Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-:3])[O-:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.COC1C(=CC=CC=1)COC(=O)OCC1C(=CC=CC=1)OC.[OH-].C[N+](C)(C)C.[OH-].[Na+]>C(OC)(=O)C1C(=CC=CC=1)O>[CH3:14][C:12]([C:9]1[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:13].[C:1]([OH:4])([OH:3])=[O:2]
Reactant: O=C([O-])[O-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: COc1ccccc1COC(=O)OCc1ccccc1OC
Agent: C[N+](C)(C)C
Solvent: COC(=O)c1ccccc1O
Product: O=C(O)O
Temperature: 180 °C
Reaction time: 0.5 h

Procedure:
Example 5 provides a general method for preparing a polycarbonate nanocomposite by in-situ polymerization of a dihydroxy compound (bisphenol A) and an activated carbonate (bis(methylsalicyl)carbonate (BMSC)) in the presence of methyl salicylate as the solvent and nanoparticles (the functionalized nanosilica of Sample A). See Table 2 for an overview of the materials used. In a round bottom flask, 1.5 ml of the functionalized nanosilica dispersion of Sample A was diluted with 20 ml of methyl salicylate. The diluted dispersion was then placed in an ultrasound bath (Transonic T 890/H sonicator) for about 30 minutes at a power of 470 Watts. The dispersion was transferred to a glass tube reactor containing bisphenol A (24 g) and BMSC (35.73 g) and mixed to obtain a homogeneous dispersion. 400 microliters of an aqueous catalyst solution containing tetramethylammonium hydroxide (2.6 milligrams (mg)) and sodium hydroxide (9.58 mg) were added, and the reactor was purged with nitrogen to remove oxygen. The mixture was heated to a temperature of 180° C. under stirring at a speed of 90 rotations per minute (rpm). After 15 minutes the pressure in the tube reactor reached 910 millibar (mbar). The temperature was increased to 220° C., and the pressure was slowly reduced from 910 mbar to 100 mbar over a period of 4 to 5 minutes at a rate of 75 to 100 mbar per 30 seconds. After holding at 100 mbar and 220° C. for 10 minutes, the temperature was increased to 280° C. The reaction mixture was then maintained at 280° C. and 100 mbar for 15 minutes to provide a bisphenol A polycarbonate nanocomposite.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH:15](SC)[CH2:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19]Cl>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH:15]([Cl:19])[CH2:14][C:13]1=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: CSC1CC(=O)N1CC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CN1C(=O)CC1Cl)OCc1ccccc1
Yield: 104.6 %

Procedure:
1-Benzyloxycarbonylmethyl-4-methylthioazetidin-2-one (2.65 g) was dissolved in methylene dichloride (50 ml) and the solution was stirred and ice cooled while a solution of chlorine (0.71 g) in carbon tetrachloride (7 ml) was added in one portion. The mixture was stirred for 3 minutes and then the solvent was evaporated under reduced pressure to yield 1-benzyloxycarbonylmethyl-4-chloroazetidin-2-one as a pale yellow oil (2.65 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.S(O[CH2:30][CH2:31][Cl:32])(C1C=CC(C)=CC=1)(=O)=O>[OH-].[Na+].O>[Cl:32][CH2:31][CH2:30][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: Oc1ccccc1C=Cc1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Reaction time: 16 h
Yield: 39.5 %

Procedure:
4 g of 2-[(1H-indol-4-yl)-ethenyl]-phenol obtained in Step A of Example 1 in 100 ml of 2N sodium hydroxide after having added 6 g of 2-chloroethanol tosylate were heated for 6 hours at reflux and the mixture was left for 16 hours at ambient temperature, then diluted with water and extracted with ethyl acetate. After eliminating the solvent under reduced pressure and chromatography on silica (eluent: benzene), 2 g of 4-[2-[2-[(2-chloro)-ethoxy]-phenyl]-ethenyl]-1H-indole (trans E) were obtained.
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH3:13])=[CH:11][C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:5]=1C(O)=O)([O-:3])=[O:2].[N-:17]=[N+]=[N-].[Na+]>OS(O)(=O)=O.O=S(=O)=O>[NH2:17][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:12]([CH3:13])[CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Na+]
Product: Cc1cc([N+](=O)[O-])cc(N)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
2.43 grams of 2,5-dinitro-3-methylbenzoic acid was dissolved in 21.5 grams of oleum (20% SO3, 80% H2SO4). While the solution is stirred with the temperature maintained at 5°-10° C., 0.84 grams of powdered sodium azide was added cautiously in portions of less than 0.1 g over one hour. Rapid addition of the sodium azide was avoided to prevent any explosion from occurring. Stirring was continued for one hour at 0°-10° C. (gas evolution occurs), 10°-30° C. for two hours and 30°-60° C. for three hours. The resulting dark mixture was then poured over 200 ml of crushed ice to yield a yellow-orange precipitate. The mixture was filtered, washed with water and dried to give 2.02 g of 3-amino-2,5-dinitrotoluene (m.p. 125°-127° C.). Recrystallization from 95% ethanol gave rust colored flakes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[CH3:15][S:16][C:17]1[C:28]2[O:27][C:26]([CH3:30])([CH3:29])[O:25][C:24]=2[C:23]([C:31]([C:33]2[C:43]3[O:44][C:45]([CH3:48])([CH3:47])[O:46][C:42]=3[C:41]([S:49][CH3:50])=[C:35]3[O:36][C:37]([CH3:40])([CH3:39])[O:38][C:34]=23)=[O:32])=[C:22]2[C:18]=1[O:19][C:20]([CH3:52])([CH3:51])[O:21]2>C1COCC1.C(OCC)C>[CH3:50][S:49][C:41]1[C:35]2[O:36][C:37]([CH3:39])([CH3:40])[O:38][C:34]=2[C:33]([C:31]([C:23]2[C:22]3[O:21][C:20]([CH3:52])([CH3:51])[O:19][C:18]=3[C:17]([S:16][CH3:15])=[C:28]3[O:27][C:26]([CH3:30])([CH3:29])[O:25][C:24]=23)([C:2]2[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[OH:32])=[C:43]2[C:42]=1[O:46][C:45]([CH3:48])([CH3:47])[O:44]2
Reactant: CSc1c2c(c(C(=O)c3c4c(c(SC)c5c3OC(C)(C)O5)OC(C)(C)O4)c3c1OC(C)(C)O3)OC(C)(C)O2
Reactant: CSc1ncc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ncc(C(O)(c2c3c(c(SC)c4c2OC(C)(C)O4)OC(C)(C)O3)c2c3c(c(SC)c4c2OC(C)(C)O4)OC(C)(C)O3)cn1
Temperature: -75 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-methylthio-pyrimidine (0.250 g, 1.2195 mmol) was dissolved in THF (50 mL, sodium benzophenone ketyl) and cooled to -105° C. n-Butyl lithium (0.455 ml in toluene, 1.2195 ml) was added and the temperature was increased to -75° C. for 15 minutes and thereafter reduced to -105° C. Bis(8-methylthio-2,2,6,6-tetramethylbenzo[1,2-d:4,5-d']-bis(1,3)dioxole-4-yl)ketone (0.63146 g, 1.1236 mmol, Example 59) was added in solid form and the temperature was gradually increased to room temperature (removal of cooling bath). The mixture was stirred overnight, NaCl (15 mL, sat.) and diethyl ether (40 mL) were added and the phases separated after 5 minutes stirring. The organic phase was dried (MgSO4) and evaporated yielding 0.59 crude product. Pure product was obtained by crystallization in diethyl ether followed by a second crystallization in diisopropyl ether. Yield 0.115 g (0.1669 mmol, 14.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1.C(O)(=O)C>CCCCCC>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1ccc(-n2cccc2)cc1
Temperature: -100 °C
Yield: 40.6 %

Procedure:
The title compound was prepared in analogy to the procedure described in European Patent Application 480204. 4-Methylaniline (30 g, 280 mmol), 2,5-dimethoxytetrahydrofuran (22 g, 166 mmol) and acetic acid (200 mL) were combined under a nitrogen atmosphere and heated at -100° C. for 90 minutes. The solvent was removed under reduced pressure and the residue obtained suspended in hexane and filtered. The filtrate was passed through a pad of silica gel and concentrated in vacuo. The residue obtained was crystallized from methanol to afford 10.6 g (45%) of the title compound. MS (DCI/NH3) m/e 158 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[Br:12][C:13]1[C:14](Cl)=[N:15][C:16](Cl)=[N:17][CH:18]=1>C1COCC1>[Br:12][C:13]1[C:14]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:15][C:16]([O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Oc2ncc(Br)c(Oc3ccc(F)cc3F)n2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
2,4-Difluorophenol (22 mL, 241.34 mmol) was dissolved in 140 mL of dry THF and cooled to 0° C. Sodium hydride (9.43 g, 235.85 mmol, 60% suspension in oil) was added in portions, and the reaction mixture was stirred for 30 minutes at 0° C. 5-Bromo-2,4-dichloro-pyrimidine (25.0 g, 109.7 mmol) was added in portions over 10 minutes, and the reaction mixture was allowed to warm to room temperature and was stirred overnight at room temperature. The reaction was quenched by addition of 30 mL saturated aqueous ammonium chloride and 100 mL of water. The aqueous mixture was extracted three times with 100 mL EtOAc, and the combined organic layers were dried (MgSO4), filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by FLASH chromatography (2% to 6% EtOAc/Hexanes. The resulting solid was recrystallized from diethyl ether/hexanes to afford 12.6 g of 5-bromo-2,4-bis-(2,4-difluoro-phenoxy)-pyrimidine as a white solid. Mass Spec. M+H=416.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[C:3]#[CH:4].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.O.C(OCC)(=O)C>C(NCC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)[C:3]#[C:4][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Ic1ccccn1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: CC(C)(C#Cc1ccccn1)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.2 %

Procedure:
53 mg of copper(I) iodide, 293 mg of triphenylphosphine and 99 mg of palladium(II) chloride were dissolved in 320 ml of diethylamine. 10.4 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile and 11.5 g of 2-iodopyridine were added and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. Water and ethyl acetate were added and the organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) and then ethyl acetate/petroleum ether (1:2) for the elution to give 12.98 g of 4-[1,1-dimethyl 3-(2-pyridyl)-2-propynyloxy] benzonitrile in the form of an oil.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:6][C:7]1[C:16]2[O:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([CH3:23])[C:12](=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: Cc1c(-c2ccccc2)oc2c(N)cccc2c1=O
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1cccc2c(=O)c(C)c(-c3ccccc3)oc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.75 ml of acryloyl chloride in 15 ml of anhydrous tetrahydrofuran was added dropwise at -10° C. to a stirred mixture of 5 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran and 3 ml of triethylamine in 60 ml of anhydrous tetrahydrofuran. After stirring at 0° C. for 1 hour and at ambient temperature for 1 hour, the reaction mixture was poured into water and filtered under suction. The filter cake was washed with water. Desiccation gave 5.5 g of the title compound, m.p. 229°-230° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]=[O:25])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:26][Mg]I.CO>ClCCl.CCOCC>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]([OH:25])[CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C=O)cccc2c1Nc1ccccc1C
Reactant: C[Mg]I
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC(=O)c1cnc2c(C(C)O)cccc2c1Nc1ccccc1C

Procedure:
A solution of 3-butyryl-4-(2-methylphenylamino)quinoline-8-carbaldehyde (2.0 g, 6 mmol) in dichloromethane (100 ml) was stirred at 0°-5° C. and treated with a solution of methylmagnesium iodide in ether until T.L.C. (2% methanol in dichloromethane) showed that mostly new product had formed. The mixture was washed with ammonium chloride solution, dried and evaporated. Chromatography (silica gel, 0.5% methanol in dichloromethane) afforded the required 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxyethyl)quinoline (0.28 g) as yellow crystals, m.p. 140°-2° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(O)c1N
Yield: 131.8 %

Procedure:
2,3-dinitrophenol (80%) 25 g (0.11 mol) was dissolved in 700 ml ethanol and 0.5 g Pd/C was added. The mixture was hydrogenated at room temperature until the uptake of hydrogen ceased (4 h). The solution was filtered (celite) in N2 -atmosphere and evaporated to dryness in vacuo to give the title compound as an unstable oil (18 g), which was used immediately for the next step.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:20])[CH3:19])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][Cl:35])=[O:32]>ClCCl>[Cl:35][CH2:34][O:33][C:31]([NH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:19])[CH3:20])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:32]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (2.9 g, 9 mmole) and pyridine (2 ml) in dichloromethane (50 ml) was added chloromethyl chloroformate(1.55 g, 12 mmole) and the mixture was stirred for 3 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate was added. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 1.1 g=29%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8](OC(=O)C)(=[O:10])[CH3:9].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8](=[O:10])[CH3:9]
Reactant: NCc1cccs1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A mixture of thiophen-2-ylmethanamine (600 mg, 5.30 mmol), DMAP (130 mg, 1.06 mmol, 0.2 equiv) and acetic anhydride (648 mg, 6.36 mmol, 1.2 equiv) in DCM (20 mL) was stirred at room temperature for 2 h. Water was added and the reaction was extracted with EA. The combined organic layers were dried (Na2SO4), filtered. The filtrate was concentrated to afford the compound N-(thiophen-2-ylmethyl)acetamide (745 mg, 91%). LC-MS (m/z)=156 [M+H]+.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OC)c1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
To a solution of methyl vanillate (7.29 g, 40 mmol) in dimethylformamide (25 mL), potassium carbonate (8.29 g, 60 mmol) and benzyl bromide (5.26 mL, 44 mmol) were added. The mixture was heated to 100° C. for 3 h. After cooling to r.t., water was added and the product was extracted several times with ethyl acetate. The combined organic phases were washed with water and brine. After drying over Na2SO4, the solvent was removed to yield methyl 4-benzyloxy-3-methoxybenzoate (10.8 g, 39.7 mmol, 99%) as a grey solid which was used without further purification. LC/ESI-MS: m/z=273 [M+H]+; Rt=3.82 min.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[Ca+2:38].[OH-]>C(O)(C)C>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[Ca+2:38].[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Ca+2]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Placed 52.71 mg of the product of Example 49-7 into a 3 mL reactivial. Added 300 μL of isopropyl alcohol and warmed on a hot-plate. Added 7.34 mg of calcium hydroxide. Solution clarified. Allowed to cool to ambient temperature. Apparent precipitate formed upon cool down. Warmed vial at 40° C. for approximately 20 minutes. No apparent change in precipitate. Allowed to stir at ambient for 6 days. Collected solid by vacuum filtration.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH:11]([CH2:12][OH:13])[CH2:10][C:9]1=[O:14])=[O:5])[CH3:2].C(N(CC)CC)C.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH:11]([CH2:12][O:13][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][C:9]1=[O:14])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCN1C(=O)CC1CO
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)CCN1C(=O)CC1COS(C)(=O)=O
Yield: 85 %

Procedure:
1.6 g. (8 mmoles) of 1-(2-ethoxycarbonylethyl)-4-(hydroxymethyl)-2-azetidinone prepared according to Example 5 are dissolved in 50 ml. of dry benzene, whereupon 2.2 ml. (1.16 g, 16 mmoles) of triethylamine are added to the solution, followed by a dropwise addition of 1.2 ml. (1.8 g., 16 mmoles) of mesyl chloride at 0° C., with stirring. After 30 minutes the salt is filtered off and the filtrate is evaporated in vacuo. The evaporation residue is dissolved in 50 ml. of chloroform, the solution is shaken with two 10-ml. portions of a 10% aqueous sodium carbonate solution and subsequently with three 10-ml. portions of water. The chloroform phase is dried over magnesium sulfate, filtered and the filtrate is evaporated. 1.9 g. (85%) of the named compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([F:17])=[CH:12][C:11]=2[Cl:18])[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2[CH2:25][CH2:26][CH2:27][CH2:28][C:20]1=2>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1([S:9][C:10]2[CH:15]=[C:14]([N:16]3[C:22](=[O:23])[CH:21]4[C:20](=[CH:28][CH2:27][CH2:26][CH2:25]4)[C:19]3=[O:24])[C:13]([F:17])=[CH:12][C:11]=2[Cl:18])[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CCC1
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: COC(=O)C1(Sc2cc(N3C(=O)C4=CCCCC4C3=O)c(F)cc2Cl)CCC1
Temperature: 0 °C
Yield: 62.1 %

Procedure:
A mixture of 4.4 g of 1-(5-amino-2-chloro-4-fluorophenylthio)-cyclobutanecarboxylic acid methyl ester and 2.4 g of 3,4,5,6-tetrahydrophthalic anhydride in 60 ml of glacial acetic acid is heated under reflux for 5 hours while stirring. The reaction mixture is then introduced into ice-water and the resulting glutinous product is extracted with ethyl acetate. After drying the organic phase over sodium sulfate and concentrating by evaporation in vacuo, petroleum ether is added to the resulting residue and the substance solidifies. Filtering yields 4 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclobutanecarboxylic acid methyl ester having a melting point of +98° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[CH:11][N:10]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(F)ccc2F)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cc(F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To tert-butyl 6-(2,5-difluorophenyl)nicotinate in DCM (12 mL) at 0° C. was added TFA (5 mL). After stirring at room temperature overnight, toluene was added (10 mL) and the solvent removed to give a white solid (176 mg, 97%), 6-(2,5-difluorophenyl)nicotinic acid. LC/MS (M+H)=236.0 observed, 236.05 expected
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[CH:13]=[C:14]([C:17]([C:19]3([NH2:38])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28]C)[CH:26]=4)[N:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:20]3=[O:37])=[O:18])[N:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].B(Br)(Br)Br.CO>ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[CH:13]=[C:14]([C:17]([C:19]3([NH2:38])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=4)[N:21]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:20]3=[O:37])=[O:18])[N:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(N)(C(=O)c1cc3c4ccccc4n(C(C)=O)c3cn1)C(=O)N2c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)n1c2ccccc2c2cc(C(=O)C3(N)C(=O)N(c4ccc(F)cc4)c4ccc(O)cc43)ncc21
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
In 40 ml of dichloromethane was suspended 1.54 g (3.04 mmole) of 3-{9-acetyl-9H-pyrido[3,4-b]-indol-3-yl-carbonyl}-amino-5-methoxy-1-(4-fluorophenyl)-2-indolinone, and to the suspension was added dropwise under ice cooling a solution of 1.1 ml (4 mole equivalent) of boron tribromide dissolved in 10 ml of dichloromethane. After completion of the dropwise addition, the mixture was stirred for 10 minutes under ice cooling and then stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was treated with methanol under ice cooling, and then the solvent was removed under reduced pressure. Methanol was added to the residue, and the precipitates were collected by filtration to obtain 1.07 g of a hydrobromide of the title compound as pale yellow crystals. Melting point: 239° to 241° C., IR (Nujol) (cm-1): 1720, 1680, FAB-MS (m/z): 495 (MH+, base)