ml), and filtered off the solution to separate any excess magnesium. The solvent was removed from the filtrate to get the residual mass. The residual mass was crystallized in Acetone (278 ml) at a temperature of 0–5° C. to afford optically pure Esomeprazole magnesium trihydrate salt. The resulting product had the following characteristics. Weight: 11.5 g. Chiral Purity: ˜100%. Optical rotation: −125° (c=0.5% methanol)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([NH:21][NH2:22])=[O:20])=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:7]=1.O.[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O.O>C(O)(=O)C.C(OCC)(=O)C.O>[F:24][C:25]([F:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=[N:22][NH:21][C:19](=[O:20])[C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:4]=1
Reactant: NNC(=O)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl
Reactant: O=CC(F)(F)C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NN=CC(F)(F)C(F)(F)F)c1nc(Oc2cccc(C(F)(F)F)c2)ccc1Cl

Procedure:
3-chloro-6-[3-(trifluoromethyl)phenoxy]-2-picolinic acid hydrazide (0.4 g, 0.0012 mol) was dissolved in 5 ml of acetic acid. The obtained solution was mixed with 2,2,3,3,3-pentafluoropropionaldehyde monohydrate (0.199 g, 0.0012×1.0 mol), and the resultant mixture was stirred at 80° C. for 3 hours. A chilled water was poured into the obtained reaction solution which was then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with water and then dried with anhydrous sodium sulfate. After distilling off the solvent from the dried product, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][S:5][C:6]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1>CC(C)=O>[I:1][CH2:4][S:5][C:6]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1
Reactant: ClCSc1ncc(Cl)cn1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1cnc(SCI)nc1
Yield: 86 %

Procedure:
Sodium iodide (30 mmol) was added to a solution of 2-chloromethylthio-5-chloropyrimidine (6.7 mmol) in acetone (30 ml) and the mixture heated under reflux for 4 h. The precipitated sodium chloride was removed by filtration, the filtrate evaporated to dryness, the residue triturated with water and recrystallized from ethanol; yield 86%, m.p. 67° C. 1H NMR (CDCl3): δ4.82 (SCH2), 8.67 (H-4, H-6).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-:30].[K+].[K+].O>CS(C)=O>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([O:30][C:6]2[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=2[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:22][CH:23]=1)#[N:26]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccccc2N2CCN(c3ccncc3)CC2)cc1
Yield: 13.5 %

Procedure:
A solution of 1-(4-hydroxyphenyl)-4-(4-pyridyl)piperazine (670 mg), 4-fluorobenzonitrile (354 mg) and powdered potassium carbonate (445 mg) was stirred at 95° C. in DMSO (12 ml) for 18 hours. The solution was poured into water (180 ml) to give a precipitate which was filtered, washed with water and dried. The solid was purified by chromatography on alumina (ICN Alumina N 32-63) using 1% methanol in dichloromethane as eluant. This gave a solid which was recrystallised from a mixture of ethyl acetate/isohexane to give 1-(4-cyanophenoxyphenyl)-4-(4-pyridyl)piperazine (126 mg) as a solid. m.p. 180-182° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[C:12]([OH:21])[C:11]=2[C:22]([F:25])([F:24])[F:23])=[CH:6][CH:5]=1.[CH3:28][N:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[N:31]=[CH:30]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O>[OH:21][C:12]1[C:11]([C:22]([F:23])([F:24])[F:25])=[C:10]([CH:15]=[CH:14][C:13]=1[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:34]([C:32]2[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=2)=[O:35])=[CH:27][CH:26]=1
Reactant: CC(C)C(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)c1ccc(OCc2ccc(CNC(=O)c3cn(C)cn3)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.3 %

Procedure:
Mechanically stir suspensions of 1-[4-(4-aminomethyl-benzyloxy)-2-hydroxy-3-trifluoromethyl-phenyl]-2-methyl-propan-1-one hydrochloride (244 g, 604 mmol), 1-methyl-imidazole-4-carboxylic acid (95 g, 753 mmol), and 1-hydroxybenzotriazole hydrate (118 g, 770 mmol) in tetrahydrofuran (8 L) in two separate 22-L Morton flasks. Treat each solution with diisopropylethylamine (269 mL, 1.54 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 g, 756 mmol) in single portions and stir overnight at room temperature. Dilute each with 4 L of water and extract twice with 4 L of ethyl acetate. Wash organic layers with saturated sodium chloride solution, dry with magnesium sulfate, filter, and evaporate the filtrates to tan foams. Combine the foams and recrystallize from isopropanol (6 L) to afford the title compound (426 g, 74% yield). m.p. 164.7° C.; HPLC Rt=4.86 min; 1H NMR (DMSO-d6) δ 13.95 (s, 1H), 8.45 (t, J=8.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.63 (d, J=12.0 Hz, 2H), 7.33 (ABq, J=12.0, 8.0 Hz, 4H), 6.89 (d, J=8.0 Hz, 1H), 5.32 (s, 2H), 4.39 (d, J=8.0 Hz, 2H), 3.71 (hept, J=8.0 Hz, 1H), 3.67 (s, 3H), 1.12 (d, J=8.0 Hz, 6H); 19F NMR (DMSO-d6) δ-54.10; MS (m/z): 476.0 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:14][N:15]=[C:16]2[C:20](=O)[O:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17]2)[CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:2][CH2:3][CH3:4].O.[NH3:29].Cl>CC(C)=O>[CH2:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][C:16]([C:20]([NH2:29])=[O:19])=[N:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:2][CH2:3][CH3:4]
Reactant: N
Reactant: CCCCOCc1cc(NN=C2N=C(c3ccccc3)OC2=O)ccc1Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCCOCc1cc(-n2nc(C(N)=O)nc2-c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
In 10 ml of acetone, 1.157 g (3 mmol) of 4-[(3-butoxymethyl-4-chlorophenyl)hydrazono]-2-phenyl-2-oxazolin-5-one synthesized in the similar way to Examples 1~2, Reference Example 1 was suspended, the suspension being then added with 0.6 ml of concentrated ammonia water and stirred at room temperature for 30 minutes. The resulting solution was made acid by adding 0.6 ml of concentrated hydrochloric acid and further stirred at 50° C. for 30 minutes. Acetone was distilled off and the residue was extracted by adding benzene and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were distilled off to obtain a crude product. This crude product was purified by silica gel chromatography using hexane/ethyl acetate (1/2, v/v) as developing solvent and further recrystallized to obtain 1.087 g (94.2% yield) of 1-(3-butoxymethyl-4-chlorophenyl)-5-phenyl-1H-1,2,4-triazole-3-carboxamide (m.p 96°-98° C.).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]([O:9][CH3:10])=[O:8]>[Ru].[Co]>[CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCCC1
Reactant: COC=O
Agent: [Co]
Agent: [Ru]
Product: COC(=O)C1CCCCC1
Temperature: 120 °C

Procedure:
In a pressure reactor made of stainless steel and having an internal volume of 50 ml, 0.05 mmol of [Ru(CO)3Cl2]2 as a ruthenium compound, 0.05 mmol of Co2(CO)8 as a cobalt compound, and 1.0 mmol of [bis(triphenylphosphine)iminium]iodide as a halide salt were introduced and mixed at room temperature, and thus a catalyst system was obtained. 5.0 mmol of cyclohexene and 5.0 mL of methyl formate were added to this catalyst system, subsequently the reactor was purged with nitrogen gas at 0.5 MPa, and the system was maintained for 15 hours at 120° C. Thereafter, the reactor was cooled to room temperature, and the pressure was released. A portion of the remaining organic phase was withdrawn, and the components of the reaction mixture were analyzed by using gas chromatography. According to the analysis results, the amount of methyl cyclohexanecarboxylate produced by the reaction was 2.47 mmol (yield in terms of cyclohexene 49.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].C(O)=O>O1CCCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: -20 °C

Procedure:
To a solution of 2.75 gm (0.01 mol) of 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyric acid in 50 ml of absolute tetrahydrofuran 0.20 gm (0.005 mol) of lithiumaluminumhydride in 50 ml of absolute tetrahydrofuran was added dropwide, while stirring and cooling at -20° C. After stirring for 4 hours at -20° C., the reaction mixture was poured into ice water and acidified with aqueous 50% sulfuric acid. Subsequently, the mixture was made alkaline by adding aqueous 20% sodium hydroxide, and was again acidified with formic acid. The precipitated semi-solid product was dissolved in ether, and after evaporating the ether, the crystalline residue was dissolved in acetone. From this solution the cyclohexylamine salt of 4-(4'-fluoro-4-biphenylyl)-4-hydroxy-butyric acid was precipitated by addition of cyclohexylamine, and the salt was recrystallized from ethyl acetate/absolute ethanol. Melting point 176°-178° C. (decomp.); yield: 2.2 gm.
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[C:20]([CH3:21])=[CH:19][NH:18][N:17]=1.[CH3:22]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:18]1[CH:19]=[C:20]([CH3:21])[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[N:17]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:22]
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1F
Reactant: Cc1c[nH]nc1-c1ccccc1
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccccc2F)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-(o-fluorophenyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole, there was obtained α-ethyl-3-(o-fluorophenyl)-N,N,4-trimethylpyrazole-1-acetamide, b.p. 171°-173° C./0.15 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1.[CH3:12][CH2:13][O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][C:18]([NH:17][C:15](=[O:16])[O:14][CH2:13][CH3:12])=[S:19])[C:6]([O:10][CH3:11])=[CH:5][N:4]=1
Reactant: COc1ncc(OC)c(N)n1
Reactant: CCOC(=O)N=C=S
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)Nc1nc(OC)ncc1OC
Temperature: 78 °C
Reaction time: 11 h
Yield: 87 %

Procedure:
2,5-Dimethoxypyrimidin-4-amine (6) (3 g, 0.0193 moles) was dissolved in 18 g of ethyl acetate. Ethyl isothiocyanatidocarbonate (2.77 g, 0.0208 moles) was added in one portion. The solution was heated to 78° C. and held at that temperature for 11 h. An additional 1.4 g of the ethyl isothiocyanatidocarbonate was added and the mixture heated for 2.5 h. The mixture was allowed to cool to 22° C. and filtered. The resulting solid was washed with ethyl acetate (20 mL) and dried to a constant weight in a fume hood to afford the title compound as a yellow solid (4.81 g, 89%): 13C NMR (DMSO-d6, 100 MHz) δ 177.5, 158.4, 153.3, 149.5, 142.3, 139.5, 62.6, 57.6, 55.2, 14.4; HRMS (ESI), calcd for C10H14N4O4S, 286.0736; found, 286.0727.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[NH:11])[O:15][CH2:13][CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccc(OC)cc1

Procedure:
A solution of 4-methoxyphenylacetonitrile (50 g, 0.34 mol) in absolute ethanol (200 ml) was treated with dry HCl gas with ice cooling for 1 hour. The solvent was evaporated in vacuo, and the residual oil triturated with ether. The solid was filtered off, washed with ether and dried (66 g, 84%), then used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[C:18]=[O:19]>C1COCC1>[CH3:26][C:22]1[CH:21]=[C:20]([NH:17][C:18]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A 0° C. mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5.03 g, 23 mmol) and 1-isocyanato-3-methylbenzene (2.95 mL, 23 mmol) in THF (90 mL) was stirred at room temperature for 1 hour, concentrated, suspended in acetonitrile, and filtered. The filter cake was dried to provide 8.09 g of the desired product.