Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][C:10]3(OCC[O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1

Procedure:
A mixture of 2-[2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]-1H-isoindole-1,3(2H)-dione (7-2) (3.1 g, 7.48 mmol) and p-toluenesulfonic acid monohydrate (0.14 g, 0.75 mmol) in acetone (50 mL) was refluxed for 2 days. The cooled mixture was diluted with EtOAc, washed with sat. NaHCO3, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0˜100% EtOAc in hexane, to give 2-[1-(4-bromophenyl)-3-oxocyclobutyl]-1H-isoindole-1,3(2H)-dione (7-3) as a colorless form.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8]O)[O:4][C@H:3]1[N:10]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].C(Br)(Br)(Br)Br>CO.CN(C)C=O>[N:39]([CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@H:2]([F:1])[C@@H:6]1[OH:7])=[N+:40]=[N-:41]
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1cn([C@@H]2O[C@H](CN=[N+]=[N-])[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 0.4 g of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil, 0.44 g of triphenylphosphine, 0.48 g of sodium azide and 6 ml of dry dimethylformamide was stirred at room temperature under nitrogen while 0.48 g of carbon tetrabromide was added portionwise. The mixture was stirred at room temperature under nitrogen for 20 hours. 3 ml of methanol were added, the mixture was stirred for 0.5 hour and then evaporated. The residue was stirred for 0.5 hour with 8 ml of 0.5M sodium hydroxide solution. The resulting suspension was filtered and the insoluble triphenylphosphine oxide was washed with water. The filtrate was acidified to pH 5 by the addition of hydrochloric acid and then extracted three times with 20 ml of ethyl acetate. The extracts were dried over magnesium sulfate, filtered and evaporated. The residual solid was washed on to a filter with 10 ml of diethyl ether/petroleum ether (1:1) and then dried in vacuo to give 0.4 g of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 185°-188° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[CH:7]=1.O>C(O)(=O)C>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=c1cc(O)c2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
Fuming nitric acid (262 mL) was added at about 20° C. to a suspension of 4-hydroxy-2(1H)-quinolinone (1.0 Kg) in acetic acid (7.57 L). The mixture was heated at 40° C. for 2.5 h. The resulting solution was cooled to about 20° C. and poured into 8 L of water. The resulting mixture was stirred for 20 min, filtered, washed with water until the filtrate was neutral, and dried. The product 4-hydroxy-3-nitro-2(1H)-quinolinone was isolated in 98% yield and showed only one spot upon analysis by thin layer chromatography (silica gel, 20:80 (V/V) chloroform in methanol).
Reaction SMILES: Br.C(O)(=O)CC.C1(O)C=CC=CC=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:18]2>O>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][NH:19][CH2:18]2
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of aqueous hydrobromic acid (16 mL, 48% solution in water), propionic acid (2.8 mL) and phenol (2 g) was added 5-bromo-2-(p-tolylsulfonyl)isoindoline (2.4 g, 6.8 mmol). The resulting mixture was heated to reflux and stirred at this temperature for 10 hr then cooled to room temperature. This mixture was diluted with water (20 mL) and extracted with ether (2×50 mL). The aqueous extract was brought to pH 14 with 5M sodium hydroxide solution. This solution was extracted with ether (3×). The ether extract is washed with brine, dried over magnesium sulfate, and concentrated to give the title compound as an oil.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9]([O:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11].[N-]=C=O.Cl>O.CN(C)C(=O)C>[C:9]([O:14][CH2:15][CH2:16][NH:17][C:18]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:19])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: Nc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: Cl
Agent: [N-]=C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(O)cc1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Into a 1 liter fask 500 g of N,N-Dimethyl acetamide and 173.5 g (1.6 mole) of p-aminophenol were added. This mixture was placed in cold bath and 234.9 g (1.5 mole) of methacryloyl oxyethyl isocyanate was added over a period of 1 hour. After the addition was complete, stirring was continued for 5 hours at room temperature. The mixture was tested for isocyanate functionality using IR spectroscopy. 30 ml of concentrated HCl was added to the mixture and was stirred for 15 minutes. The mixture was poured into 4.5 liter of water. The deposit was filtered, washed and dried to produce 370 g of 2-(N′-(4-hydroxyphenyl)ureido)ethyl methacrylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]2=[O:37])=[C:11]([OH:39])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2ccc(OCc3ccccc3)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using [4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-1,3-dihydro-2H-indol-2-one was obtained (57%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ9.01 (s, 1H), 7.45-7.16 (m, 15H), 7.13-7.01 (m, 2H), 6.96 (s, 1H), 6.85-6.76 (m, 1H), 6.71-6.65 (m, 1H), 6.55-6.49 (m, 1H), 6.49-6.42 (m, 1H), 5.10 (s, 1H), 4.99 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCO.O>[Fe].CC(O)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Temperature: 80 °C
Reaction time: 1.75 h

Procedure:
Iron powder (5.4 g, 97 mmol, 4 equiv) is added portionwise to an 80° C. mixture of 1-benzyl-4-(4-nitro-phenyl)-piperazine (7.2 g, 24.2 mmol), EtOH (150 mL), H2O (40 mL), and AcOH (20 mL). The reaction mixture is stirred for 1.75 h at 80° C., allowed to cool to RT, and concentrated. The residue is diluted with EtOAc and an aqueous saturated solution of Na2CO3. The layers are separated and the aqueous phase is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound: ES-MS: 268.3 [MH]+; single peak at tR=1.30 min (system 1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[C:11]([N+:20]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+].CCOC(C)=O>C1(C)C=CC=CC=1.O.[Fe]>[NH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reaction time: 48 h
Yield: 86 %

Procedure:
A mixture of 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)ethanone (3.6 g, 12 mmol), iron powder (4.5 g) and ammonium formate (5.5 g) in toluene (50 mL) and water (50 mL) was heated at reflux temp. for 2 days with stirring. To this mixture was added EtOAc (100 mL), stirred for 20 minutes, the solid was filtered through a celite bed and washed with EtOAc (150 mL). The EtOAc layer was separated from the filtrate solution, washed with water (2×100 mL), dried over MgSO4 and concentrated in vacuo to afford the product (2.80 g, 86%) as a beige-colored solid. 1H NMR (CDCl3) δ 7.41-7.30 (m, 5H), 7.13 (s, 1H), 6.15 (br s, 2H), 6.10 (s, 1H), 5.13 (s, 2H), 3.84 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: OC1C=C(O)C=CC=1[CH:9]([C:16]([CH:18]([C:25]1[CH:30]=[CH:29]C(O)=CC=1O)C1C=CC=CC=1)=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:33]([O:35][CH:36]([O-])[O-])[CH3:34].N1CC[O:42]CC1>C(Cl)(Cl)Cl>[OH:42][C:29]1[CH:34]=[C:33]2[C:18]([C:16](=[O:17])[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:36][O:35]2)=[CH:25][CH:30]=1
Reactant: C1COCCN1
Reactant: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reactant: CCOC([O-])[O-]
Solvent: ClC(Cl)Cl
Product: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Yield: 90.6 %

Procedure:
A mixture of 20 g (0.0877 mole) 2,4-dihydroxy-phenyl-benzyl-ketone, 20.7 g (0.14 mole) ethyl-orthoformate and 1 ml of morpholine is stirred on a hot water bath. Crystallization starts after heating for 25 minutes. The inert temperature falls back to 87° C. from 96° C. during the reaction. After stirring for 5 hours the reaction mixture is diluted with 48 ml of chloroform and then one may proceed as disclosed in Example 5. 18.9 g of 7-hydroxy-isoflavone are obtained.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.CCOC(C)=O>CS(C)=O>[Br:15][CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Br)C(=O)c1ccccc1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Ethyl benzoylacetate (0.27 mL, 1.6 mmol) [Fluka cat#12990] was dissolved in dimethyl sulfoxide (5.0 mL) at room temperature and the N-bromosuccinimide (0.30 g, 1.7 mmol) was added portion wise. The reaction mixture was stirred for 3 h and EtOAc was added and washed with water, water saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give Ethyl 2-bromo-3-oxo-3-phenylpropanoate (0.40 g, 95%) as an oil %). LCMS calc. for C11H12BrO3 (M+H)+: m/z=271.0, 273.0. found: 271.0, 273.0.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.C(O)(=O)CCCCC(O)=O>>[CH3:1][C:2]1[CH2:3][C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=C(O)CCCCC(=O)O
Product: CC1=CC(C)(C)CC(=O)C1

Procedure:
In a flask (capacity: 1 liter; connected to a plate column) were fed 3,5,5-trimethylcyclohexa-2-en-1-one (553 g) and adipic acid (38 g). Isomerization was carried out under a pressure of 340 Torr with a temperature (liquid phase) of 190° C. in the flask, while controlling the charge (supply) of 3,5,5-trimethylcyclohexa-2-en-1-one to keep the temperature at 154° C. at the top of the column, and simultaneously, continuous distillation was effected using a distilling column "Order show" equipped with 30 plates, adjusting the liquid level in the flask at a predetermined level. As a result, 3,5,5-trimethylcyclohexa-3-en-1-one was constantly obtained from the top of the column in 25 g per hour, its concentration being 99% or higher (analysed by gas chromatography).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:19]1([CH2:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)([CH3:13])[CH3:12])[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(n1cncn1)C1(c2ccc(Cl)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(n1cncn1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 71 %

Procedure:
A mixture of 2-(4-chlorophenyl)-2-[2-(1H-1,2,4-triazol-1-yl)prop-2-yl]oxirane (1.1 g.), 1,2,4-triazole (2 g.), potassium carbonate (5 g.) and dry dimethylformamide (25 ml.) was heated at 80° under a nitrogen atmosphere for 16 hours. The reaction mixture was then cooled, filtered, washed with xylene and the filtrate was evaporated in vacuo. The residue was azeotroped with xylene (2×30 ml.) and then partitioned between methylene chloride (50 ml.) and water (50 ml.). The aqueous phase was extracted with methylene chloride (3×50 ml), and the combined organic phases were washed with water (50 ml.), and dried (MgSO4). The residue obtained after removal of the solvent was flash chromatographed on silica (150 g) using methylene chloride/methanol/saturated aqueous ammonia (93:7:1 v/v/v), for elution. The product-containing fractions on evaporation followed by crystallisation from ethyl acetate/hexane yielded 983 mg. (71% yield) of the title compound, m.p. 128°-9°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.53 g (10 mmol) of 3-methyl-4-nitrophenol, 1.95 g (10 mmol) of t-butyl bromoacetate and 2.76 g (20 mmol) of potassium carbonate in 10 mL of DMF are stirred at RT for 2 h. Water is added and the mixture is extracted with EtOAc and the organic phase is washed with water and brine, and dried over anhydrous Na2SO4. The solvent is removed under reduced pressure and the residual oil is filtered through a pad of silica gel using CH2Cl2 as the eluant to give (3-methyl-4-nitrophenoxy)-acetic acid t-butyl ester as an oil: 1H-NMR (CDCl3) δ 8.08 (d, J=9.56, 1H), 6.82-6.75 (m, 2H), 4.58 (s, 2H), 2.63 (s, 3H), 1.49 (s, 9H); Anal. Calcd for C13H17NO5 C, 58.42; H, 6.41; N, 5.24; Found C, 58.04; H, 6.51; N, 5.09.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8]CC)=[O:7])[CH3:2].O.Cl>C(OCC)(=O)C.C(O)C.[OH-].[K+]>[CH2:1]([S:3][CH2:4][CH:5]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CSCC)CC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCSCC(CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101.9 %

Procedure:
650 mg of ethyl 2-ethylthiomethyl-4-methylpentanoate was dissolved in 6 ml of an ethanol/water (10/1) solution, 8.9 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide was added thereto. The solution was stirred at room temperature for 2.5 hours, and then, the reaction solution was distilled off under reduced pressure to obtain a suspension. To this suspension, 40 ml of water was added, and the reaction solution was adjusted to pH2 with 2N hydrochloric acid under cooling with ice, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 577 mg of 2-ethylthiomethyl-4-methylpentanoic acid as colorless oily substance.
Reaction SMILES: B([O-])([O-])[O-].[Na+].[Na+].[Na+].O.[OH-].[Na+].[CH2:11]([O:13][C:14]([C@:16]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]>CS(C)=O>[CH2:11]([O:13][C:14]([C@@:16]1([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:15])[CH3:12]
Reactant: C=C[C@H]1C[C@@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 48 °C
Reaction time: 2 h

Procedure:
A solution of 5 L of 0.2M sodium borate buffer (pH 9) at 45° C. in a 20 L jacked reactor stirred at 400 rpm was treated with 3 L of DI water and 4 L of Savinase 16 L, type EX (Novozymes North America Inc.). When the temperature of the mixture closed to 45° C., the pH was adjusted to 8.5 with 10N NaOH. A solution of (1R,2S)/(1S,2R)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (200 grams) in 2 L DMSO was added to the reactor over a period of 40 minutes via addition funnel. The reaction temperature was then adjusted to 48° C. After 2 hours, the pH was adjusted to pH 9.0 with 10N NaOH. At 18 hours, enantio-excess of the ester reached 72% and the pH was adjusted to 9.0 with 10N NaOH. At 24 hours the temperature was lowered to 35° C. At 42 hours the temperature was raised to 48° C. and the pH was adjusted to 9.0 with 10N NaOH. Heating was stopped at 48 hours and the reaction was slowly cooled down to room temperature (about 25° C.) and stirred overnight. At 66 hours, the pH of the reaction mixture was 8.6. The mixture was extracted with MTBE (2×4 L). The combined MTBE extracts were washed with 5% NaHCO3 (6×300 mL) and water (3×300 mL) and concentrated to give enantiomerically pure (1R,2S)N-Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester as light yellow crystals (101A g; purity: 95.9% (210 nm, containing no acid; 98.6% ee).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23]>C(Cl)Cl>[CH2:21]([S:24]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:26])=[O:25])[CH2:22][CH3:23]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring ice-cold solution of tert-butyl piperazine-1-carboxylate (1, 10.0 g, 53.69 mmol) and Et3N (22.4 mL, 161.07 mmol) in CH2Cl2 (200 mL) was slowly added 1-propanesulfonyl chloride (7.65 g, 53.69 mmol). The mixture stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was washed with 2 N NaOH (50 mL), 2 N HCl (50 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford tert-butyl 4-(propylsulfonyl)piperazine-1-carboxylate (2) as an off-white solid (15.70 g, quantitative): 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J=1.7 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.21 (m, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H); MS (ESI+) m/z 293.
Reaction SMILES: [C-:1]#[N:2].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[Co:13].[Cl-].[Zn+2:15].[Cl-]>O>[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[C-:1]#[N:2].[Co+3:13].[Co+3:13].[Zn+2:15].[Zn+2:15].[Zn+2:15]
Reactant: [Co]
Agent: [C-]#N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: [Co+3]
Reaction time: 0.17 h

Procedure:
Potassium hexacyanocobaltate (4.0 g) is dissolved in deionized water (150 mL) in a beaker. Zinc chloride (10 g) is dissolved in deionized water (15 mL) in a second beaker. The aqueous solutions are quickly combined and magnetically stirred for 10 min. The precipitated solids are isolated by centrifugation. The solids are reslurried in deionized water (100 mL) for 10 min. with stirring, and are again recovered by centrifugation. The catalyst is dried in a vacuum oven at 50° C. and 30 in. (Hg) to constant weight. This catalyst is identified as Catalyst A, and has the powder X-ray diffraction pattern shown in FIG. 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](=[O:15])([O:12][CH2:13][CH3:14])N>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2].C(O)C>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[C:6]([NH:8][C:10]([O:12][CH2:13][CH3:14])=[O:15])[CH:5]=[CH:4][C:3]=1[CH3:9])=[O:15])[CH3:14]
Reactant: CCOC(N)=O
Reactant: Cc1ccc(N)cc1N
Agent: CCCCCCCC(=O)[O-]
Agent: [Zn+2]
Solvent: CCO
Product: CCOC(=O)Nc1ccc(C)c(NC(=O)OCC)c1
Reaction time: 6.1 h

Procedure:
733 g of 2,4-diamino-toluene, 1069 g ethyl carbamate, 1160 g ethanol (approximately 96%) and 5.5 g zinc octoate were reacted in the apparatus described in Example 1 for 6.1 hours at 200° C. After the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography (HPLC). A yield of 1220 g (76% of the theoretical yield) of 2,4-bis-(ethoxy carbonylamino)-toluene was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1F>CS(C)=O.C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([N+:23]([O-:25])=[O:24])[CH:19]=[CH:20][C:21]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 60 °C
Yield: 103.1 %

Procedure:
A suspension of morpholine (4.72 mL, 4.72 g, 54.2 mmol) and dibasic potassium phosphate (9.44 g, 54.2 mmol) in DMSO (27 mL) was treated with 3,4-difluoronitrobenzene (3.0 mL, 4.31 g, 27.1 mmol) was warmed at 60° C. for 18 h. The solution was cooled and diluted with ethyl acetate and extracted with water (3×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded the title compound (6.32 g, ca. 100%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.00 (ddd, J=9.0, 2.6, 0.9 Hz, 1H), 7.92 (dd, J=13.1, 2.6 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 3.88 (m, 4H), 3.29 (dd, J=5.5, 4.0 Hz, 4H). MS+DCI m/z (rel abundance) 227 (10, M+H), 244 (100, M+NH4).