Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.C[O:23]B(OC)OC.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:5]=[CH:6][C:7]=1[OH:23]
Reactant: COB(OC)OC
Reactant: CCCc1ccc(-c2cccc(F)c2)cc1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCCc1ccc(-c2ccc(O)c(F)c2)cc1
Temperature: -74 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
In a nitrogen atmosphere, 44.32 g of 3-fluoro-1-(4-propylphenyl)benzene was dissolved in 220 mL of THF, the resultant solution was cooled to −74° C., and 210 mL of secondary butyl lithium (1.0 mol/L, hexane solution) was added at such a rate that the inside temperature did not exceed −60° C. After stirring at −74° C. for 1 hour, 23.64 g of trimethoxyborane was added at such a rate that the inside temperature did not exceed −60° C. After stirring at −74° C. for 1 hour, the inside temperature was increased to room temperature, and 10% hydrochloric acid was added until the system became acidic. Then, an organic layer was separated, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and cooled with ice, and 54 g of a 15% aqueous hydrogen peroxide solution was added to the mixture, followed by stirring under ice cooling for 3 hours. Further, an organic layer was separated, and an aqueous layer was subjected to extraction with toluene. The toluene extract was combined with the organic layer and washed with a 10% aqueous sodium sulfite solution and saturated brine. The organic layer mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to yield 41.01 g of 2-fluoro-4-(4-propylphenyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](Cl)(Cl)[Cl:10])=[CH:4][N:3]=1.C(O)(=O)C>[Zn].CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][Cl:10])=[CH:4][N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: ClCc1cnc(Cl)c(Cl)c1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
2,3-dichloro-5-trichloromethylpyridine (36.60 g, 0.139 mol) was added to a flask containing acetic acid (53.50 g, 0.892 mol) and methanol (200 mL). The mixture was cooled to −5° C., and zinc dust (20.01 g, 0.308 mol) was added in small portions at 10 minute intervals. The mixture was stirred mechanically for 4 hours, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with brine, followed by saturated aqueous sodium bicarbonate, followed by a second brine wash. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield 21.55 g (79%) of Preparatory Compound P, 2,3-dichloro-5-(chloromethyl)pyridine, as a yellow liquid (about 65% purity). 1H NMR δ 8.31 (d, 1H, J=2.3 Hz), 7.85 (q, 1H, J=0.4 Hz and J=2.2 Hz), 4.56 (s, 2H). MS (ESI) m/z 199 ([M+4]+, 8), 197 ([M+2]+, 27), 195 ([M]+, 28), 164 (11), 162 (66), 160 (100), 124 (19)
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:8]2[CH2:9][CH2:10][C:11](=[O:12])[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][C:6]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:7]2=3)=[CH:26][CH:25]=1
Reactant: O=CCc1ccc(Cl)cc1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (50.0 mg, 0.203 mmol) from Example 1 in dichloroethane (2 ml) at 0° C. was added acetic acid (0.035 ml, 0.609 mmol), 2-(4-chlorophenyl)acetaldehyde (47.0 mg, 0.304 mmol) prepared as above and sodium triacetoxyborohydride (129.0 mg, 0.609 mmol). The mixture was stirred overnight at room temperature and then sodium bicarbonate was added followed by extraction with dichloromethane. The organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (pentane/ethyl acetate: 1/1) of the obtained residue gave the desired compound as a yellow oil (59 mg, 76%).
Reaction SMILES: [N:1]([C:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=1)=[N+]=[N-].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:26]1([P:19](=[N:1][C:4]2[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH:5]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC1OC(=O)C=C1N=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC1OC(=O)C=C1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 65 °C
Yield: 44.6 %

Procedure:
A solution of 4-azido-5-ethoxy-5H-furan-2-one (0.17 g, 1.0 mmol) and triphenylphosphine (0.26 g, 1.0 mmol) in toluene (5 mL) at room temperature under nitrogen was stirred for 1 h, then heated at 60-70° C. for 8 h. The reaction was cooled, was diluted with ethyl acetate, was washed with sodium bisulfate, sodium bicarbonate and brine, was dried over sodium sulfate and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes afforded 4-[(triphenylphosphoranylidene)amino]-5-ethoxy-5H-furan-2-one (0.18 g, 45% yield) as an off-white solid. 1H-NMR (500 MHz, CDCl3) δ 7.73 (m, 6H), 7.65 (m, 3H), 7.55• (m, 6H), 5.58 (s, 1H), 4.33 (s, 1H), 3.81 (m, 1H), 3.64 (s, 1H), 1.27 (t, J=7.1 Hz, 3H) ppm. MS (ES+) m/e=404 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cccc(Cl)c1
Yield: 92.3 %

Procedure:
Prepared according to the procedure described for Example 121 using 3-chlorobenzenesulfonyl chloride (2.27 g, 10 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10.0 mmol) to afford the product (3.846 g); m.p. 197-199° C.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:33].[Na+].O>CC(C)=O>[CH2:26]([O:25][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:14][CH2:13][CH2:12][I:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OCCCC(COc2ccc(F)cc2)OCc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Fc1ccc(OCC(CCCI)OCc2ccccc2)cc1
Yield: 79.7 %

Procedure:
A solution of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentanol tosylate (3.78 g., 8.24 mmoles) and sodium iodide (3.71 g., 25 mmoles) in acetone (70 ml.) is stirred at room temperature overnight (ca. 17 hours) and then heated on the steam bath for 15 minutes. The mixture is poured into cold water and extracted with ether three times. The combined extracts are washed with aqueous sodium thiosulfate and dried over anhydrous magnesium sulfate. The solvent is removed on a rotary evaporator to leave an oil residue which is further purified by chromatography on a silica gel (70 g.) column. Elution with chloroform gives the pure title compound (2.72 g., 6.57 mmoles, 79%). ir (neat) 3.28, 3.40, 6.20, 6.62, 6.87, 8.00, 8.23, 9.10, 12.07, 13.16, 13.58, 14.37μ; pmr (CCl4)δ1.4-2.2 (4H, m), 3.08 )2H, t, J=6Hz), 3.5-4.1 (3H, m), 4.47 (1H, d, J=12 Hz), 4.69 (1H, d, J=12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH3:12].[CH2:14]1COCC1.C[Li].Cl>CCOCC>[C:11]([C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])([CH3:12])=[CH2:14]
Reactant: COc1ccc(C(C)=O)c(OC)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li]C
Solvent: CCOCC
Product: C=C(C)c1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.57 g of 1-(2,4-dimethoxyphenyl)ethanone are dissolved in 100 ml of ether and 50 ml of THF under nitrogen. 55 ml of 1.6M methyllithium in ether are added at −50° C. and the mixture is left stirring for 2 hours between −60° C. and −40° C. and then for 30 minutes between −40° C. and 0° C. and for 3 hours at RT. It is cooled to 0° C. and 70 ml of 2N HCl are added. After separation of the phases by settling, the aqueous phase is extracted with ether and the organic phase is then dried over Na2SO4. This solution is concentrated and the residue is then taken up in 150 ml of THF and 75 ml of 2N HCl are added. After stirring for 4 hours at RT, 100 ml of water are added and this mixture is then extracted with ether. The organic phase is washed with Na2CO3, with water and then dried over Na2SO4 and concentrated. The residue is chromatographed on silica, eluting with a DCM/pentane mixture (70/30 and then 60/40). 5 g of the expected compound are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[OH:13])[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CO>[N+:10]([C:6]1[C:5]2[O:13][CH:2]([CH2:3][OH:19])[CH2:1][C:4]=2[CH:9]=[CH:8][CH:7]=1)([O-:12])=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1cccc2c1OC(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
To a solution of 2-nitrophenol (13.9 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added with sodium hydride (4.2 g, 100 mmol 60%) followed by allyl bromide (13.3 g, 110 mmol) and the reaction was allowed to stir at room temperature for 2 hours The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 1-(allyloxy)-2-nitrobenzene. The oil was re-dissolved in mesitylene (500 mL) and heated at reflux for 3 d. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, dichloromethane:hexanes 0.5:9.5) provided 6.8 g, (50%) of 2-allyl-6-nitrophenol as a yellow oil. To a solution of 2-allyl-6-nitrophenol (6.6 g, 36.84 mmol) in dichloromethane (300 mL) was added 3-chloroperoxybenzoic acid (77%, 16.5 g, 73.67 mmol) The reaction mixture was allowed to stir at room temperature for 8 h. The reaction mixture was washed with a 1:1 solution of 10% sodium sulfite:saturated sodium bicarbonate (2×300 mL). The solvent was removed in vacuo to give crude yellow oil. The oil was diluted with methanol (300 mL) and added to a solution of potassium carbonate (15.0 g, 108.5 mmol) the solution was allowed to stir at room temperature 2 h. The solvent was removed in vacuo. The residue was washed with water (1000 mL) and ethyl acetate (500 mL). The aqueous layer was acidified with 1 N aqueous hydrogen chloride and washed with ethyl acetate (500 mL). The combined organics were washed with water (500 mL), saturated aqueous sodium chloride (500 mL), dried (magnesium sulfate) and the solvent removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, dichloromethane:hexanes 4:10) provided 3.18 g (44%) of (±)-(7-nitro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow solid. mp 63-65° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[O:3]1.F[B-](F)(F)F.[O:25]=[N+:26]=[O:27]>C(#N)C>[CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([N+:26]([O-:27])=[O:25])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: Cc1cccnc1C1CC(C)(C)Oc2ccccc21
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: Cc1cccnc1C1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Yield: 46.4 %

Procedure:
685 mg of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were dissolved in 20 ml of acetonitrile at room temperature and 360 mg of nitronium tetrafluoroborate were added. After 30 minutes the solvent was removed by evaporation and ethyl acetate and water were added. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution. There were obtained 374 mg of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl) -6-nitro-2H-1-benzopyran in the form of a solid of melting pOint 164-165° C. after recrystallization from t-butyl methyl ether.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[O-])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:25])(=[O:36])=[O:35])=[CH:32][CH:33]=1)#[N:27]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C#N)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-cyanobenzenesulfonamide. MS (ESI) m/z 500 [M+H]+, 498 [M−H]−, 1H-NMR (DMSO-d6) δ 1.14 (3H, t, J=7.5 Hz), 2.61 (2H, q, J=7.5 Hz), 2.72 (2H, t, J=7.1 Hz), 3.10-3.30 (2H, m), 6.60 (1H, br), 7.19 (1H, t, J=7.1 Hz), 7.28-7.39 (6H, m), 7.70 (1H, s), 7.78 (2H, d, J=7.1 Hz), 8.00-8.08 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[CH:34]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][C@@H:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:37]([CH:34]2[CH2:36][CH2:35]2)[C:38]1=[O:39])(=[O:9])=[O:10]
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: O=C=NC1CC1
Agent: [I-]
Agent: [Na+]
Product: O=C([C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1C1CC1)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (example 72, step 3) was reacted with sodium iodide and cyclopropylisocyanate to give the title compound as a colorless foam. MS: 557.6 ([M+H]+)
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:15])=[O:14])=[CH:10][C:4]=2[O:3]1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:15]=[C:13]([CH:12]=[CH:11][C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:16])[O:3][C:4]=3[CH:10]=2)[O:14][CH:21]=1
Reactant: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: FC1(F)Oc2ccc(C=Cc3nc(CCl)co3)cc2O1

Procedure:
6.90 g (30.4 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide, 4.76 g (37.5 mmol) 1,3-dichloro acetone and 50 ml toluene were kept at reflux temperature for 48 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was treated with 60 ml of a 1:1 mixture of water/isopropanol. After filtration the precipitate was washed first with isopropanol, then with heptane. Drying at 40° C. in vacuo gave 4-Chloromethyl-2-[2-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-vinyl]-oxazole.
Reaction SMILES: C([Mg]Cl)(C)C.C1COCC1.I[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.[CH2:19]([O:21][Si:22](OCC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:20]>CCOCC>[CH2:19]([O:21][Si:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1)[CH3:20]
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Ic1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 61.1 %

Procedure:
Firstly, 2-M i-PrMgCl (24 mL (solvent: THF, 48 mmol) was added dropwise to a mixture of 1,4-diiodobenzene (15 g, 45.6 mmol) and dist. THF (114 mL) at −30° C. Then the resultant mixture was stirred under a nitrogen atmosphere at −30° C. for 5.5 hours to obtain a reaction solution. Subsequently, the reaction solution was added dropwise (3 drops/second) using a cannular into a mixture of tetraethoxysilane (TEOS: 60.6 mL, 272 mmol) and dist. THF (90 mL), which was cooled to −30° C. The resultant mixture was stirred at −30° C. for 1 hour, and then was stirred at room temperature for 44 hours to obtain a reaction mixed solution. Thereafter, the obtained reaction mixed solution was added with ether (100 mL), and then was washed with distilled water (dist. H2O). After that, an aqueous layer was extracted with ether. Then, an organic layer thus collected was washed with sat. NaCl, and was dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. Subsequently, the obtained crude product was purified by a reduced-pressure distillation process (1.5 mmHg, 120° C.) to obtain 4-(triethoxysilyl)iodobenzene (10.2 g, 61% yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:25]/[O:26][CH2:27][CH3:28])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[Na+].[C:30]([CH2:33][S:34][CH2:35][CH2:36][N:37]1[C:41]([SH:42])=[N:40][N:39]=[N:38]1)(=[NH:32])[NH2:31]>CN(C=O)C>[C:30]([CH2:33][S:34][CH2:35][CH2:36][N:37]1[C:41]([S:42][CH2:18][C:15]2[CH2:16][S:17][C@@H:12]3[C@H:11]([NH:10][C:8](=[O:9])/[C:7](/[C:4]4[N:3]=[C:2]([NH2:1])[S:6][N:5]=4)=[N:25]\[O:26][CH2:27][CH3:28])[C:23](=[O:24])[N:13]3[C:14]=2[C:20]([OH:22])=[O:21])=[N:40][N:39]=[N:38]1)(=[NH:31])[NH2:32]
Reactant: N=C(N)CSCCn1nnnc1S
Reactant: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1nsc(N)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCSCC(=N)N)CS[C@H]12)c1nsc(N)n1
Temperature: -20 °C
Yield: 31.6 %

Procedure:
To a solution of sodium 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-ethoxyiminoacetamido]-3-hydroxymethyl-3 -cephem-4-carboxylate (360 mg) and 1-(2-amidinomethylthioethyl)-5-mercapto-1H-tetrazole (262 mg) in 8 ml of DMF was added 1.0 g of ethyl o-phenylenephophate under stirring at -20° C. After stirring under ice-cooling for 1.5 hours, the reaction mixture was subjected to a column chromatography (silica gel, 100 g), being washed with acetonitrile and eluted with acetonitrile/water (4:1). The eluate was concentrated under reduced pressure and then subjected to a column chromatography (XAD-II, 150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and lyophilized to give 159 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]([NH:4][CH:5]([O:16][CH2:17][CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)Br.O([C:25]1[CH:30]=CC=[CH:27][CH:26]=1)[Na]>>[C:1]([NH:4][CH:5]([O:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:30][CH:18]=1)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: [Na]Oc1ccccc1
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Agent: BrB(Br)Br
Product: CC(=O)NC(Oc1ccccc1)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (3.00 g, 12.0 mmol), BBr3 (1M in CH2Cl2, 15.0 mL, 15.0 mmol), and NaOPh (4.18 g, 30 mmol) gave a brown oily residue which was purified by flash column chromatography on SiO2 gel using first CHCl3 and then 2% MeOH/CHCl3 as the eluents to give the desired product. The compound was recrystallized from chloroform/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:25]1CCN2C(=NCCC2)CC1.IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH3:25])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Product: COC1=CC(=O)OC(CCc2ccc(OC)c(Cl)c2)(C2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of 6-[2-(3-Chloro-4-methoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (60 mg, 0.17 mmol) from Example B(87), dissolved in DMF (1.5 mL), were added DBU (0.028 mL, 0.188 mmol) and iodomethane (0.011 mL, 0.17 mmol). The reaction was stirred at room temperature overnight, and then was quenched with water. The reaction was extracted with EtOAc, and the organic layers were combined. After washing with saturated NaCl, the organic layer was dried over Na2SO4. The solids were removed by filtration, and the liquid was concentrated by rotary evaporation. Purification by preparatory HPLC gave the desired product (8.2 mg, 13% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:15]=[O:16])=[CH:4][C:3]=1[CH:9]1[O:10][CH2:11][CH2:12][O:13]1
Reactant: Nc1ccc(Cl)c(C2OCCO2)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C=Nc1ccc(Cl)c(C2OCCO2)c1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
2.0 g of 4-chloro-3-(1,3-dioxolan-2-yl)-aniline in 25 ml of ethyl acetate were added to a solution of 3.0 g of trichloromethyl chloroformate in 50 ml of toluene at about 20-25° C. This mixture was stirred for 2 hours at 20-25° C. and then for a further 5 hours at the reflux temperature. Thereafter, the reaction mixture was evaporated down and the residue was dried under greatly reduced pressure.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[OH:14][C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]>ClCCl>[CH3:10][O:11][CH2:12][O:14][C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)C(C)(C)O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(C)(C)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N,N-diisopropylethylamine (131 ml) and chloromethyl methyl ether (57 ml) in dichloromethane (50 ml) was added under ice-cooling to a solution of 3-hydroxy-3-methyl-2-butanone (52.6 ml) in dichloromethane (450 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous solution (250 ml×2) of 10% citric acid, a saturated aqueous solution (200 ml) of NaHCO3 and saturated brine (200 ml), and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was distilled under atmospheric pressure to give 53.6 g of the title compound (bp=155°-165° C.) as a colorless liquid (see Table 5).