Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:14]I)(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[Na].[K].[C:18]([OH:31])(=[O:30])/[CH:19]=[CH:20]/[C:21]1[CH:29]=[CH:28][C:26]([OH:27])=[C:23]([O:24][CH3:25])[CH:22]=1>>[CH3:8][O:7][C:6]1[CH:5]=[C:4](/[CH:3]=[CH:2]/[C:1]([CH2:14][O:31][C:18](/[CH:19]=[CH:20]/[C:21]2[CH:29]=[CH:28][C:26]([OH:27])=[C:23]([O:24][CH3:25])[CH:22]=2)=[O:30])=[O:13])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: COc1cc(/C=C/C(=O)CI)ccc1O
Agent: [K]
Agent: [Na]
Product: COc1cc(/C=C/C(=O)COC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O

Procedure:
Calebin-A (10a) was prepared by reacting feruloyliodomethane with sodium or potassium salt of ferulic acid with reaction steps and conditions maintained as mentioned in the general synthetic scheme discussed herein above in Para 0010. The yield of the product was 60%.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][CH2:15][O:14]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18]2)=[O:9])[N:22]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C(OCCC1OCCCO1)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCCC2OCCCO2)n1
Reaction time: 1 h

Procedure:
0.84 Gram of 2-(1,3-dioxan-2-yl)ethyl salicylate and 0.73 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was dissolved in 10 ml of N,N-dimethylformamide, and 0.51 g of anhydrous potassium carbonate was added thereto. The resulting solution was stirred at 100° to 110° C. for 1 hour. The reaction solution was allowed to cool, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 0.50 g of 2-(1,3-dioxan-2-yl)ethyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (V-1)].
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[O:29][CH3:30])=[O:20])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:31]>C(OC(C)C)(C)C>[ClH:31].[F:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH3:30])=[C:22]([NH:21][C:19]([NH:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)=[O:20])[CH:27]=1
Reactant: COc1ccc(F)cc1NC(=O)Nc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CC(C)OC(C)C
Product: COc1ccc(F)cc1NC(=O)Nc1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
A suspension of 6-[3-(5-fluoro-2-methoxy-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.20 g) obtained in Example (22a) and 4 N hydrochloric acid (1,4-dioxane solution, 10 mL) was stirred at room temperature for 15 hours and diluted with diisopropyl ether. The precipitate was collected by filtration and dried to obtain the title compound (1.20 g, 94%) as a light beige solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:28])[CH3:27])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:27][C:10]1([CH3:28])[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:11]1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (380.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (330.0 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH2:30]>C(#N)C>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1Cl

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3,4-dichlorobenzylamine and acetonitrile essentially as described above in example 18 except that the column is eluted using a graded solvent mixture of 40% ethyl acetate in heptane, to 100% ethyl acetate. Purity by LC/MS (APCI)=100%, [M+H]+=419.
Reaction SMILES: C1(C[NH:8][CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[O:13]1[C:12]2([CH2:17][CH2:18][CH:9]([NH2:8])[CH2:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC1CCC2(CC1)OCCO2
Reaction time: 20 h
Yield: 127.3 %

Procedure:
20% Palladium hydroxide (1.00 g) was carefully wetted down under nitrogen with methanol (50 mL) then N-(phenylmethyl)-1,4-Dioxaspiro[4.5]decan-8-amine (7.91 g) in methanol (50 mL) was added. The mixture was hydrogenated on a Parr shaker for 20 hours. Worked up by filtering off the catalyst under nitrogen through fiberglass filter paper. The filtrate was stripped to give 1,4-dioxaspiro[4.5]decan-8-amine (6.40 g) as an oily solid. Yield=100%. LCMS detects (M+H)+=158.1.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[CH:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCC=C1CCc2ccc3nc(C)oc3c21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)NCCC1=CCc2ccc3nc(C)oc3c21
Temperature: 100 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
N-[2-(2-Methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)ethyl]acetamide (63.5 mg, 0.248 mmol) was dissolved in toluene (2.5 mL), sulfuric acid (24.3 μL, 0.248 mmol) was added, and the mixture was stirred at 100° C. for 5 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (40.0 mg, yield 63%).
Reaction SMILES: FC(F)(F)OC1C=CC(CNC([C@H]2CNCCN2S(C2C=CC(OC(F)(F)F)=CC=2)(=O)=O)=O)=CC=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+].C(OC([N:71]1[CH2:76][CH2:75][N:74]([S:77]([C:80]2[CH:85]=[CH:84][C:83]([O:86][C:87]([F:90])([F:89])[F:88])=[CH:82][CH:81]=2)(=[O:79])=[O:78])[C@@H:73]([C:91](=[O:103])[NH:92][CH2:93][C:94]2[CH:99]=[CH:98][C:97]([CH2:100][CH2:101][CH3:102])=[CH:96][CH:95]=2)[CH2:72]1)=O)(C)(C)C.Cl.O1CCOCC1>CN(C)C=O.O1CCOCC1.O>[CH2:100]([C:97]1[CH:96]=[CH:95][C:94]([CH2:93][NH:92][C:91]([C@H:73]2[CH2:72][NH:71][CH2:76][CH2:75][N:74]2[S:77]([C:80]2[CH:85]=[CH:84][C:83]([O:86][C:87]([F:89])([F:90])[F:88])=[CH:82][CH:81]=2)(=[O:79])=[O:78])=[O:103])=[CH:99][CH:98]=1)[CH2:101][CH3:102]
Reactant: CCCc1ccc(CNC(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCN2S(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: CCCc1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
To a solution of the compound (6.65 g) obtained in Example 783, Step 2,4-propylbenzylamine (3.26 g) and 1-hydroxybenzotriazole hydrate (2.69 g) in N,N-dimethylformamide (33 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.37 g). After stirring overnight at room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added under ice-cooling, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product (7.40 g). This was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give a crude product containing (R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a main component. The obtained crude product was dissolved in 1,4-dioxane (40 ml), 4N hydrogen chloride/1,4-dioxane solution (50 ml) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. Further, 4N hydrogen chloride/1,4-dioxane solution (20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium carbonate, filtrated, and concentrated under reduced pressure to give a crude product (3.70 g) containing the title compound as a main component. The residue was crystallized from a mixed solvent of diisopropyl ether and n-hexane, and collected by filtration. The obtained crude crystals were suspended in diisopropyl ether, collected by filtration and dried to give the title compound (3.0 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]O)=[CH:30][CH:29]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:35][CH2:34][C:31]1[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=1
Reactant: Oc1ccccc1I
Reactant: OCCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccccc1OCCc1ccncc1
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A stirred solution of 2-iodophenol (8.8 g, 0.040 mole), triphenylphosphine (10.5 g, 0.040 mole) and 2-(4-pyridyl)ethanol (D65, 5.5 g, 0.045 mole) in THF (200 ml) at 0° C. under argon was treated with a solution of diethyl azodicarboxylate (6.3 ml, 0.040 mole) in THF (30 ml). The solution was allowed to warm to room temp. and stirred for 4 h, then concentrated in vacuo and the residue treated with 10% Na2CO3 solution (80 ml) and extracted with ethyl acetate (2×80 ml). The combined organic was extracted with 1M HCl acid (150 ml), then the acid extract basified by addition of potassium carbonate and extracted with ethyl acetate (2×100 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo to leave a brown oil, which was chromatographed on silica gel eluting with 0 to 15% ethyl acetate/ether to afford the title compound as a colourless oil (9.3 g, 72%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[CH:8][O:7][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:12][O:11][C:5]1[C:6]2[O:7][CH:8]=[CH:9][C:10]=2[C:2]([O:1][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(O)c2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(OC)c2occc12

Procedure:
A mixture of 4-hydroxy-7-methoxybenzo[b]furan (2.0 g, 12.2 mmol; prepared according to Eur. J. Med. Chem. 1981, 16, 563), ethyl bromoacetate (2.2 g, 13.2 mmol), potassium carbonate (2.0 g, 14.5 mmol) and 2-butanone (50 mL) was refluxed for 10 h, then filtered and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, chloroform) affording ethyl (7-methoxybenzo[b]furan-4-yloxy)acetate.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH3:31])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([S:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([N+:28]([O-])=O)[CH:21]=1)[N:6]=2)[CH3:2]>ClCCl.CO.[Pd]>[NH2:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][S:18][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH3:31])=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=1
Reactant: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c([N+](=O)[O-])c3)nc2n1C
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c(N)c3)nc2n1C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
8-ethyl-9-methyl-6-morpholino-2-(3-nitro-4-methoxybenzylsulfanyl)-9H-purine (4.10 g, 9.23 mmol) was dissolved in dichloromethane (50 ml) and methanol (50 ml), 1.0 g of Pd/C was added and catalytic hydrogenation was performed under normal pressure for 18 hours. Celite was used to filter off Pd/C, and the filtrate was distilled away under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to obtain 2.74 g (72% yield) of 2-(3-amino-4-methoxybenzylsulfanyl)-8-ethyl-9-methyl-6-morpholino-9H-purine.
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.FC1C=CC(P(=O)(C2C=CC(F)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+]([C:49]1[CH:50]=[C:51]([C:57]#[N:58])[C:52](=[CH:55][CH:56]=1)[C:53]#[N:54])([O-])=O.Cl>CN(C)C=O.C1(C)C=CC=CC=1>[C:57](#[N:58])[C:51]1[C:52](=[CH:55][CH:56]=[CH:49][CH:50]=1)[C:53]#[N:54]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C#N
Temperature: 140 °C
Yield: 344.6 %

Procedure:
To a 100 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added bisphenol A (5.00 g, 21.9 mmol), bis(4-fluorophenyl)phenylphosphine oxide (3.49 g, 11.1 mmol), powdered anhydrous K2CO3 (7.55 g, 54.7 mmol), toluene (10 mL), and N,N-dimethylformamide (DMF) (40 mL). The resulting mixture was degassed with argon at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 135-145° C. under an argon atmosphere for 12 to 18 h or until no more water was observed being collected by azeotropic distillation in the Dean-Stark trap. FTIR spectroscopy was used to confirm and to monitor the formation of the desired oligomeric product. The toluene was then removed by distillation and the reaction mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (3.87 g, 22.4 mmol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into 300 mL of a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was dissolved in chloroform (200 mL) and washed with 200 mL of a 5% aqueous KOH solution, with 200 mL of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL of water until neutral. The solvent was removed in vacuo and the solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile (9.89 g, 91%). 1H-NMR (300 MHz, CDCl3): δ 7.61-7.52 (m, aromatic-H), 7.43-7.31 (m, aromatic-H), 7.34-7.19 (m, aromatic-H), 7.02-6.92 (m, aromatic-H), 1.75-1.66 (m, CH3). IR [cm−1]: λ3058 (C═CH), 2969 (CH3), 2231 (CN), 1589 (C═C), 1491 (aromatic), 1281 (CH3), 1248 (C—O), 1173 (C—O), 1117, (P═O), 970 (C—O), 834 (aromatic).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][O:13]1.I[CH3:29]>C1COCC1>[O:11]=[C:12]1[NH:16][C@@H:15]([C@@H:17]([CH3:29])[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][O:13]1
Reactant: CI
Reactant: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OCc1ccccc1)[C@H]1COC(=O)N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (1M in THF; 68.0 mL) under argon atmosphere was added THF (40.4 mL). The mixture was cooled to −78° C. and a solution of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (7.80 g, 33.2 mmol) in THF (85 mL) was added slowly over ˜15 min. The mixture was stirred for 1 hr at −78° C. and a solution of iodomethane (4.25 mL, 68.0 mmol) in THF (40.4 mL) was added slowly over ˜10 min. The reaction mixture was stirred for 1 hr at −78° C. and ˜1 hr at −40° C. The mixture was quenched with saturated aqueous ammonium chloride solution (˜100 mL) and allowed to warm to room temperature. The mixture was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane] to provide (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (7.47 g) as a colorless oil. MS m/z 250.1 (M+H)+; Rt-0.65 min. 1H NMR (400 Mhz, DMSO-d6) δ ppm 7.85 (s, 1H), 7.44-7.28 (m, 5H), 5.10 (s, 2H), 4.36 (t, J=1.0 Hz, 1H), 4.11 (dd, J=5.4, 8.9 Hz, 1H), 4.06-3.98 (m, 1H), 2.69 (quin, J=6.9 Hz, 1H), 1.08 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].N1CCCC1.[C:20]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O>C1(C)C=CC=CC=1>[OH:14][C:5]1[CH:6]=[CH:7][C:8]2[C:11](=[O:12])[CH2:13][C:23]([CH2:22][CH2:21][C:20]([O:27][CH2:28][CH3:29])=[O:26])([CH3:25])[O:10][C:9]=2[C:4]=1[CH2:3][CH2:2][CH3:1]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2=O

Procedure:
A solution of 58.0 g (0.299 mole) of 2,4-dihydroxy-3-propylacetophenone and 29.5 ml (0.36 mole) of pyrrolidine in 250 ml of toluene was heated to reflux for three hours under a Dean-Stark trap. After cooling the mixture, 68.2 ml (0.48 mole) of ethyl levulinate was added and the mixture was refluxed for two hours. An additional 10 ml (0.12 mole) of pyrrolidine was added and the mixture was refluxed overnight under a Dean-Stark trap.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1([S:14]([N:17]2[C:21]3=[N:22][CH:23]4[N:29]([CH3:30])[CH:28]=[N:27][CH:24]4[C:25]([Cl:26])=[C:20]3[N:19]([C:31]3[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=3[F:38])C2=O)(=[O:16])=[O:15])[CH2:13][CH2:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+]>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1([S:14]([NH:17][C:21]2[C:20]([NH:19][C:31]3[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=3[F:38])=[C:25]([Cl:26])[CH:24]3[N:27]=[CH:28][N:29]([CH3:30])[CH:23]3[N:22]=2)(=[O:16])=[O:15])[CH2:13][CH2:12]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN1C=NC2C(Cl)=c3c(n(S(=O)(=O)C4(CCO[Si](C)(C)C(C)(C)C)CC4)c(=O)n3-c3ccc(I)cc3F)=NC21
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1C=NC2C(Cl)=C(Nc3ccc(I)cc3F)C(NS(=O)(=O)C3(CCO[Si](C)(C)C(C)(C)C)CC3)=NC21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(1-(2-(tert-butyldimethylsilyloxy)ethyl)cyclopropylsulfonyl)-8-chloro-1-(2-fluoro-4-iodophenyl)-5-methyl-3,4a,5,7a-tetrahydrodiimidazo[4,5-b:4′,5′-e]pyridin-2(1H)-one (86 mg, 0.124 mmol) in THF (5 ml) is added potassium trimethylsilanolate (80 mg, 0.62 mmol). The resulting solution is stirred at room temperature for 24 h. The reaction is quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution is washed with brine (10 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]12[CH2:19][C:10]1([C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[N:9]1[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:8]1[S:7]2>ClCCl>[CH3:5][CH:6]1[CH:19]=[C:10]([C:11]([O:13][CH2:14][C:15]([Cl:16])([Cl:17])[Cl:18])=[O:12])[N:9]2[C:20](=[O:32])[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:8]2[S:7]1
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Temperature: 25 °C
Reaction time: 7 h
Yield: 26.1 %

Procedure:
Aluminum chloride (2.66 g.) was added under ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylate (9.2 g.) in dried dichloromethane (100 ml.) and the mixture was stirred for 7 hours at room temperature. After the reaction, the reaction mixture was washed in turn with 2% hydrochloric acid three times, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was purified by column chromatography on silica gel (200 g.) using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (2.4 g.), mp 175° to 178° C.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[P:25](=O)([OH:28])([OH:27])[OH:26]>>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:25]([OH:28])([OH:27])=[O:26])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=P(O)(O)O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(P(=O)(O)O)CC3)c(F)cc2c1=O

Procedure:
To a stirred solution of 2.34 g of the product of Example 40 in 25 ml of methylene chloride under argon was added 2.57 g of N,O-bis(trimethylsilyl)triflouroacetamide and then (after 10 minutes) 2.68 g of bromotrimethylsilane. After 17 hours, the solution was evaporated to dryness at 40° C./0.02mm. The evaporation was then repeated twice after redissolving the residue in 25 ml portions of methylene chloride. A solution of the residual solid in 25 ml of methylene chloride was added to a stirred solution of 1 ml of water in -00 ml of acetone and then stirred for 15 minutes, to hydrolyze silyl ester groups. The resulting solid was collected and washed with acetone to give 2.24 g of cream-colored solid, m.p. 246°-252° (dec.); 31P-NMR (in DMSO with 5% triethylamine) δ 9.34 compared to δ 0.54 (at 50° C.) for a salt of ciprofloxacin with an equimolar amount of phosphoric acid, and δ0 0.35 for phosphoric acid. The product was soluble in 0.1 M phosphate buffer, pH 7.5, unlike ciprofloxacin.