Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:13](/[CH:17]=[CH:18]/[Cl:19])[CH2:14][S:15](=O)[C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:36](=[O:37])[N:11]2[C:12]([C:20]([O:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:21])=[C:13](/[CH:17]=[CH:18]/[Cl:19])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS(=O)[C@H]12
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of benzhydryl 7-t-butoxycarbonylamino-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate-1-oxide (7.3 g) in N,N-dimethylformamide (35 ml) was added phosphorus trichloride (1.76 ml) at -40° C. After stirring at the same temperature for 30 minutes, the mixture was poured into ice-water. The resulting precipitate was collected by filtration and dried to give benzhydryl 7-t-butoxycarbonylamino-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (6.3 g).
Reaction SMILES: C1N2CCN(CC2)C1.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[Cl-].[NH4+]>C(OCC)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([OH:34])([C:16]2[C:15]([Cl:14])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1cccnc1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ncccc2Cl)CC1
Reaction time: 0.5 h
Yield: 23 %

Procedure:
DABCO (0.31 g, 2.75 mmol) in diethyl ether (11 mL) was cooled to −40° C., under nitrogen. n-Butyl lithium (2.5 M, 1.0 mL, 2.5 mmol) was added dropwise and stirred for 30 minutes. The temperature was decreased to −65° C., 3-chloropyridine (0.284 mL, 2.5 mmol) was slowly added and stirred for 30 minutes before a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) in diethyl ether (5 mL) was added for 30 minutes. Ammonium chloride was added and the mixture extracted into ethyl acetate, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.18 g). LCMS m/z 313.3 [M+H]+. R.T.=4.51 min (Analytical Method 3).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][O:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]2[C:17]([O:16][CH3:15])=[N:18][S:19](=[O:24])[N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: COC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (3.30 g; 15.4 mmoles) in 25 ml of methanol was added dropwise over a period of 14 minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.50 g; 15.4 mmoles) [prepared according to the procedure in Example 4, Step A] that was cooled to 12°-15° in an ice-water bath. The solution was stirred at ambient temperature for 1.5 hours to yield a methanolic solution of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@H:4]([CH2:31][CH2:32][S:33][CH3:34])[NH:5][C:6](=[O:30])[C@H:7]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:22])[C@@H:16]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1)[CH:11]([CH3:13])[CH3:12].[Li+].[OH-]>CO.O>[NH:17]1[C:18](=[O:21])[CH2:19][CH2:20][C@H:16]1[C:15]([NH:14][C@@H:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:35])=[O:2])[CH2:31][CH2:32][S:33][CH3:34])=[O:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)[C@@H]1CCC(=O)N1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product of Step E was dissolved in 15 mL of methanol and a solution of 60 mg of LiOH in 7 mL of water added. The mixture was stirred for 3 h at room temperature under argon, diluted with water and filtered. The filtrate was neutralized with 10% citric acid and cooled. The product was isolated by filtration and further purified by reverse phase HPLC. Lyophilization gave the title compound as a white solid. 1H-NMR (D2O) δ7.40 (3H, m), 7.29 (2H, m), 4.36 (1H, dd, J=4.9, 8.5 Hz), 4.29 (1H, m), 4.22 (1H, dd, J=6.2, 8.7 Hz), 3.96 (1H, dd, J=7, 13 Hz), 3.33 (1H, dd, J=6.4, 14.3 Hz), 3.20 (3H, m), 2.54 (1H, m), 2.44 (2H, m), 2.39 (1H, m), 2.32 (1H, m), 2.09 (2H, m), 2.06 (3H, s), 1.92 (1H, m), 1.87 (1H, m), 0.92 (3H, d, J=7.8 Hz), 0.90 (3H, d, J=7.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH2:23][C:24]#[N:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:23][C:24]#[N:25])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: N#CCBr
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Reaction time: 24 h
Yield: 100.6 %

Procedure:
(5-Bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (342 mg) was added bromoacetonitrile (122 mg), acetone (2 mL) and K2CO3 (140 mg), and the reaction was stirred for 24 h. The reaction mixture was concentrated and the residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO4) and concentrated to give 383 mg (100%) yellow solid, that was used directly in the next step: LC/MS (an10p8): Rt 4.39 min, m/z 381.5 [M+1]+; 1H NMR (CDCl3): δ 4.80 (s, 2H), 7.07 (d, J=8.7 Hz, 1H), 7.35-7.42 (m, 1H), 7.45-7.54 (m, 2H), 7.60-7.69 (m, 2H), 7.69-7.75 (m, 2H), 8.03 (s, 1H), 8.31 (s, 1H); 13C NMR (CDCl3): δ 55.2, 114.7, 116.6, 116.7, 120.1, 125.1, 128.2, 129.9, 131.0, 132.6, 133.2, 135.0, 139.3, 142.7, 153.0, 186.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[CH:5]=[O:6].[Br:12]Br.O>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:12][C:8]1[C:7]([CH3:11])=[C:4]([C:3]([O:2][CH3:1])=[CH:10][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cccc(C)c1C=O
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(Br)c(C)c1C=O
Reaction time: 1 h
Yield: 91.9 %

Procedure:
2-Methoxy-6-methylbenzaldehyde (7.32 g, 0.049 mol) in carbon tetrachloride (183 ml) was cooled to −10° C., and iron powder (150 mg, 0.002 mol) was added to it. Bromine (3.0 ml, 0.058 mol) was added over a period of 10 minutes. The mixture was stirred for 1 hour and then poured into water (225 ml). The organic layer was washed with sodium thiosulfate solution (2×50 ml), water (50 ml) and brine solution (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 3-Bromo-6-methoxy-2-methyl-benzaldehyde (10.32 g, 92.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH:13][CH2:14][CH2:15][OH:16])([O-])=O.[OH-].[Na+].[ClH:19]>>[ClH:19].[ClH:19].[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH:13][CH2:14][CH2:15][OH:16]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(N)c1NCCO
Temperature: 80 °C

Procedure:
18.3 g (0.0805 mol) of 2-[(2,6-dinitrophenyl)amino]ethanol in a solution containing 144 g of stannous chloride dihydrate in 146 ml of a concentrated hydrochloric acid solution are heated at 80° C. in an oil bath for 15 minutes. The reaction mixture is cooled in an ice bath, 460 ml of a concentrated sodium hydroxide solution are slowly added and then extraction is carried out three times with dichloromethane. The organic phases are combined, are dried and evaporated to dryness.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29]2[N:33]3[CH:34]=[C:35](F)[CH:36]=[CH:37][C:32]3=[N:31][N:30]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([CH2:28][C:29]2[N:33]3[CH:34]=[C:35]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:36]=[CH:37][C:32]3=[N:31][N:30]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
To a solution of Intermediate A (392 mg, 2.40 mmol) in dry DMF (5 mL) was added NaH (60% dispersion in mineral oil, 240 mg, 6.00 mmol) and the resulting brown suspension was stirred at RT for 45 min (CARE: gas evolution). Intermediate 22a (669 mg, 2.00 mmol) was added and the dark brown solution stirred at 60° C. for 2 h. The cooled solution was concentrated in vacuo, redissolved in MeOH (5 mL), applied to an SCX-2 cartridge (20 g) and washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a dark brown residue. FCC, using 4-9% [2M NH3 in MeOH] in DCM, gave the title compound as a brown oil (421 mg, 44%). LCMS (Method 3): Rt 2.45 min, m/z 478 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.[NH2:22][NH2:23]>>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:22][NH:23][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2C(=O)O)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2n[nH]c(=O)c3cc(Cl)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-chloro-2-(4-methoxybenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][CH3:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>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.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.[Pd].C1(C)C=CC=CC=1>[CH2:10]([C:4]1[C:5](=[O:9])[NH:6][C:7]([CH3:8])=[C:2]([C:18]2[CH:19]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:12]#[N:13])[CH:3]=1)[CH3:11]
Reactant: CCc1cc(Br)c(C)[nH]c1=O
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1cc(-c2cccc(C#N)c2)c(C)[nH]c1=O
Reaction time: 2 h
Yield: 36 %

Procedure:
A stirred mixture of 5-bromo-3-ethyl-6-methyl-1H-pyridin-2-one, prepared in accordance with the procedures of PREPARATION 1, Step 2, (100 mg, 0.46 mmol), 3-cyanophenylboronic acid (88 mg, 0.6 mmol), 2M aq sodium carbonate (0.69 mL, 1.38 mmol), palladium tetrakis(triphenylphosphine) (16 mg, 0.014 mmol) and toluene (5 mL) is heated at reflux under a nitrogen atmosphere. After 2 hr, more catalyst (16 mg) is added and heating is continued overnight. The reaction is cooled and the mixture is partitioned between water and dichloromethane. The organic layer is separated and the solvents are removed. The residue is purified by chromatography eluting with ethyl acetate and with dichloromethane-5% methanol. Fractions containing product are combined, concentrated and the residue is triturated with hot ether to afford 3-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzonitrile (40 mg, 36%) as a white solid. LC/MS: MS m/e=239 (M+H); RT 2.83 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[SH:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([S:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:13]=[N:12][C:11]=1[NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CCS
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A nitrogen purged 50 mL round-bottomed flask was charged with 3-(benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 1.50 g, 3.99 mmol), Pd2dba3 (0.091 g, 0.099 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.115 g, 0.199 mmol), and dioxane (20 mL). N-ethyl-N-isopropylpropan-2-amine (1.4 ml, 8.0 mmol) and methyl 3-mercaptopropanoate (0.49 mL, 4.4 mmol) were added and the flask was plunged into a 100° C. oil bath for 2 hours. The reaction mixture was cooled to room temperature and solvent removed. The residue was purified on silica gel (20 to 30% ethyl acetate/hexanes) to afford methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (1.30 g, 78.5% yield) as a white solid. 1H NMR (CDCl3) δ 8.57 (bs, 1H), 8.04 (d, 1H), 7.41 (m, 5H), 7.22 (d, 1H), 6.42 (s, 1H), 5.12 (s, 2H), 3.68 (s, 3H), 3.03 (t, 2H), 2.56 (t, 2H), 2.32 (s, 3H); Mass spectrum (apci) m/z=325.0 (100) 416.0 (50).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:15]([CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccccc1
Yield: 94 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate (3.33 g), which is the product of Reference example 4(c), 2-(2-bromoethoxy)tetrahydropyran (7.27 g) and potassium carbonate (6.41 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (4.53 g) as a syrup.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH2:16]>Cl.S(=O)(=O)(O)O>[F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]([C:11]([OH:10])=[O:12])[C:7]=1[C:8]([OH:16])=[O:9]
Reactant: O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O

Procedure:
In the second step, high-purity tetrafluorophthalic acid can be obtained by first isolating tetrafluorophthalic anhydride formed as a reaction intermediate, or separating the product in solution from the reaction system, and hydrolyzing the product under acidic or neutral conditions, and this embodiment is particularly preferred. For example, by hydrolyzing the N-substituted tetrafluorophthalimide under acid conditions (e.g., H2SO4 concentration: from about 50 to 98%) and, after cooling, extracting the product with an aprotic solvent (e.g., toluene, benzene, chlorobenzene, xylene, etc.), a solution of tetrafluorophthalic anhydride can be obtained. Furthermore, by removing the solvent from the extract thus obtained, tetrafluorophthalic anhydride can be isolated. In this case, the tetrafluorophthalic anhydride may be purified by distillation, if desired, under a reduced pressure. Then, by hydrolyzing the tetrafluorophthalic anhydride thus obtained under acid or neutral conditions, tetrafluorophthalic acid can be obtained. In the hydration reaction, water is generally used in an amount of from 1 to 5000 mols per mol of the tetrafluorophthalic anhydride and the reaction temperature is usually from about 0° to 100° C. The reaction can be conducted by adding an acid (e.g., hydrochloric acid and sulfuric acid) as a catalyst. This technique of isolating tetrafluorophthalic anhydride or separating it as a solution is preferred, since the purification of tetrafluorophthalic acid, which is the desired product, can be easily performed and high-purity tetrafluorophthalic acid can be obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(O)C>[N:9]1[CH:10]=[CH:11][C:6]([CH:3]([OH:5])[CH3:4])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Sodium borohydride (310.0 mg; 8.25 mmol) was added portionwise to a cooled (0° C.) solution of 4-acetylpyridine (500.0 mg; 4.13 mmol) in ethanol under argon atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 4 hours. Quenched with water and solvent removed. Extracted with dichloromethane, washed with water, brine, dried and solvent removed to yield 500 milligrams of 1-(4-pyridyl)ethanol.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]([C:16](=[O:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[Ru]>[C:1]([NH:9][CH2:10][C@@H:11]([C@H:16]([OH:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CNC(=O)c1ccccc1)C(C)=O
Agent: [Ru]
Solvent: ClCCl
Product: COC(=O)[C@@H](CNC(=O)c1ccccc1)[C@@H](C)O
Yield: 89.5 %

Procedure:
A solution was prepared by dissolving 2.5 g (10 mmol) of methyl 2-[(N-benzoylamino)methyl]-3-oxobutyrate and 84.5 mg (0.05 mmol) of the ruthenium-optically active phosphine complex prepared by following the general procedures of Referential Example 1 (Ru2Cl4 ((+)-BINAP)2 (NEt3)) in 17.5 ml of methylene chloride. The solution was placed in a 100 ml stainless steel autoclave wherein the inside air was replaced with nitrogen gas in advance. Reaction was allowed to proceed at 50° C., under a hydrogen pressure of 100 kg/cm2 for 20 hours under stirring. The solvent was distilled off and the remainder was subjected to the silica gel column chromatography (eluent; mixture of n-hexane and ethyl acetate) for removal of the catalyst to obtain 2.25 g of the title compound (yield: 90%, optical purity: 98% ee). To determine the optical purity, the compound was further derived to an ester of (+)-α-methoxy-α-trifluoromethylphenyl acetic acid, then applied to high performance liquid chromatography (column; Develosil® 100-3(4.6 mm×250 mm), manufactured by Nomura Kagaku K.K.; wave length (UV): 254 nm; eluent: hexane/diethylether=90/10; flow rate: 1 ml/min).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19](=[S:21])[NH2:20])=[C:12]2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH:24]([C:29](OC)=[O:30])[C:25]([O:27][CH3:28])=[O:26].O>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[C:17]([CH3:22])[C:18]([C:19]3[S:21][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:29]([OH:30])[N:20]=3)=[C:12]2[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1nn2ccc(OCc3ccccc3)cc2c1C(N)=S
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc(-c2c(C)nn3ccc(OCc4ccccc4)cc23)nc1O
Temperature: 100 °C
Reaction time: 7.5 h

Procedure:
To a suspension of 5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride(3.45 g, 10.3 mmol) in DMF (100 mL), was added 94% dimethyl chloromalonate (2.79 mL, 20.6 mmol) and the mixture was stirred for 7.5 h at 100° C. The reaction mixture was allowed to cool to 50° C. and then was dropwise added water (100 mL). The resulting precipitate was collected by filtration and then washed with EtOH (20 mL) and diethyl ether (20 mL) to obtain methyl 2-[5-(benzyloxy)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-4-hydroxy-1,3-thiazole-5-carboxylate as a orange solid, which was used in the next step without further purification. 1H-NMR (DMSO-d6, 300 MHz) δ 2.59 (3 H, s), 3.75 (3 H, s), 5.27 (2 H, s), 6.87 (1 H, dd, J=2.6, 7.6 Hz), 7.32-7.51 (3 H, m), 7.52-7.64 (2 H, m), 7.88 (1 H, d, J=2.6 Hz), 8.67 (1 H, d, J=7.6 Hz), 11.79 (1 H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[CH:10][C:5]([NH:6][CH2:7][CH2:8][NH2:9])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[CH2:16]([CH2:18][NH2:19])[OH:17]>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[C:5]([NH:6][CH2:7][CH2:8][NH2:9])=[CH:10][C:11]=1[NH:19][CH2:18][CH2:16][OH:17]
Reactant: NCCNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: NCCO
Solvent: O
Product: NCCNc1cc(NCCO)c(Cl)cc1[N+](=O)[O-]

Procedure:
0.04 mole (10 g) of 4,5-dichloro-2-nitro-N-β-aminoethylaniline prepared in the 1st stage is heated in 40 ml of monoethanolamine for 30 minutes to 100° C. The reaction mixture is diluted with 450 ml of iced water. An impurity is precipitated by adding hydrochloric acid and is removed by filtration. The filtrate is made alkaline with concentrated sodium hydroxide solution. The expected product precipitates. After filtration and drying, it is purified as its hydrochloride before being recrystallized from alcohol. It melts at 160° C.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3]/[CH2:4]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:27])(=O)=O>CN(C=O)C>[Cl:27][CH2:4]/[CH:3]=[C:2](/[CH3:1])\[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)=CCC/C(C)=C\CO
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)=CCC/C(C)=C\CCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
To a stirred solution of 10.0 g (64.83 mmol) of (Z)-3,7-dimethyl-2,6-octadien-1-ol and 9.42 mL (71.31 mmol) of 2,4,6-collidine under argon at room temperature was added dropwise 2.74 g (64.83 mmol) of lithium chloride in 30 mL of DMF. The mixture was cooled to 0° C. and treated with 5.52 mL (71.31 mmol) of methanesulfonyl chloride dropwise over 10 minutes. The reaction was stirred at 0° C. for 4 hours (solid present), then was poured into 300 mL of ice/water. The aqueous solution was washed three times with 200 mL portions of hexane. The organic layers were combined and washed with 5% KHSO4, water, saturated NaHCO3, brine, dried (MgSO4) and evaporated to provide 9.48 g (85%) of title chloride as a pale yellow oil.