Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=1F)=[O:5].[Cl-:16].[Al+3].[Cl-].[Cl-]>CCCCCCC.C(Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([OH:13])[CH:9]=[C:8]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: COc1ccc(NC(=O)CCCl)c(F)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(O)cc(Cl)c2N1
Temperature: 110 °C
Reaction time: 72 h
Yield: 6.9 %

Procedure:
A suspension of 3-chloro-N-(2-fluoro-4-methoxyphenyl)propaneamide (1.0 g, synthesized from 3-chlorobutyryl chloride and 2-fluoro-4-methoxyaniline) and aluminum chloride (5.0 g) in n-heptane (2.0 mL) was stirred at 110° C. for 3 days. The reaction mixture was diluted with chloroform, followed by addition of ice-cold water under ice cooling. After stirring at room temperature for 2 hours, the organic layer and the aqueous layer were separated. The aqueous layer was extracted with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=3/2) and NH-type silica gel column chromatography (eluting solvent: chloroform/methanol=99/1 to 9/1) to give the titled compound (0.059 g, 7%) as a light-yellow solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([CH2:10][CH3:11])=[CH:9][C:5]=2[CH:4]=1.CI.[C:16](=[O:18])=[O:17].Cl>CCOCC>[C:16]([C:3]1[CH:13]=[CH:12][C:6]2[O:7][C:8]([CH2:10][CH3:11])=[CH:9][C:5]=2[CH:4]=1)([OH:18])=[O:17]
Reactant: CCc1cc2cc(Br)ccc2o1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CCc1cc2cc(C(=O)O)ccc2o1
Reaction time: 0.08 h

Procedure:
Magnesium (1.50 g) was stirred in ether (30 ml) at room temperature. Thereto was dropwise added a solution of 5-bromo-2-ethylbenzo[b]furan (8.30 g) and methyl iodide (0.55 g) in ether (30 ml) over 30 min. Then, the mixture was refluxed for 50 min and cooled in an ice water bath. In a different container, pulverized dry ice was stirred in ether and the Grignard reagent prepared above was transferred over about 5 min. 2N Hydrochloric acid was added to the reaction mixture to acidify the solution, and the ether layer was separated. The solution was basified with a 5% aqueous solution of sodium hydroxide and the separated aqueous layer was acidified with 2N hydrochloric acid. After extraction with ether, the extract was dried over sodium sulfate and concentrated to give the objective compound (2.48 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:18])[CH:11]=[C:12]([CH2:16][OH:17])[O:13]2)=[CH:8][CH:7]=1.Cl.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C(=O)(O)[O-].[Na+].[I-].[K+]>C(#N)C.C(OCC)C.O>[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:15]=[C:14]5[C:9]([C:10](=[O:18])[CH:11]=[C:12]([CH2:16][OH:17])[O:13]5)=[CH:8][CH:7]=4)[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=c1cc(CO)oc2cc(OCCCCl)ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: O=c1cc(CO)oc2cc(OCCCN3CCC(c4noc5cc(F)ccc45)CC3)ccc12
Yield: 40.2 %

Procedure:
A mixture of 3 g (11 mmoles) of the compound obtained in Example 5, 2.88 g (11 mmoles) of 6-fluoro-3-(4-piperidinyl)-benzo[d]isoxazole hydrochloride, 2.16 g (26 mmoles) of sodium bicarbonate and a catalytic amount of potassium iodide in 80 mL of acetonitrile was heated at reflux for 48 hours. The mixture was then allowed to cool, poured onto 100 mL of water and extracted with 100 mL of chloroform. The chloroform extract was washed with water, dried over sodium sulphate and evaporated. The residue obtained was suspended in ethyl ether, filtered and dried at vaccum to give 2 g of 7-[3-[4-(6-fluorobenzo[d]isoxazole-3-yl)piperidin-1-yl]propoxy]-2-(hydroxymethyl)-chromen-4-one in 40% yield.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([OH:18])[C:14]=3[CH:19]=2)=[CH:6][CH:5]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:21][C:2]([F:1])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]=3[CH:19]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (500 mg, 1.69 mmol), tert-butyl 2-bromoacetate (500 mg, 2.56 mmol) and cesium carbonate (1.65 g) were combined in 5 mL DMF and stirred at ambient temperature for 1 hour. The reaction mixture was diluted with 80 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-100% ethyl acetate in hexane gave tert-butyl 2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetate (285 mg, 0.70 mmol).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]([CH2:15][C:16]([OH:18])=[O:17])[N:13]=[N:12][N:11]=1.S(=O)(=O)(O)O.[CH2:24](O)[CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][O:17][C:16](=[O:18])[CH2:15][N:14]1[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[N:11][N:12]=[N:13]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1cc2ccccc2o1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1cc2ccccc2o1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 75.4 %

Procedure:
To a solution of 2.4 g (9.8 mM) of [5-(2-benzofuryl) tetrazol-1-yl]acetic acid in 12 ml of ethylene glycol was added 1 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and the precipitated crystal was filtered off, washed with water and then dissolved in ethyl acetate. The organic solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was recrystallized from methyl alcohol, to give 2.14 g (yield 75.4%) of [5-(2-benzofuryl)tetrazol-1-yl]acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH:5]1[CH2:8][CH:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=3)=[N:14][CH:15]=2)[CH2:6]1.[OH-].[Na+]>CO>[CH:2]([N:5]1[CH2:6][CH:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=3)=[N:14][CH:15]=2)[CH2:8]1)([CH3:4])[CH3:1]
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OC5CNC5)cn4)cc23)n1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CC(Oc2ccc(Oc3ccc4ncnc(Nc5ccn(C)n5)c4c3)nc2)C1
Reaction time: 0.17 h

Procedure:
Acetone (0.019 ml, 0.26 mmol) was added to a methanol solution (1 ml) of 6-{[5-(azetidin-3-yloxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (50 mg, 0.13 mmol) obtained in Example 6-5), stirred for 10 minutes, then a methanol solution (1.7 ml, 0.26 mmol) of 0.15 M zinc cyanotrihydroborate was added and stirred for 1 hour. 1 N sodium hydroxide was added to the reaction solution, then extracted with a mixed solution of chloroform/methanol (9:1). The organic layer was washed with saturated saline water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by thin-layer silica gel column chromatography (chloroform:methanol=90:10) to obtain 6-({5-[(1-isopropylazetidin-3-yl)oxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine. The compound was dissolved in methanol, then aqueous 5 M hydrochloric acid solution (0.017 ml, 0.085 mmol) was added and concentrated under reduced pressure to obtain the entitled compound (40 mg, yield: 67%) as a pale yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:10][C:9]([C:22](OCC)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[OH:23][CH2:22][C:9]1[CH:10]=[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CCOC(=O)c1cc(NS(=O)(=O)c2ccccc2)n(-c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(CO)nn1-c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of ethyl 1-phenyl-5-[(phenylsulfonyl)amino]-1H-pyrazole-3-carboxylate (445 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/L solution (4 mL) of diisobutylaluminum hydride in toluene was added dropwise. After stirring at 0° C. for 1 hr, the mixture was treated with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate again, and the combined extracts were washed with 1.0 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:3) to give the title compound as a pale-yellow oil (yield 379 mg, yield 96%).
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]([CH2:10]P(OC)(OC)=O)=[O:9].[H-].[Na+].[CH3:19][CH2:20][C:21](=O)[CH2:22][CH2:23][CH:24]=[CH2:25]>O>[CH2:24]([C:23]([CH2:22][CH2:21][CH:20]=[CH2:19])=[CH:10][C:8]([O:7][CH3:6])=[O:9])[CH3:25]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C=CCCC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCC(=CC(=O)OC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (25 mL) solution of trimethyl phosphonoacetate (4.67 g, 25.1 mmol) was added dropwise at 0° C. over 1 hour to a tetrahydrofuran (25 mL) suspension of sodium hydride (1.04 g, 63%, 27.4 mmol). To the mixture, tetrahydrofuran (25 mL) was further added, and the mixture was then stirred at 0° C. for 1 hour. To this solution, a tetrahydrofuran (25 mL) solution of 6-hepten-3-one (2.56 g, 22.8 mmol) was added dropwise at 0° C. over 20 minutes, and the mixture was stirred at room temperature for 2.5 hours and subsequently stirred at 65° C. for 3 hours. The mixture was treated with water, and volatile portions were then distilled off under reduced pressure, followed by extraction with hexane. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (3.04 g, 79%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH:10]([NH2:29])[CH2:11][C@H:12]([C:26](=[O:28])[NH2:27])[N:13](C(OC(C)(C)C)=O)[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9](=[O:30])[CH:10]([NH2:29])[CH2:11][C@H:12]([C:26](=[O:28])[NH2:27])[NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)N(C(=O)OC(C)(C)C)[C@H](CC(N)C(=O)OCc1ccccc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)N[C@H](CC(N)C(=O)OCc1ccccc1)C(N)=O
Reaction time: 0.5 h

Procedure:
In trifluoroacetic acid (7 ml) was dissolved the above t-butyloxycarbonyl-α-aminoisobutyroyl-D-isoglutamine benzyl ester (632 mg, 1.5 m mols) and the reaction was conducted at room temperature for 30 minutes. The solvent was distilled off and diethyl ether was added to the residue. The precipitated α-aminoisobutyroyl-D-isoglutamine benzyl ester trifluoroacetate was recovered by filtration. It was dissolved in tetrahydrofuran (10 ml) and, under ice-cooling neutralized with triethylamine (0.21 ml). By the above procedure there was obtained a solution of α-aminoisobutyroyl-D-isoglutamine benzyl ester in tetrahydrofuran.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]1[CH:12]=[C:11]([C:13]2[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH:10]=[C:9]([C:28]#[N:29])[C:8]1=[O:30])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C>[C:3]([CH2:5][CH2:6][N:7]1[CH:12]=[C:11]([C:13]2[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH:10]=[C:9]([C:28]#[N:29])[C:8]1=[O:30])([OH:4])=[O:2]
Reactant: COC(=O)CCn1cc(-c2c(-c3ccccc3)nn3ccccc23)cc(C#N)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1cc(-c2c(-c3ccccc3)nn3ccccc23)cn(CCC(=O)O)c1=O
Temperature: 80 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A mixture of 3-[1-(2-methoxycarbonylethyl)-3-cyano-2-oxo-1,2-dihydropyridin-5-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.46 g) and potassium carbonate (0.92 g) in 80% aqueous ethanol (4.6 ml) was stirred for 6 hours at 80° C. The mixture was acidified with 5% hydrochloric acid (pH≈2). The resultant precipitates were collected by filtration, washed with water (10 ml), and subjected to a column chromatography on silica gel (10 g) with a mixture of chloroform, methanol and acetic acid (40:4:1). The fractions containing the object compound were combined and evaporated in vacuo to give 3-[1-(2-carboxyethyl)-3-cyano-2-oxo-1,2-dihydropyridin-5-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.40 g).
Reaction SMILES: [CH:1]([S:4][C:5]1[C:10]([CH2:11]O)=[CH:9][CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].O=S(Cl)[Cl:15]>CC#N>[Cl:15][CH2:11][C:10]1[C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)Sc1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: CC(C)Sc1ncccc1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
(2-Isopropylsulfanyl-pyridin-3-yl)-methanol (3.0 g, 16.37 mmol) obtained in Step B was dissolved in CH3CN (20 mL), and SOCl2(2.39 mL, 32.74 mmol) was added thereto dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure. After the addition of EtOAc, the organic layer was washed with water, dried with MgSO4, filtrated and concentrated under reduced pressure to obtain the title compound (3.04 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[F:12][C:13]([F:22])([F:21])[C:14]1[N:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[C:9]=1[O:20][C:17]1[CH:18]=[N:19][C:14]([C:13]([F:22])([F:12])[F:21])=[CH:15][CH:16]=1)[CH:5]=[O:6]
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Temperature: 100 °C
Yield: 93.9 %

Procedure:
3,4,5-trifluorobenzaldehyde (1 g, 6.25 mmol), which is commercially available 6-(trifluoromethyl)-3-pyridinol (1.019 g, 6.25 mmol) and K2CO3 (1.727 g, 12.49 mmol) were added into a microwave vial. Then, N,N-dimethylformamide (DMF) (15 mL) was added. The microwave vial was sealed and heated in Biotage Initiator at 100° C. for 1 h. The mixture was extracted with by EtOAc. The organic extracts were dried over Na2SO4 and evaporated to give 1.78 g of the title product (94%).
Reaction SMILES: [CH3:1][CH:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[CH2:11][O:10]1.[CH3:23][NH:24][CH3:25]>O1CCCC1>[CH3:23][N:24]([CH3:25])[CH2:11][CH:9]([OH:10])[CH2:8][O:7][C:6]1[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(CCc1ccccc1OCC1CO1)Cc1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: CC(CCc1ccccc1OCC(O)CN(C)C)Cc1ccccc1
Yield: 86 %

Procedure:
Following a procedure similar to that described in Example 1(b), 1.0 g of 2-[2-(3-methyl-4-phenylbutyl)phenoxymethyl]oxirane [prepared as described in step (a) above] dissolved in 20 ml of tetrahydrofuran was treated with 4 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 0.99 g (yield 86%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[NH:5][N:4]=1.C1C(=O)N([Cl:20])C(=O)C1>CC#N>[Cl:20][C:7]1[C:3]([C:2]([F:1])([F:11])[F:12])=[N:4][NH:5][C:6]=1[CH:8]([CH3:10])[CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)c1cc(C(F)(F)F)n[nH]1
Solvent: CC#N
Product: CC(C)c1[nH]nc(C(F)(F)F)c1Cl

Procedure:
Following protocol L, to the solution of 3-trifluoromethyl-5-isopropyl-pyrazole (0.22 g, 1.23 mmol) in CH3CN (10 mL) was added NCS (0.19 g, 1.43 mmol) in portions with vigorous stirring. The reaction mixture was then heated under reflux for 14 h, cooled and the reaction quenched with saturated NaHCO3, extracted with methylene chloride (2×30 mL) and the combined organic extracts was washed with brine, dried with Na2SO4 and evaporated to give the title compound as a white solid.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:47][O:48][CH3:49])[C:10]([NH:12][CH:13]2[C:45](=[O:46])[N:15]3[C:16]([C:29]([O:31][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:30])=[C:17]([S:20]/[CH:21]=[CH:22]\[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O.C(=O)(O)[O-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:47][O:48][CH3:49])[C:10]([NH:12][CH:13]2[C:45](=[O:46])[N:15]3[C:16]([C:29]([O:31][CH:32]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:30])=[C:17]([S:20]/[CH:21]=[CH:22]\[C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S/C=C\c3cccnc3)CS[C@H]12)c1csc(N)n1
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)-vinylthio]-3-cephem-4-carboxylate (syn isomer) (1 g) in a mixture of methanol (10 ml) and tetrahydrofuran (5 ml) was added conc. hydrochloric acid (0.31 ml) at ambient temperature and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture were added water and ethyl acetate and the mixture was adjusted to pH 7 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(3-pyridyl)vinylthio]-3-cephem-4-carboxylate (syn isomer) (0.86 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][C:21]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][C:21]=1[NH:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Reactant: Fc1ccc(CBr)cc1Nc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(COCc2ccc(F)c(Nc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 120 mg of sodium hydride (60% oil dispersion) was added to 10 ml of dry THF. A solution of 0.69 of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 0.82 g or 4-fluoro-3-anilinobenzyl bromide in 20 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 46 hours. Thereafter, the reaction mixture was poured into ice water and adjusted to pH 6 with dilute HCl and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 368 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20][N:19]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2nccc3ccccc23)CC1
Yield: 10.2 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 1-chloroisoquinoline (131 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (15 mg), an off-white solid, in 10% yield.
Reaction SMILES: C(Cl)/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C.[Al].[CH3:23][C:24]1[C:33]([CH3:34])=[C:32]2[C:27]([CH2:28][CH2:29][C:30]([CH2:36][CH2:37][CH2:38][CH:39]([CH2:41][CH2:42][CH2:43][CH:44]([CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40])([CH3:35])[O:31]2)=[C:26]([CH3:52])[C:25]=1[OH:53].[C:54](OCC)(=[O:56])[CH3:55]>>[CH3:34][C:33]1[C:24]([CH3:23])=[C:25]([O:53][C:54]([CH3:55])=[O:56])[C:26]([CH3:52])=[C:27]2[CH2:28][CH2:29][C@:30]([CH2:36][CH2:37][CH2:38][C@@H:39]([CH2:41][CH2:42][CH2:43][C@@H:44]([CH2:46][CH2:47][CH2:48][CH:49]([CH3:51])[CH3:50])[CH3:45])[CH3:40])([CH3:35])[O:31][C:32]=12
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Al]
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 2.283 g of TMHQ and 6.013 g of phytyl chloride in 12.0 ml of ethyl acetate were added 0.075 g of metallic aluminum powder and 0.904 g of stannous chloride, and the mixture was agitated at 80° C. for 3 hours. At this stage, the metallic aluminum powder adhered to the walls of the reactor and the reaction mixture turned to reddish brown. The obtained dl-α-tocopherol was acetylated in the same manner as described in Comparative Example 1 without isolating said dl-α-tocopherol to produce 8.023 g of dl-α-tocopheryl acetate. The absorbance of this crude dl-α-tocopheryl acetate was measured: E430 mμneat =0.982, E415 mμ40%EtOH =0.719. Estimation of the crude dl-α-tocopheryl acetate by liquid chromatography indicated that its purity was 84.2% and the yield was 95.3%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1F.[NH:13]1[C:17]2[N:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=2[CH:15]=[CH:14]1>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[O:22][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:13][CH:14]=[CH:15][C:16]=12
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Oc1ccnc2[nH]ccc12
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc3[nH]ccc23)cc1F
Yield: 40 %

Procedure:
Following a similar procedure as described in Step A of Example 313 and using 1,2,4-trifluoro-5-nitrobenzene, 1H-pyrrolo[2,3-b]pyridin-4-ol (268 mg, 2.0 mmol) was converted to the title compound (230 mg, 40%). MS(ESI) m/z 292.2 (M+H)+.