Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[CH:3]=1.[I:21]N1C(=O)CCC1=O.CCCCCC>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[I:21]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CC#N
Solvent: CCCCCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reaction time: 0.08 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (5.0 g) in acetonitrile (60 ml) at room temperature was added N-iodosuccinimide (3.52 g), portionwise over a period of five minutes. Stirring was continued for 1 hr and the mixture was then evaporated to dryness to provide the crude product (8.2 g), still containing succinimide. This may be used without further purification or, if desired, purified by partitioning between dichloromethane and water, separating, drying (MgSO4) and evaporating the organic layer to produce a yellow solid. Trituration with hexane provides the title compound as a white solid, m.p. 213° C. (decomp.).
Reaction SMILES: [Na].[C:2]([O:12]CC)(=[O:11])[CH2:3][C:4]([C:6]([O:8]CC)=O)=O.[OH-].[Na+].Cl.[CH:18]1([C:21](=[NH:23])[NH2:22])[CH2:20][CH2:19]1.Cl>O.C(O)C>[CH:18]1([C:21]2[NH:23][C:6](=[O:8])[CH:4]=[C:3]([C:2]([OH:12])=[O:11])[N:22]=2)[CH2:20][CH2:19]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A 500-mL jacketed reactor equipped with a pH meter, temperature probe and metering addition funnel was charged with denatured ethanol (contained 5% 2-propanol, 30 mL) and water (150 mL). The reaction mixture was stirred while diethyl oxalacetate sodium salt (70 g, 0.33 mol) was added over 10 minutes. A solution of 25% aqueous NaOH (14 g, 56 mL, 0.35 mol) was metered into the stirring vortex over 1 h while maintaining the temperature in a range of 25 to 30 ° C. The reaction mixture was stirred for an additional 30 minutes at 30 ° C., and cyclopropanecarboximidamide monohydrochloride (32 wt % solution in water, 32 g, 0.267 mol) was added. A solution of 25% aqueous NaOH (31 g, 0.19 mol) was added at a temperature ranging from 30 to 35 ° C. over about 1 h so as to maintain the pH in the range of 10.5-11.5. Then the resulting orange mixture was gradually heated to 60 ° C. over a period of 1 h and held at the same temperature for additional 30 minutes. The reaction mixture was cooled to 45-50 ° C., and hydrochloric acid (37 wt. % in water, 50 mL, 0.60 mol) was added over 1 h at about 45 ° C. (CAUTION: foaming) until the pH reached to about 1.5. The reaction mixture was cooled to 5 ° C. and filtered. The resulting wet cake was washed with water (3×20 mL), suction-dried, and dried in a vacuum-oven at 70 ° C. for 16 h to afford 42 g (85% yield) of the title compound as a beige solid (97% purity by HPLC assay) decomposing at 235-236 ° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4(OCC[O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O>CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc3c(c2)OCO3)CC1
Yield: 94.9 %

Procedure:
A solution of 8-(1,3-benzodioxol-5-yl)-1,4- dioxaspiro[4.5]decan-8-ol (IIIb; 5 g, 18 mmole) in 75 ml acetone, 1 ml 12N HCI, and 50 ml water, was stirred for 2 hr. After dilution with an additional 50 ml water the solid was collected to give the product (4.0 g, 95%, mp: 166°-168° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[CH3:9][C:10](C)([CH3:14])[C:11](O)=O.FC(F)(F)C(O)=O.[OH-].[Na+]>[N+]([O-])([O-])=O.[Ag+].ClC1C=CC=CC=1.O>[C:10]([C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=1)([CH3:14])([CH3:11])[CH3:9]
Reactant: CC(C)(C)C(=O)O
Reactant: N#Cc1ccncc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Clc1ccccc1
Product: CC(C)(C)c1cc(C#N)ccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
p-cyanopyridine (4.00 g, 38.4 mmol) was added to a 1:1 mixture of chlorobenzene/water (750 mL) in a 1 L round-bottom flask. Trimethylacetic acid (10.88 g, 106-5 mmol), (NH4)2S2O8 (17.53 g, 76.8 mmol), trifluoroacetic acid (4.390 g, 38.5 mmol) and AgNO3 (0.521 g, 3.1 mmol) were added and the heterogeneous mixture was vigorously stirred at 50° C. for 2 h. The reaction was cooled down to 0° C. and 8 M NaOH was added slowly until pH 9-10. The mixture was filtered through Celite and extracted with EtOAc (×3). The combined organic extracts were dried with MgSO4 and the solvent removed in vacuo. The dark-brown oil was purified via flash chromatography (1:6 EtOAc/Hexane) to afford a brown solid (4.305 g, 70%); 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 7.38 (d, J=5.2 Hz, 1H), 7.63 (s, 1H), 8.73 (d, J=4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 29.2, 37.3, 116.4, 119.9, 120.4, 121.6, 149.1, 170.3; HRMS-EI (m/z): [M+H+] calcd for [C10H13N2]+, 161.1079. found 161.1070.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[CH:23][N:24]=1
Reactant: COc1ccc(C#N)cn1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (1.8 g, 8.7 mmol) in toluene (50 ml) at 0° C., trimethylaluminum (2M solution in toluene, 5.2 ml, 10.4 mmol) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 6-methoxy-3-cyanopyridine (1.75 g, 13 mmol) in toluene (100 ml) was added over 10 minutes and the mixture was heated to 85–90° C. After 24 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride and methanol and later with methanol. The combined filtrates were concentrated and the resulting yellowish solid was stirred with ethyl acetate (1000 ml) and filtered. The white solid (2 g, 75%) was used in the next reaction without further purification. Anal. Calc'd. for C14H16N3SClO3.0.5H2O: C, 47.93; H, 4.88; N, 11.98. Found: C, 48.01; H, 4.82; N, 11.32.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: OCCO
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-cyanobenzaldehyde (5-1) (20.0 g, 152.5 mmol) and ethylene glycol (25.5 mL, 457.5 mmol) in toluene (250 mL) was added p-toluenesulfonic acid (300 mg). The flask was equipped with a Dean-Stark trap and the mixture heated to reflux. After 5 hours, the mixture was concentrated. The residue was taken up in ethyl acetate and washed with saturated NaHCO3, H2O (2×), and brine. The organic layer was dried (MgSO4), filtered, and concentrated to give 4-(1,3-dioxolan-2-yl)benzonitrile as a clear oil which solidified under vacuum: 1H-NMR (500 MHz, CDCl3) δ 7.67 (d, J=8.06 Hz, 2H), 7.59 (d, J=8.30 Hz, 2H), 5.85 (s, 1H), 4.13-4.05 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])[O:6][CH2:5][CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C1COCC1>[CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH2:10][NH2:11])[CH:12]=[CH:13][CH:14]=2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2cccc(C#N)c2)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1(c2cccc(CN)c2)OCCO1
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
A solution of cyano ketal 19 (290 mg, 1.53 mmol) in dry THF (10 mL) was cooled to 0° C. under a nitrogen atmosphere. Then a solution of 2 M lithium aluminum hydride (3 mmol) in THF was added over a 10-min period. The reaction mixture was stirred for 1.5 h and then ethyl acetate was added followed by slow addition of water to decompose the excess LAH. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by column chromatography using chloroform and methanol as an eluent to give 20 (176 mg, yield 60%). 1H NMR (CDCl3, 400 MHz) δ 1.66 (s, 3H), 3.79 (t, J=6 Hz, 2H), 3.88 (s, 2H), 4.04 (t, J=6 Hz, 2H), 7.24-7.42 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:17]3[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Product: COc1ccc(-c2cnc3ccc(Br)cn23)cc1

Procedure:
The title compound, brown oil (0.47 g, 72%), MS (ISP) m/z=303.4 [(M+H)+], was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available 4-methoxy-phenylboronic acid (0.36 g, 2.38 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[CH3:23]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:33])=[CH:27][CH:28]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C:8](=[O:31])[CH2:9][C@H:10]([OH:30])[CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO.[BH4-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([OH:31])[CH2:9][C@H:10]([OH:30])[CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (5S)-6-(tert-butyl-diphenyl-silanyloxy)-5-hydroxy-3-oxo-hexanoic acid tert-butyl ester (20 g, 0.044 mol) in THF (60 mL) was stirred under nitrogen and methanol (20 mL) was added. The reaction mixture was stirred for 15 min. and cooled to −50° C. to −55° C. Anhydrous CeCl3 (10.8 g, 0.044 mol) was added and stirred for 30 min., maintaining the temperature between −50 and −55° C. Sodium borohydride (2.5 g, 0.066 mol) was added in 6 portions maintaining the temperature between −70 and −90° C. The resulting mixture was stirred for 6 h at the same temperature. After warming the reaction mixture to RT, it was concentrated to a residue under vacuum at about 45° C. Methanol (60 mL) was added and the resulting mixture was concentrated. The resulting residue was cooled to RT, water (50 mL) was added and the resulting aqueous mixture was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed with brine solution (50 mL), and concentrated to obtain the title compound. Yield: 17 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[C:11]1([S:17]([NH:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
To a solution of 2.76 g. (0.02 mol) of m-nitroaniline in 5 ml. of pyridine cooled to 0° C. is added 3.52 g. (0.02 mol) of benzenesulfonyl chloride dropwise and the mixture is stirred for one hour at room temperature. The reaction mixture is decomposed with dilute hydrochloric acid and ice, and the solid filtered off to give m-(phenylsulfonamido)-nitrobenzene, m.p. 132°-134° C. The latter, 1.4 g. (0.005 mol), is dissolved in 100 ml. of ethanol, 300 mg. of 10% palladium-on-carbon is added and the mixture is hydrogenated in a Parr shaker. After hydrogen uptake has ceased, the catalyst is filtered off and the filtrate is used directly in the subsequent reaction. Thus the ethanolic solution (100 ml.) containing 1.2 g. (0.005 mol) of 3-phenylsulfonamidoaniline and 1.06 g. (0.005 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one is refluxed for one hour. The reaction mixture is concentrated and filtered to give 5-acetyl-4-hydroxy-3 -[1-(3-phenylsulfonamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 209° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([OH:11])=[C:5]([F:12])[C:4]=1[F:13])#[N:2].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].C(=O)([O-])[O-].[Ca+2].Cl>C1C=CC=CC=1>[C:14]([O:11][C:6]1[C:5]([F:12])=[C:4]([F:13])[C:3]([C:1]#[N:2])=[C:8]([F:9])[C:7]=1[F:10])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1c(F)c(F)c(O)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Product: C=C(C)C(=O)Oc1c(F)c(F)c(C#N)c(F)c1F
Yield: 63.9 %

Procedure:
In 30 ml of benzene, 3.0 g (0.0157 mol) of 4-cyano-2,3,5,6-tetrafluorophenol and 1.80 g (0.0173 mol) of methacrylic acid chloride were dissolved. The resultant solution, and 1.73 g (0.0173 mol) of calcium carbonate added thereto as a hydrogen chloride trapping agent were stirred under reflux for 32 hours. The resultant reaction mixture was cooled off and filtered to separate calcium carbonate. The filtrate was dried with magnesium sulfate and then evaporated with a rotary evaporator. Consequently, there was obtained 2.6 g of 4-cyano-2,3,5,6-tetrafluorophenyl methacrylate (yeild 63.9% and purity 95.4%). The analyses obtained of the novel substance for the determination of its chemical structure were the same as those of Example 2.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O>N1C=CC=CC=1>[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])(=[O:14])=[O:13]
Reactant: C=CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: C=CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
29.3 millimoles of 3-buten-1-ol are added to a solution of 525 millimoles of p-toluenesulphonyl chloride in 200 ml of anhydrous pyridine cooled to 0° C. The mixture thus obtained is kept stirred overnight at −5° C. It is then added with stirring to a mixture of 200 g of water and ice. An oily product is extracted from the aqueous mixture by 3 ether washes, each of 300 ml. The ether fractions are washed twice with 300 ml of a cold solution of hydrochloric acid (HCl:water being 1:1 by weight) to remove pyridine, and then with 300 ml of water, and are then dried over potassium carbonate and sodium sulphate and decolorized with active carbon. The suspension is filtered and the ether is evaporated from the filtrate at reduced pressure to leave an oily product. The oily product is then washed with cold pentane to remove the impurities and obtain γ-butenyl 1-tosylate.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([NH:7][CH2:8][CH2:9][O:10][CH3:11])[CH3:6]>CCOCC>[CH3:11][O:10][CH2:9][CH2:8][N:7]([CH2:5][CH3:6])[C:1]([Cl:4])=[O:2]
Reactant: CCNCCOC
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Product: CCN(CCOC)C(=O)Cl
Temperature: 25 °C

Procedure:
To a stirred solution of 89.1 g. phosgene in 500 ml. dry ether at -20°C. was added a solution of 30.9 g. N-ethyl-N-2-methoxyethylamine in 50 ml. dry ether, whilst the temperature of the reaction mixture was maintained at -20°C. The stirred mixture was then allowed to warm to room temperature during 1 hour. The reaction mixture was filtered and the filtrate evaporated in vacuo below 25°C. to remove the solvent and give the product, N-(2-methoxyethyl)-N-ethylcarbamoyl chloride as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20]I)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[C:43]([NH2:51])(=[O:50])[C:44]1[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=1.C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:40][O:41][CH3:42])[C:8]([NH:10][CH:11]2[C:38](=[O:39])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH:18]=[CH:19][CH2:20][N+:47]4[CH:48]=[CH:49][C:44]([C:43](=[O:50])[NH2:51])=[CH:45][CH:46]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: NC(=O)c1ccncc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a stirred solution of diphenylmethyl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (IX-1) (E, 716 mg, 1 mmole) in dry DMSO (2 ml) was added isonicotinamide (244 mg, 2 mmoles). The mixture was stirred at room temperature for 1 hour and then poured into ethyl acetate (200 ml). The resulting precipitate was collected by filtration, washed well with ethyl acetate and dried. A stirred mixture of the quaternized material (400 mg) and sodium bisulfite (40 mg) in HCOOH (4 ml) was heated at 40°-50° C. for 1 hour, and evaporated to dryness under reduced pressure. The crude solid was dissolved in water (40 ml). After filtration of an insoluble material, the filtrate was chromatographed on a reverse phase column (packing of PrepPAK/C18, 100 ml) using water and 5%, 10%, 20% and 30% aqueous CH3OH as eluant. The fractions containing the desired compound were combined, evaporated and lyophilized to give 21 mg (3.8%) of the title compound (I-1H) (E) as a pale yellow powder. Mp. >180° C. (dec.).
Reaction SMILES: C(NC(C)C)(C)C.[Li].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[Br:17].C([O:22]O)(C)(C)C>O>[OH:22][C:15]1[C:10]([F:9])=[C:11]([Br:17])[CH:12]=[CH:13][C:14]=1[F:16]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OO
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: O
Product: Oc1c(F)ccc(Br)c1F
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A quantity of 40.2 ml of 2.0 M lithium diisopropylamine (LDA) is dissolved in 80 ml of TIF at −78° C. and 15.4 g of 2,4-difluorobromobenzene is added keeping the temperature below −65° C. The reaction is stirred at −65° C. for 2 hours and 6.6 ml of 6 M anhydrous t-butyl hydroperoxide is added. After warming at room temperature, 100 ml of water is added and the mixture acidified. The solvent is removed by evaporation and the aqueous layer extracted with ether. The extracts are dried and then concentrated to give the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([OH:18])[CH:16]=[CH2:17].C(N(CC)CC)C>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH2:16][CH:15]=[O:18])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C=CCO
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=CCCc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 166.1 %

Procedure:
In 3 mL of dimethylformamide, 50 mg (0.19 mmol) of 4-bromo-3-(trifluoromethyl)nitrobenzene was dissolved, and 33 mg (0.56 mmol) of allyl alcohol, 43 mg (0.19 mmol) of tetrabutylammonium bromide, 2.1 mg (5 mol %) of palladium acetate and 52 μL (0.37 mmol) of triethylamine were added thereto and the mixture solution was stirred in an argon atmosphere at 90° C. for two hours. The reaction solution was partitioned between water and ethyl acetate, and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The product was purified by a silica gel column (n-hexane:ethyl acetate=5:1) to obtain 78 mg (79%) of a target product as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29](O)=[O:30])=[CH:21]1.C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)Cl>CN(C=O)C>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:30])=[CH:21]1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1c[nH]c2ccccc12
Reaction time: 18 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (49.2 mg, 0.196 mmol), indole-3-carboxylic acid (37.9 mg, 0.235 mmol) and 1M DCC in CH2Cl2 solution (0.235 ml, 0.235 mmol) were mixed in DMF (2 ml) and the pH adjusted to 9.0 with triethylamino (32.7 μl, 0.235 mmol). The reaction was stirred 18 hrs. at 25° C., the DMF removed in vacuo, and the residue chromatographed on a Waters Semi-Prep C-18 30×0.9 cm column (gradient elution of 5 to 95% CH3CN in H2O) to give the title compound as a white solid from MeOH/ether: (m.p. 265°-268°).