Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.CC(C)=O.C(=O)=O.C([Li])CCC.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21].[Cl-].[Li+]>O1CCCC1.[Cl-].[Na+].O.O.CCCCCC>[CH3:21][Si:20]([CH3:23])([CH3:22])[C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1]
Reactant: C[Si](C)(C)Cl
Reactant: Clc1ccsc1
Agent: O=C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCCCCC
Product: C[Si](C)(C)c1sccc1Cl
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To 3-chlorothiophene (5.0 g, 42.16 mmol), dissolved in 50 mL of tetrahydrofuran stirring at -72° C. (acetone/dry ice bath), was added 16.8 ml of 2.5M hexane solution of n-butyllithium over a 15 minute period. The reaction temperature was maintained below -70° C. during the addition. Soon after complete addition of the n-butyllithium a white precipitate formed. After 40 minutes of stirring below -70° C., 5.88 mL of chlorotrimethylsilane was slowly added over a 5 minute period. After addition the solution momentarily became clear before turning cloudy again by the formation of lithium chloride by-product. After 10 minutes the reaction solution was warmed to 0° C. At 0° C. 5 mL of water followed by 25 mL of brine was added to quench the reaction. The aqueous solution was then extracted with ethyl acetate (2×30 mL). The organic extract was dried (Na2SO4), filtered and evaporated to 8.0 g of title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Reactant: CCCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1Cl

Procedure:
By customary procedures, 3-chloro-4-hydroxybenzoic acid was reacted with dodecylbromide in a mixed solution of ethanol and water containing sodium hydroxide to produce 3-chloro-4-dodecyloxybenzoic acid, and this acid was reacted with thionyl chloride to obtain 3-chloro-4-dodecyloxybenzoic acid chloride. Separately, 100 mg of (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone and 200 mg of 4-benzyloxybenzoic acid were dissolved in 200 ml of benzene, 190 mg of diethyl azodicarboxylate and 250 mg of triphenylphosphine were added to the solution, and a reaction was carried out at room temperature with stirring overnight. The reaction mixture was concentrated under a reduced pressure, and the concentrate was separated and purified by the silica gel column chromatography to obtain 120 mg of 2-(4'-benzyloxybenzoyloxy)-5-hexyl-δ-valerolactone. This compound was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to obtain 2-(4'-hydroxy-benzoyloxy)-5-hexyl-δ-valerolactone. The obtained compound was dissolved in 20 ml of benzene, and 200 mg of 3-chloro-4-dodecyloxybenzoic acid chloride described above, 200 mg of triethylamine and 20 mg of N,N-dimethylaminopyridine were added to the solution, and a reaction was carried out with stirring overnight. The reaction liquid was treated by customary procedures and the intended product was separated and purified by the silica gel column chromatography. Recrystallization from ethanol gave 80 mg of (2R,5S)-2-[4-(3'-chloro-4'-dodecyloxybenzoyloxy)-benzoyloxy]-5-hexyl-δ-valeerolactone ##STR127##
Reaction SMILES: [CH2:1]1[CH2:12][O:11][CH:3]([CH:4]([CH3:10])[CH2:5][C:6](OC)=[O:7])[O:2]1.[Li].[H-].C(=O)(O)[O-].[Na+]>CCOCC>[CH2:1]1[CH2:12][O:11][CH:3]([CH:4]([CH3:10])[CH2:5][CH2:6][OH:7])[O:2]1
Reactant: COC(=O)CC(C)C1OCCO1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Li]
Solvent: CCOCC
Product: CC(CCO)C1OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.1 %

Procedure:
A solution of methyl 4,4-ethylenedioxy-3-methyl-butanoate (63.2 g) in ether (200 ml) is added dropwise to a mixture of lithium alumnium hydride (13.8 g, 0.363 m) in ether (500 ml) at 0° C. under nitrogen. The resulting mixture is stirred for 2 hours, treated with 5% sodium bicarbonate solution (100 ml), allowed to warm to room temperature and filtered. The filtrate is dried (Na2SO4) and the solvent is evaporated in vacuo to give the crude product (26 g). This material is further purified by column chromatography on silica gel (300 g, 20% ethyl acetate in hexane) to give 4,4-ethylenedioxy-3-methyl-1-butanol as a colorless liquid (14.9 g).
Reaction SMILES: [N:1]([CH:4]1[C:34](=[O:35])[N:6]2[CH:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:8]([CH2:16][O:17][C:18](=[O:20])[CH3:19])(OS(C)(=O)=O)[CH2:9][S:10][C@:5]12[S:36][CH3:37])=[N+:2]=[N-:3]>CCOC(C)=O>[N:1]([CH:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[CH2:9][S:10][C@:5]12[S:36][CH3:37])=[N+:2]=[N-:3]
Reactant: CS[C@]12SCC(COC(C)=O)(OS(C)(=O)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Solvent: CCOC(C)=O
Product: CS[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-3-methylsulfonyloxy-cepham-4-carboxylate (20 mg.) and EM silica gel 60 (500 mg.) in 3:1 φH-EtOAc (1 ml.) is stirred at room temperature for 4 hours. The mixture is diluted with EtOAc (3 ml.) and filtered through a small sintered glass funnel containing a pad of MgSO4. The silica gel is washed with more EtOAc (2 × 2 ml.). Evaporation of the filtrate in vacuo provides a 3:7 mixture (19 mg.) of starting material and p-nitrobenzyl 7-azido-6-methylthio-3-acetoxymethyl-ceph-3-em-4-carboxylate.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18].N([O-])=O.[Na+]>O.O1CCCC1>[CH:13]1[CH:12]=[C:11]([N:16]2[NH:7][N:6]=[N:5][C:17]2=[O:18])[C:10]([Cl:9])=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C=Nc1ccccc1Cl
Agent: O=N[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1nn[nH]n1-c1ccccc1Cl
Temperature: 0 °C
Yield: 25.5 %

Procedure:
Anhydrous aluminum chloride (1.5 g) was added to tetrahydrofuran (30 ml) with ice bath cooling and the resulting mixture was stirred for fifteen minutes. To the mixture was added sodium azide (0.65 g) and 2-chlorophenylisocyanate (1.53 g), followed by a sixteen hour-refluxing. After cooling, the reaction mixture was added with stirring to a mixture of sodium nitrite (1 g), water (200 ml) and ice (100 g) and the resulting mixture was worked up in the same way as in Comparative Synthesis Example 1 to obtain the desired 1-(2-chlorophenyl)-5(4H)-tetrazolinone (0.5 g) having a m.p. in the range of from 124.5° to 125.5° C. in a yield of 25% of theory.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16]C)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].S([O-])(O)(=O)=O.[K+]>CO.O1CCCC1>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Yield: 97.4 %

Procedure:
Methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate (2.00 g, 8.57 mmol) was dissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (10 ml), followed by adding thereto a 2N aqueous lithium hydroxide solution (8.6 ml, 17.2 mmol), and the resulting mixture was heated under reflux for 20 minutes. After completion of the reaction, the reaction solution was ice-cooled, made into an acidic solution with an aqueous potassium hydrogensulfate solution, and then extracted with ethyl acetate. The ethyl acetate layer was concentrated, washed by repulping (ethyl acetate/hexane), and then dried to obtain 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid (1.83 g, 97%).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>[Fe].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 60 °C
Yield: 78 %

Procedure:
An amount of 2 g (6.48 mmol) of, tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate, 1.4 g (25.9 mmol) of iron, and acetic acid (3.1 mL, 48.6 mmol) were placed in a flask. Methanol (30 mL) is added and heat at 60° C. for 2 hours. After cooling to room temperature, the precipitate is filtered, the methanol is removed in a vacuum and saturated sodium bicarbonate is added. The mixture is extracted 3× with ethyl acetate. Dried over sodium sulfate, and evaporated to give 1.43 g (78% yield) as a purple solid. MS (ESI) m/z 279.1(M+1)+.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A 500-mL bottle was purged with nitrogen and charged with 188a (3.1 g, 10 mmol), 10% palladium on carbon (50% wet, 1.0 g) and ethanol (100 mL). It was evacuated, charged with hydrogen gas, and stirred for 16 h at room temperature. The hydrogen was then evacuated and nitrogen was charged into the bottle. The catalyst was removed by filtration through a pad of Celite and the filtrate concentrated under reduced pressure to afford 188b (2.7 g, 97%). MS: [M+H]+ 279
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]NC(=O)C>C(Cl)Cl>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: CC(=O)NBr
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Yield: 82 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, 7.8 mmol) in CH2Cl2 (25 mL) was added N-bromoacetamide (1.2 g, 8.7 mmol) in CH2Cl2 (25 mL). The reaction mixture was refluxed for 40 minutes, then concentrated and washed with cold water. The crude material was recrystallized from a minimal amount of isopropanol and dried under vacuum to give the title compound (82%) as light-gray solid. MS (ES+) [M+H]+=232.
Reaction SMILES: CC(OCC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O)=O.CC1(C)OC(=O)C(C(=O)CC)C(=O)O1.O=C(CCC)C(N[C@@H]1C(=O)N2C(C(O)=O)=C(COC(=O)C)CS[C@H]12)=O.[O:58]=[C:59]([CH2:81][CH3:82])[CH2:60][C:61]([NH:63][C@@H:64]1[C:79](=[O:80])[N:66]2[C:67]([C:76]([OH:78])=[O:77])=[C:68]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[CH2:69][S:70][C@H:65]12)=[O:62].[N:83]([O-])=[O:84].[Na+].[Cl-].[Na+]>C(O)(=O)C.O1CCCC1.O.C(OCC)(=O)C.O.O1CCCC1>[OH:84][N:83]=[C:60]([C:59](=[O:58])[CH2:81][CH3:82])[C:61]([NH:63][C@@H:64]1[C:79](=[O:80])[N:66]2[C:67]([C:76]([OH:78])=[O:77])=[C:68]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[CH2:69][S:70][C@H:65]12)=[O:62]
Reactant: CCC(=O)CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Reactant: O=N[O-]
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CCC(=O)C1C(=O)OC(C)(C)OC1=O
Agent: CCCC(=O)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(=O)C(=NO)C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 8.2 g. 7β-aminocephalosporanic acid in 100 ml. of tetrahydrofuran and 24 ml. of N,O-bistrimethylsilylacetamide is heated to reflux and stirred for two hours to yield a limpid solution. 6 grams of 2,2-dimethyl-4,6-dioxo-5-propanoyl-1,3-dioxane are added and the mixture is stirred for 3 hours at reflux and then cooled to room temperature and evaporated to dryness. The residue is dissolved in 300 ml. of ethyl acetate and 200 ml. of water. The insoluble phase is filtered off and separated. The organic phase is washed with 100 ml. of water, dried, decolourised over charcoal and evaporated to dryness. The residue is taken up with diisopropyl ether and a gummy product is obtained, which is triturated with diethyl ether to give 2 g. of 7β-(2-oxovaleramido)-3-acetoxymethylceph-3-em-4carboxylic acid melting at 127°-134° C. (with decomposition). To a solution of 1.6 g. of 7β-(3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid in 25 ml of glacial acetic acid are added dropwise 0.6 g of sodium nitrite dissolved in 6 ml. of water. The mixture is stirred for one hour and a half, then 100 ml. of ethyl acetate and 100 ml. of a saturated solution of sodium chloride are added thereto. The organic phase is separated, washed twice with 50 ml. of water, made anhydrous and concentrated to small volume. The precipitate is filtered off and gives 0.9 g. of 7β-(2-hydroxyimido-3-oxovaleramido)-3-acetoxymethylceph-3-em-4-carboxylic acid melting at 190°-204° C. (with decomposition); [α]D =+97° C. (c=0.2 in tetrahydrofuran/water 1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][C:25](=O)[NH:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.Cl>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:27][CH2:26][CH:25]=[N:24][C:23]=4[CH:29]=3)[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1COc2ccc(Nc3ncc(F)c(Nc4cccc([N+](=O)[O-])c4)n3)cc2N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(Nc2nc(Nc3ccc4c(c3)N=CCO4)ncc2F)c1
Yield: 21.2 %

Procedure:
N4-(3-Nitrophenyl)-N2-[(2H) 1,4-benzoxazin-3(4H)-one-6-yl]-5-fluoro-2,4-pyrimidinediamine (940 mg, 2.5 mmol) and Pd/C10% (300 mg, 50% water content) were suspended in EtOH (7 mL) and 10% aqueous HCl (5 mL) and hydrogenated in a Parr apparatus for 3 hours (22° C., 60 psi). The suspension was filtered over celite and neutralized by addition of K2CO3. The solvents were removed and the resulting black slurry was suspended in MeOH. Silica gel (4 g) was added and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give 186 mg of N4-(3-aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine as brownish solid. 1H NMR (DMSO-d6): δ 8.92 (s, 1H), 8.64 (s, 1H), 7.95 (d, 1H, J=3.6 Hz), 7.11 (s, 1H), 6.84-6.95 (m, 3H), 6.66 (dd, 1H, J=2.4, 9.0 Hz), 6.46 (d, 1H, J=8.1 Hz), 6.28 (d, 1H, J=8.1 Hz), 5.62 (s, 1H), 4.98 (s, 2H), 4.03 (m, 2H), 3.31 (m, 2H); LCMS purity: 98.4%; MS (m/e): 352.7 (M+, 100).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[O:19][C@@H:18]1[CH2:20]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(OCC)(=O)C>CC(=O)CC>[O:19]1[CH2:17][C@H:18]1[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: c1cc2c(cc1OC[C@@H]1CO1)OCO2
Yield: 57.4 %

Procedure:
A mixture of sesamol (2.49 g, 18.02 mmol), potassium carbonate (2.74 g, 19.83 mmol) and (2S)-(+)-glycidyl-3-nitrobenzenesulfonate (4.67 g, 18.02 mmol) in 2-butanone (50 mL) was heated to reflux for 18 h. To the cooled reaction mixture was added 35 mL of ethyl acetate and the solids were remove by vacuum filtration. The filtrate was evaporated in vacuo and the residue was taken up into ethyl acetate (65 mL). The solution was washed with aqueous sodium bicarbonate (2×), and water (2×), dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 50% diethyl ether/hexane) to leave 2.01 g of the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15][Cl:16])(=O)C.Cl>C(O)C>[NH2:4][C:5]1[CH:10]=[C:9]2[O:11][CH2:12][O:13][C:8]2=[CH:7][C:6]=1[C:14](=[O:17])[CH2:15][Cl:16]
Reactant: CC(=O)Nc1cc2c(cc1C(=O)CCl)OCO2
Agent: Cl
Solvent: CCO
Product: Nc1cc2c(cc1C(=O)CCl)OCO2
Yield: 51.7 %

Procedure:
To 2'-acetylamino-4',5'-methylenedioxy-2-chloroacetophenone (0.9 g, 3.53 mmol) or an equivalent amount of 2'-pivoylamino-4',5'-methylenedioxy-2-chloroacetophenone in ethanol (60 mL) at about 5° C. is added, dropwise, conc. HCl (12.5 mL, 149.7 mmol). The reaction mixture is then heated at reflux for about an hour, then poured over 2N NaOH/ice (80 mL/60 g) and washed with ethyl acetate (3×70 mL). The organic portions are combined and washed with brine (50 mL), dried (anhydrous sodium sulfate) and concentrated in vacuo to yield a greenish-yellow solid. This solid is recrystallized from ethyl acetate/isopropanol/hexane, treated with activated charcoal, to yield 2'-amino-4',5'-methylenedioxy-2-chloroacetophenone (0.39 g, 52% of theory).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.F.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:20])=[O:19]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Agent: F
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
1,000 g of anthraquinone and 500 ml of hydrogen fluoride (90 percent strength) are initially introduced into a 4 liter Venuleth vessel and stirred for 15 minutes. A mixture of 500 ml of hydrogen fluoride (90 percent strength) and 240 ml of nitric acid (98 percent strength) is added at room temperature over the course of 5 minutes. The bath temperature of the Venuleth vessel is then raised to 50°C and the mixture is stirred at this temperature for 4 hours. Working up takes place as in Example 6. 1,200 g of nitro-anthraquinone of the following composition are obtained:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(Cl)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 146.2 %

Procedure:
4-(5-Chloro-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3.4 g, 10.2 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 3.5 g (97%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C12H15ClN2, 234.09; m/z found, 235.1 [M++H].
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9]O>O1CCCC1>[O:5]=[C:4]1[N:3]2[C@H:2]([O:11][C:7]([CH:8]=[CH2:9])=[CH:6]2)[CH2:1]1
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Solvent: C1CCOC1
Product: C=CC1=CN2C(=O)C[C@H]2O1
Yield: 83.3 %

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0]hept-2-ene (ca 2.5 mmole) in tetrahydrofuran (20 ml) was prepared from clavulanic acid (3.0 mmole) as described in Example 1.
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:18]#[N:19])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:20])=O.Cl>C(O)C>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2([C:18]#[N:19])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Agent: Cl
Solvent: CCO
Product: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Yield: 62.9 %

Procedure:
101.5 g of 5-Cyano-5-(4-fluoro-phenyl)-2-oxo-cyclohexanecarboxylic acid methyl ester (11) were dissolved in 680 mL of ethanol and 171 mL of concentrated aqueous hydrochloric acid were added. The mixture was heated to reflux for 40 h, then evaporated. The residue was taken up in water and extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulphate and evaporated to give 95.2 g of crude product, that was purified by silica gel filtration (heptanes:ethyl acetate) to yield 50.4 g of the desired product 12. Rt=1.26 min (Method 1). Detected mass: 218.2 (M+H+).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1)([CH3:3])[CH3:2].O.[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Br)[C:21]([O:23][CH3:24])=[O:22].COC=C(C1C=CC=CC=1CON1C(=O)C=C(C(F)(F)F)N=C1OC(C)C)C(OC)=O>C1(C)C=CC=CC=1.[Cu-]=O>[CH3:17][O:18][CH:19]=[C:20]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][O:11][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[N:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CC(C)Oc1nc(O)cc(C(F)(F)F)n1
Agent: O=[Cu-]
Agent: COC=C(C(=O)OC)c1ccccc1COn1c(OC(C)C)nc(C(F)(F)F)cc1=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC=C(C(=O)OC)c1ccccc1COc1cc(C(F)(F)F)nc(OC(C)C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22.3 %

Procedure:
2.22 g of 2-isopropoxy-6-trifluoromethyl-4-hydroxypyrimidine and 0.72 g of copper(I) oxide were suspended in 30 ml of toluene. The suspension was refluxed until no water was recognized to form, while formed water was being taken into a quantitative water receiver. 3.08 g of methyl 3-methoxy-2-(2-bromomethylphenyl)acrylate was added at an instance. The reaction was carried out for 5 hours at reflux of toluene. Then the solution was cooled down to room temperature. Insoluble matter was filtrated and further washed with 20 ml of acetone twice. The mixed solution of the obtained filtrate and washings was analyzed with high-performance liquid chromatography. The reaction yield was 22.3% and as for byproducts 0.7% for methyl 3-methoxy-2-[2-(2-isopropoxy-6-trifluoromethylpyrimidin-4-on-3-yloxymethyl)phenyl]acrylate and 77% for 4-(α-methoxy) methylen-2H-chromen-3(4H)-one.