Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)CCC>>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-tributylstannyl pyridine as in Example 39 to afford 0.085 g (36%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C28H21NO4F4 512.1485, found 512.1487.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:13][C:14]([O:16]CC)=[O:15])[OH:12].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2([CH2:13][C:14]([OH:16])=[O:15])[OH:12]
Reactant: CCOC(=O)CC1(O)CCc2c(F)cc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1(O)CCc2c(F)cc(F)cc21

Procedure:
A mixture of ethyl 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetate (12.0 g 0.047 mol) and 1.0N sodium hydroxide (48 mL, 0.048 mol, Universal Scientific Supply Co.) in ethanol (75 mL) was stirred for 18 h at ambient temperature. The reaction mixture was concentrated in vacuo, diluted with water and washed with diethyl ether. The aqueous phase was neutralized with 1.0N hydrochloric acid (48 mL, 0.048 mol, Universal Scientific Supply Co.) and extracted with diethyl ether. The diethyl ether extract was dried over sodium sulfate, filtered and concentrated in vacuo to give a quantitative yield of crude 2-(4,6-difluoro-1-hydroxy-1-indanyl)acetic acid. This material was used immediately without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:16])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:24]1[CH2:29][CH2:28][O:27][C:25]1=[O:26]>CN(C)C=O>[C:1]([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH:24]2[CH2:29][CH2:28][O:27][C:25]2=[O:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1OCCC1Br
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1CCOC1=O

Procedure:
51 g. of Methyl 4-acetylamino-5-chloro-2-hydroxybenzoate and 36.8 g. of anhydrous potassium carbonate were suspended in 350 ml. of N,N-dimethylformamide. To the suspension was added 55 g. of α-bromo-γ-butyrolactone, and the mixture was stirred at 60° C. for 12 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to remove the solvent. The residue was dissolved in chloroform, and subjected to column chromatography on silica gel, using chloroform as the eluent. The product was recrystallized from methanol. By the above procedure there was obtained α-[(5-acetylamino-4-chloro-2-methoxycarbonylphenyl)oxy]-γ-butyrolactone as pale yellow prisms, m.p. 118°-119° C.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([S:28]([NH:31][C@H:32]3[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[C:33]3=[O:41])(=[O:30])=[O:29])=[CH:25]2)=[CH:20][CH:19]=1.[NH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][C:48]=1[NH2:49]>C1COCC1.CN(C=O)C>[NH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][C:48]=1[NH:49][C:38](=[O:39])[CH2:37][N:34]1[CH2:35][CH2:36][C@H:32]([NH:31][S:28]([C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH:25]=2)(=[O:29])=[O:30])[C:33]1=[O:41]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(CC(=O)O)C3=O)cc2c1
Reactant: Nc1ccncc1N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(CC(=O)Nc4ccncc4N)C3=O)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and isobutyl chloroformate (0.18 g, 1.3 mmol) are added to a solution of [3-(S)-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxopyrrolidin-1-yl]-acetic acid (0.5 g, 1.3 mmol) in THF (15 mL) at −10° C. The mixture is stirred for 20 minutes then treated with a solution of 3,4-diaminopyridine (0.16 g, 1.5 mmol) in DMF (5 mL). The resulting mixture is warmed to room temperature and stirred for 3 hours. The reaction mixture is concentrated in vacuo, then diluted with methylene chloride. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (5-8% MeOH/CH2Cl2). to give the title compound (0.27 g, 0.58 mmol) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)[C:16](Cl)=[S:17])C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:16]=[S:17]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CCN(CC)C(=S)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(N=C=S)c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
In 500 ml of toluene was dissolved 82.5 g of ethyl m-aminobenzoate. While stirring the solution at room temperature, 83.4 g of N,N-diethylthiocarbamoyl chloride was added dropwise to the solution over a period of about 1 hour and then the mixture was refluxed for 5 hours. The toluene was distilled off under reduced pressure, the residue thus formed was dissolved in 300 ml of ethyl acetate, and the ethyl acetate solution was washed with water. Then, ethyl acetate was distilled off under reduced pressure and the residue was further subjected to distillation under reduced pressure to provide 80 g of oily ethyl m-isothiocyanatobenzoate having a boiling point of 125° C./0.6 mm Hg at a yield of 77%.
Reaction SMILES: N(=[C:3]1[C:9]([CH3:11])([CH3:10])[CH:8]2[C:5]([CH3:13])([CH2:6][CH:7]2[OH:12])[CH2:4]1)O.C(COC)[O:15]C>O.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:13][C:5]12[CH2:6][CH:7]([OH:12])[CH:8]1[C:9]([CH3:11])([CH3:10])[C:3](=[O:15])[CH2:4]2
Reactant: CC12CC(=NO)C(C)(C)C1C(O)C2
Reactant: COCCOC
Agent: [Ti+3]
Agent: [Cl-]
Solvent: O
Product: CC12CC(=O)C(C)(C)C1C(O)C2
Reaction time: 0.5 h

Procedure:
To a solution of 600 mg of the oxime (V) in a mixture of 10 ml of dimethoxyethane and 5 ml of water, was added 6 ml of 16% titanium trichloride and the mixture was kept at 50° to 60° C. for 30 minutes under an argon atmosphere. After cooling, the mixture was admixed with 20 ml of water and extracted with methylene chloride. The extract was washed with an aqueous sodium bicarbonate solution, then with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 425 mg of an oil. This oil was chromatographed over silica gel to give 305 mg of an oil (IV): nD20 1.4787; MS: m/e 168 (M+).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1>C(O)C>[BrH:1].[S:18]1[CH:19]=[CH:20][N:21]2[CH:2]=[C:3]([C:5]3[CH:6]=[C:7]([OH:15])[C:8]([OH:14])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=3)[N:16]=[C:17]12
Reactant: Nc1nccs1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: Br
Product: O=[N+]([O-])c1cc(-c2cn3ccsc3n2)cc(O)c1O
Temperature: 25 °C

Procedure:
A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.01 g of 2-aminothiazole and 40 ml of ethanol is heated to boiling under reflux for 23 hours. The reaction mixture is then cooled to room temperature and the crystals are removed by filtration under suction. There is obtained 5-(imidazo[2,1-b]thiazol-6-yl)-3-nitropyrocatechol hydrobromide of m.p. 286°-288° (from methanol).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[C:23]2[C:22](=O)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.P([O-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>>[C:4]1([C:1]2[N:10]=[C:11]3[C:23]4=[C:22]([C:21]5[C:16]([C:15]4=[CH:14][CH:13]=[CH:12]3)=[CH:17][CH:18]=[CH:19][CH:20]=5)[CH:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc2c1C(=O)c1ccccc1-2
Reactant: CC(=O)c1ccccc1
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Product: c1ccc(-c2cc3c4c(cccc4n2)-c2ccccc2-3)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
In a round-bottomed flask, 9.0 mmol of acetophenone, 3.0 mmol of 1-amino-9-fluorenone (manufactured by Aldrich), and 1.5 mmol of diphenyl phosphate were placed, and the resultant mixture was irradiated with microwave (2,450 MHz) for 10 minutes under argon atmosphere. The reaction solution was cooled to room temperature, concentrated, and then separated and purified by silica gel column chromatography (eluant: dichloromethane and methanol), to give 2-phenylindeno[1,2,3-de]quinoline. The isolation yield was 45%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[N:21]>CC(C)=O>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[O:11][CH2:19][C:20]#[N:21]
Reactant: COc1cc(I)c(O)cc1I
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(I)c(OCC#N)cc1I
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
2,5-Diiodo-4-methoxy-phenol (2.8 g, 7.5 mmol) and potassium carbonate (2.1 g) were added to 30 mL of stirring acetone at room temperature and under nitrogen. Bromoacetonitrile (0.575 mL, 8.25 mmol) was added, and the reaction mixture was heated to 60° C. and stirred under nitrogen for 8 hours, then stirred for 18 hours under nitrogen at room temperature. The reaction mixture concentrated under reduced pressure, and the residue was poured into water and extracted into EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on 150 g of flash silica (5%-20% EtOAc/hexanes) to give 2.86 g of (2,5-Diiodo-4-methoxy-phenoxy)-acetonitrile, MS (M+H)=416.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][CH2:27][P:28](=[O:35])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31]>CN(C=O)C>[CH2:33]([O:32][P:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][CH:3]=1)([O:29][CH2:30][CH3:31])=[O:35])[CH3:34]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-hydroxyphenethylcarbamate (1 eq) in DMF (0.17 M) was added cesium carbonate (5 eq). The resulting mixture was stirred at room temperature for 30 minutes, then diethyl 3-bromopropylphosphonate (1.2 eq) was added into the reaction mixture. The resulting mixture was stirred at room temperature for another 4 hours until tert-butyl 4-hydroxyphenethylcarbamate was consumed. The mixture was then diluted with ethyl acetate, and washed with 5% citric acid three times, saturated NaHCO3 solution, water and brine. The organic layer was then dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 80-100% EtOAc/Hex to give the product as a colorless oil.
Reaction SMILES: [ClH:1].C[C:3]1[C:11]2[CH2:10][O:9][C:8](=[O:12])[C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.BrC1C([C:32]([F:35])([F:34])[F:33])=CC2C(=O)OCC=2C=1>>[ClH:1].[N:15]1([CH2:14][CH2:13][C:4]2[C:5]([C:32]([F:35])([F:34])[F:33])=[CH:6][C:7]3[C:8](=[O:12])[O:9][CH2:10][C:11]=3[CH:3]=2)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: O=C1OCc2cc(Br)c(C(F)(F)F)cc21
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Product: O=C1OCc2cc(CCN3CCNCC3)c(C(F)(F)F)cc21

Procedure:
5-[2-(piperazin-1-yl)ethyl]-6-(trifluoromethyl)-2-benzofuran-1(3H)-one hydrochloride was prepared in an analogous fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above starting from 5-bromo-6-(trifluoromethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 315 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Product: COc1cc(C(=O)/C=C/c2cn(C(=O)c3ccccc3)c3ccccc23)cc(OC)c1OC

Procedure:
Substantially the same procedure as in Example 7 was repeated using Compound 1 (1.69 g) obtained in Example 1 and benzoyl chloride (1.16 ml) to give Compound 8 (0.91 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)(=O)=O.[I-:16].[Na+]>CC(C)=O>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:6][I:16]
Reactant: COc1cccc(CCOS(C)(=O)=O)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cccc(CCI)c1
Yield: 87.9 %

Procedure:
To a flask under argon was added 14.6 g (0.0634 mole) 2-(3-methoxyphenyl)ethyl methanesulfonate in 400 ml of acetone and 36.5 g (0.243 mole) of sodium iodide. The reaction mixture was refluxed for 2.5 hr. The acetone was evaporated in vacuo and the residue dissolved in ether. The ether was washed with water, sodium bicarbonate, sodium thiosulfate, water and brine, dried over MgSO4, and evaporated in vacuo to give a light green oil. Distillation in a Kugelrohr apparatus gave 14.6 g of the desired product as a clear oil.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:29]([O:31][C:32](=O)[C:27]=12)=[O:30])(=[O:24])[CH3:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:27]=1[C:32](=[O:31])[N:1]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])[C:29]2=[O:30])(=[O:24])[CH3:23]
Reactant: NC(CC(=O)O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 2 h
Yield: 147.4 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (500 mg, 1.0 mmol) in acetic acid (10 ml) was added 3-acetamido-phthalic anhydride (390 mg, 1.9 mmol) and sodium acetate (160 mg, 1.9 mmol). The mixture was heated at reflux temperature overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×4), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was slurried with ether for 2 hours. The suspension was filtered to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid as a white solid (720 mg, 85%). 1HNMR (CDCl3): δ 0.35-0.39 (m, 2H), 0.64-0.68 (m, 2H), 1.15-1.36 (m, 1H), 2.27 (s, 3H), 3.24 (dd, J=5.8, 17 Hz, 1H), 3.82 (dd, J=10, 17 Hz, 1H), 3.88 (d, J=8.3 Hz, 2H), 5.70 (dd, J=5.8, 10 Hz, 1H), 6.59 (t, JH-F75 Hz, 1H), 7.06-7.14 (m, 3H), 7.48 (d, J=7.3 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 8.76 (d, J=8.3 Hz, 1H), 9.47 (s, 1H).
Reaction SMILES: C([OH:4])(C)C.[CH3:5][C:6]1[S:10][C:9]([S:11][CH2:12][C:13]2[CH2:30][S:29][C@@H:16]3[C@H:17]([NH:20][C:21]([CH2:23][N:24]4[N:28]=[N:27][N:26]=[CH:25]4)=[O:22])[C:18](=[O:19])[N:15]3[C:14]=2[C:31]([OH:33])=[O:32])=[N:8][N:7]=1.C(=O)([O-])[O-:35].[Na+:38].[Na+]>O>[CH3:5][C:6]1[S:10][C:9]([S:11][CH2:12][C:13]2[CH2:30][S:29][C@@H:16]3[C@H:17]([NH:20][C:21]([CH2:23][N:24]4[N:28]=[N:27][N:26]=[CH:25]4)=[O:22])[C:18](=[O:19])[N:15]3[C:14]=2[C:31]([O-:33])=[O:32])=[N:8][N:7]=1.[OH2:4].[OH2:35].[OH2:4].[OH2:4].[OH2:4].[Na+:38]
Reactant: O=C([O-])[O-]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Reactant: CC(C)O
Agent: [Na+]
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)Cn4cnnn4)[C@H]3SC2)s1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a reactor equipped with a jacket were added 5 ml isopropanol, 5 ml water, 10 g cefazolin acid and 1.2 g sodium carbonate, stirred and heated to 50° C. until the solution was clear, the finishing point pH was adjusted to be 6.5, the mixture was directly filtered into a glass crystallizer, agitated, cooled to about 33° C., added serine, turbidness occurred in the solution, hold for 1.0 hours, added anhydrous ethanol in an amount of 15 times as much as the mixture at 2 MPa, cooled to 5-15° C. and hold at the temperature for 1 hour. The resultant was filtered, the filter cake was washed with ethanol, dried at 5° C. for 8 hours to give cefazolin sodium pentahydrate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:20]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:20]([C:29]1[CH:30]=[CH:31][C:32]([C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])=[O:10])=[CH:33][CH:34]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCc1ccccc1
Reactant: COC(=O)CCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCc1ccc(C(=O)CCCCC(=O)OC)cc1

Procedure:
Adipic acid monomethyl ester (50 g; 0.31 mole) is converted to the acid chloride with thionyl chloride (50 g) in the manner described in Example 1. This product is reacted with nonylbenzene (400 ml) and aluminum chloride (80 g; 0.6 mole) and the product purified in a manner analogous to that described in Example 1 to provide methyl 5-(4-n-nonylbenzoyl)pentanoate (35.2 g). This ester (35 g) is hydrolysed with sodium hydroxide in aqueous ethanol as in Example 1 to give, on recrystallization from aqueous ethanol, 5-(4-n-nonylbenzoyl)pentanoic acid (24 g) as colorless crystals, m.p. 29°-31° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][CH2:15][C:16]2[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.NC1C(NC(=O)CCC2C=NC3C(=CC=CC=3)N=2)=C2C(=CC=1)N=CC=C2>C(O)(=O)C>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:24]=[CH:25][C:16]=1[CH2:15][CH2:14][C:13]1[NH:1][C:2]2=[C:3]3[C:8](=[CH:9][CH:10]=[C:11]2[N:12]=1)[N:7]=[CH:6][CH:5]=[CH:4]3
Reactant: Nc1c(NC(=O)CCc2cnc3ccccc3n2)ccc2ncccc12
Agent: Nc1ccc2ncccc2c1NC(=O)CCc1cnc2ccccc2n1
Solvent: CC(=O)O
Product: c1ccc2nc(CCc3nc4ccc5ncccc5c4[nH]3)cnc2c1
Reaction time: 2 h
Yield: 36.9 %

Procedure:
N-(5-Aminoquinolin-6-yl)-3-(quinoxalin-2-yl)propanamide (180 mg, 0.5 mmol) or N-(6-aminoquinolin-5-yl)-3-(quinoxalin-2-yl)propanamide (80 mg, 0.23 mmol) in acetic acid (5 mL or 2 mL, respectively) was heated to 60° C. and stirred for 2 hours. Excess acetic acid was removed under vacuum, and the residue was purified by column chromatography to afford 2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline (150 mg) and 2-(2-(quinoxalin-2-yl)ethyl)-1H-imidazo[4,5-f]quinoline (60 mg). MS (ESI) m/z 325 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[OH:11].BrC[O:14][C:15](=[O:17])[CH3:16].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:16][C:15]([OH:17])=[O:14]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)OCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
Sodium hydride (60 mg) was dissolved in dimethylformamide (3 ml) to prepare a solution. A dimethylformamide solution (5 ml) of 2,4-dichlorophenol (245 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. Subsequently, a dimethylformamide solution (5 ml) of bromomethylacetate (344 mg) was added thereto, and the mixture was further stirred at room temperature for 90 min. Water was added to stop the reaction, and the reaction solution was extracted with ethyl acetate, followed by washing with water and saturated brine. The extract was then dried over sodium sulfate. After the concentration of the extract, a 5% aqueous sodium hydroxide solution (10 ml) was added thereto, and the mixture was stirred at 80° C. for 10 hr. Subsequently, the solution was acidified by the addition of 1 N hydrochloric acid. The resultant white precipitate was collected by filtration and was dried to give 2-(2,4-dichlorophenoxy)acetic acid (310 mg, yield 94%).
Reaction SMILES: [OH:1][C:2]1([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:16]([Si:18]([O:23][CH3:24])([O:21][CH3:22])[O:19][CH3:20])=[CH2:17]>C1(C)C=CC=CC=1>[OH:1][C:2]1([C:8](=[O:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:17][CH2:16][Si:18]([O:23][CH3:24])([O:21][CH3:22])[O:19][CH3:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(c1ccccc1)C1(O)CCCCC1
Reactant: C=C[Si](OC)(OC)OC
Solvent: Cc1ccccc1
Product: CO[Si](CCc1ccccc1C(=O)C1(O)CCCCC1)(OC)OC
Yield: 49.4 %

Procedure:
14.4 g (70 mmol) of 1-hydroxy-1-benzoylcyclohexane, 11.75 ml (77 mmol) of vinyltrimethoxysilane and 1.28 g (1.4 mmol) of RuH2 (CO) (PPh3)3 in 100 ml of anhydrous toluene were stirred at reflux for 4.5 hours. Following concentration and chromatography (silica gel, CH2Cl2 /ethyl acetate), 12.2 g (49%) of a yellowish oil were obtained which was found to be pure by 1H-NMR spectroscopy but which was purified further by bulb-tube distillation (200° C., 0.2 mbar). 1H-NMR (CDCl3):1.01 ppm (2H, mc, Et-H2); 1.15-1.28 ppm (1H, m, cyclohexyl-H); 1.57-1.89 ppm (9H, m, cyclohexyl-H); 2.59 ppm (2H, mc, Et-H1); 3.33 ppm (1H, s, OH); 3.35 ppm (9H, s, Si(OCH3)3); 7.17-7.40 ppm (4H, M, Ph-H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[N:20]3[C:10](=[CH:11][N:12]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:21].C(N(CC)CC)C.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[F:29][C:30]([F:37])([F:36])[CH2:31][S:32]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[N:20]3[C:10](=[CH:11][N:12]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:21])(=[O:34])=[O:33]
Reactant: NCCCCn1c(=O)c2cccc3ncc(c1=O)n32
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2cccc3ncc(c(=O)n1CCCCNS(=O)(=O)CC(F)(F)F)n32
Yield: 38.7 %

Procedure:
To a suspension of 994 mg (3.0 mmol) of 4,5-dihydro-4-[4-(amino)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione.dihydrochloride in 50 ml of methylene chloride was added, while stirring under ice-cooling, 1.47 ml (10.5 mmol) of triethylamine. The mixture was stirred for 5 minutes, to which was added dropwise 0.66 g (3.6 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The reaction mixture was cooled with ice for one hour, which was stirred for 19 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), followed by washing with ether and dried to give 470 mg of the desired compound (38.7%, colorless solid), m.p.154.0-155.0° C.