Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9](C=O)[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.C(O)(=O)C.Cl>CO>[CH:19]1[C:20]([N:23]2[C:24](=[O:29])[CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=[C:17]([N:13]2[C:14](=[O:16])[O:15][C@@H:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:12]2)[CH:18]=1
Reactant: O=CN(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Temperature: 75 °C

Procedure:
5-chloro-N-formyl-N-({(5 S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (1.0 g) taken in mixture of acetic acid (5 ml) and conc hydrochloric acid (0.25 ml). Obtained reaction mixture is heated to 70 to 80° C. for 3 to 4 h. After completion of reaction, cooled reaction mixture 25 to 30° C. and added methanol (5 ml). The precipitated solid is filtered off and washed by methanol (3 ml).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-(Diethoxymethyl)benzaldehyde (10 g, 48 mmol) was dissolved in methanol (200 ml) and cooled to 0° C. NaBH4 (4.54 g, 120 mmol, 2.5 eq) was then added slowly and the reaction mixture was stirred for 1 hour, after which the solvent was evaporated. The residue obtained was dissolved in ethyl acetate (100 ml) and water (100 ml), the phases were separated and the organic phase was washed with water (100 ml), dried over magnesium sulphate, and evaporated to yield 1 as a clear oil (10.09 g, 48 mmol, 100%). 1H NMR (300 MHz, CDCl3) δ=7.48 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CH2OH), 7.37 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CH(OEt)2), 5.51 (s, 1H, CH(OEt)2), 4.70 (d, 3J(H,H)=5.9 Hz, 2H, CH2OH), 3.61 (dq, 3J(H,H)=7.1 Hz, 2J(H,H)=9.5 Hz, 2H, CH2CH3), 3.56 (dq, 3J(H,H)=7.1 Hz, 2J(H,H)=9.5 Hz, 2H, CH2CH3), 1.75 (t, 3J(H,H)=5.9 Hz, 1H, CH2OH), 1.24 (t, 3J(H,H)=7.1 Hz, 6H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ=140.9 (ArCCH2OH), 138.6 (ArCCH(OEt)2), 126.9 (ArCH α to ArCCH2OH), 126.8 (ArCH α to ArCCH(OEt)2), 101.3 (CH(OEt)2), 65.1 (CH2OH), 61.0 (OCH2CH3), 15.2 (OCH2CH3).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.[Li+].CC([N-]C(C)C)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31].C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:13][CH:14]1[CH2:19][CH2:18][C:17]([O:20][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:16][CH2:15]1
Reactant: CC1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1CC=C(O[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A 1.4 M n-butyl lithium solution (35.4 ml) was added dropwise to a solution of 7 ml of N,N-diisopropylamine in 20 ml of THF at −78° C. The resulting mixture was stirred at 0° C. for 30 min. Four ml of 4-methylcyclohexan-1-one in 10 ml of THF at −78° C. was added dropwise to the LDA solution. After stirring at −78° C. for 1 hour, 6.5 ml of trimethylsilyl chloride were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour and then poured into an aqueous solution of sodium bicarbonate, followed by extraction with ethyl ether. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by distillation under reduced pressure, whereby 5.83 g of 4-methyl-1-(trimethylsilyloxy)-1-cyclohexene were obtained. Yield: 96%
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14](=[N:16]O)[NH2:15].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:8][C:9]1[C:10]([F:21])=[C:11]([CH:18]=[CH:19][CH:20]=1)/[CH:12]=[CH:13]/[C:14]1[N:16]=[C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])[O:4][N:15]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: NC(/C=C/c1cccc(Cl)c1F)=NO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Fc1c(Cl)cccc1/C=C/c1noc(C(Cl)(Cl)Cl)n1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
12.7 g (0.07 mol) of trichloroacetyl chloride are added dropwise to a suspension consisting of 6.4 g (0.03 mol) of (E)-3-chloro-2-fluoro-cinnamamide oxime in 90 ml of chloroform and 6 ml (0.07 mol) of dry pyridine. During this process, there is a slight evolution of heat. Subsequently, the mixture is stirred for 1 hour and the pyridine hydrochloride which separates out is filtered off and washed with chloroform. The filtrate is concentrated in vacuo and the remaining solid material is recrystallized. 5.0 g (48.7% of theory) of (E)-3-(3-chloro-2-fluoro-styryl)-5-trichloromethyl-1,2,4-oxadiazole are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]1.CCOCC.[OH-].[Na+]>C1COCC1>[O:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]1
Reactant: CCOC(=O)CC1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1CCOCC1
Yield: 98.5 %

Procedure:
To a stirring suspension of lithium aluminum hydride (5.10 g, 138 mmol) in THF (200 mL) at 0° C. was added drop-wise a solution of ethyl 2-(4-oxanyl)acetate (22.0 g, 138 mmol) in THF (50 mL). The reaction mixture was then heated at reflux overnight. After cooling the mixture in an ice bath, ether (300 mL) was added, followed by drop-wise addition of 5N NaOH, until the formation of heavy white precipitate is complete. The suspension was filtered and the filtrate dried (K2CO3), filtered and concentrated by rotary evaporation to give a colorless liquid (17.7 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[O:7]=[CH:8][C:9]([Cl:12])([Cl:11])[Cl:10].C(N(CC)CC)C>CCOCC.[Cl-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([OH:7])[C:9]([Cl:12])([Cl:11])[Cl:10]
Reactant: Cn1cccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Reaction time: 0.08 h
Yield: 105.5 %

Procedure:
To a solution of N-methylpyrrole (8.10 g, 0.1 mol) in ether (50 ml) was added a solution of chloral (16.21 g, 0.1 mol) in ether (50 ml). To this were added p-toluene-sulfonic acid (200 mg) and hydroquinone (5 mg). Then the mixture was refluxed for 15 hours. After adding triethylamine (5 ml), the mixture was stirred for 5 minutes. Brine (100 ml) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine (100 ml). After drying over magnesium sulfate, the organic solution was filtered through a bed of activated charcoal, and concentration afforded the adduct 1-methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (24.1 g) as pale brown prisms.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([OH:13])[CH2:11][O:12][S:29]([CH3:28])(=[O:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCCCCCC
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Temperature: 50 °C

Procedure:
To a solution of the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol obtained in Reference Example 3 and dissolved in ethyl acetate 250 kg were added isopropylether 230 kg, methane sulfonylchloride 34.7 kg at 20-30° C., and triethylamine 30.6 kg and stirring at 30-40° C. for 1 hr. N-heptane was added to the reaction solution and the obtained solution was cooled down to 50° C. or lower to deposit crystals, which were filtered by centrifugation to obtain a wet crystal of crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methane sulfonyloxybutane 153.6 kg (Net.60.6 kg).
Reaction SMILES: [BH4-].[Li+].O1CCCC1.[CH2:8]([S:24][CH2:25][CH2:26][C:27](OCC)=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O>[CH2:8]([S:24][CH2:25][CH2:26][CH2:27][OH:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCSCCCO
Yield: 99.1 %

Procedure:
To a slurry of 147.4 mg of lithium borohydride in ml of tetrahydrofuran is added 2.4 g of 3-(hexadecylthio)propanoic acid, ethyl ester. This mixture is refluxed overnight, poured into water and extracted with ethyl acetate, to give 2.1 g of the desired compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[K+].F[C:10]1[CH:11]=[CH:12][C:13]2[S:14](=[O:25])(=[O:24])[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3>CN(C)C=O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:10]1[CH:11]=[CH:12][C:13]2[S:14](=[O:24])(=[O:25])[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2Oc2cc(OCC(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
1,1,1-Trifluoro-2-ethanol (Aldrich) (0.44 g, 0.004 mole) was added to a stirred, ice-bath cooled mixture of potassium hydride (approximate 50% dispersion in mineral oil) (Aldrich) (0.32 g, 0.004 mole) and N,N-dimethylformamide (75 mL). The ice-bath was removed, and the reaction was stirred at ambient temperature for 1 hour. 3-Fluorophenoxathiin 10,10-dioxide (Example 47) (1.00 g, 0.004 mole) was added, and the mixture was heated at reflux under nitrogen for 2 hours. The reaction was cooled, and the volatiles were removed by spin evaporation in vacuo. The residue was purified by column chromatography on Silica Gel 60 using ethyl acetate-hexanes:2-8. The appropriate column fractions were combined, and the volatiles were removed by spin evaporation in vacuo to give 0.43 g (32% yield) of 3-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide. Recrystallization from ethanol gave 0.23 g (17% yield) of 3-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide, m.p. 165-166° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CN(C=O)C>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH:7]([O:9][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of trans-N-Boc-4-hydroxy-L-proline methyl ester (7) in pyridine and dry DCM at 0° C. is added 4-methyl-benzenesulfonyl chloride. After adding, the mixture is refluxed overnight. The solvent is evaporated and then the residue is dissolved in CH2Cl2. After removal of solvent, the crude 4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained, which is used in the following reaction without further purification. To a solution of 4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester thus obtained above in dry DMF is added NaN3 in one portion, and the reaction mixture is stirred at about 50° C. for 5 h. The resulting mixture is purified to give 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (8).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1.CS(C)(=O)=O>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)Cl
Agent: CS(C)(=O)=O
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Yield: 228.8 %

Procedure:
500 g of chlorobenzene and 2.4 g of dimethyl sulfone (0.025 mol) were placed in the glass vessel and 30 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 78° C., with vigorous phosgene reflux being established. While stirring vigorously at 78–80° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 105 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 78–80° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 50° C. by means of nitrogen. The reaction mixture obtained was a suspension from which the solid obtained was separated by filtration. 7.8 g of solid were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 86.8 g of cyclohexyl isocyanate (0.694 mol). This corresponds to 69.4% of the theoretical yield.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].CO>C1C=CC=CC=1>[CH2:6]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: C[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Aminopropan-1-ol (20.00 g, 266.3 mmol) was dissolved in benzene (266 mL) before benzaldehyde (26.91 mL, 266.3 mmol) was added and the reaction refluxed under a Dean-Stark trap for 1.5 h collecting 4.2 mL of water. The reaction mixture was cooled in an ice bath before sodium borohydride (10.07 g, 266.3 mmol) was added. The mixture was warmed to RT and stirred overnight. In an ice bath, methanol was added to the reaction mixture to quench the hydride, then the reaction concentrated, filtered, washed with dichloromethane, concentrated, and purified by flash chromatography to give the title compound. MS (ES+): 166 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
2.54 g of 6-Methoxy-2H-isoquinolin-1-one (65) were dissolved in 50 mL of dry dichloromethane and at 0° C. 2.74 mL of boron tribromide were carefully added. The mixture was allowed to stir at room temperature for 18 h and was then poured on ice/water. The organic layer was separated, washed with brine, dried over sodium sulphate and evaporated to dryness. The crude material was purified by silica gel chromatography to yield 1.96 g of the desired product.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][C:6]1=[CH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.S(=O)(=O)(O)O>ClC1C=CC=CC=1Cl.O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:9](=[O:10])[CH2:8][C:6](=[CH2:7])[C:5]([OH:11])=[O:12])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: C=C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 20 °C
Yield: 70 %

Procedure:
193.3 g (1.45 mol) of anhydrous aluminum chloride are introduced in 1100 g of o-dichlorobenzene and the mixture is brought to 45° C. with stirring. A solution of 80.9 g (0.72 mol) of itaconic anhydride and 132 g (0.7 mol) of 4-chlorobiphenyl in 700 g of o-dichlorobenzene at 50° C. is added dropwise in the course of three hours. The reaction mixture is stirred at 25° C. for four hours and then added to an ice-cold mixture of 1000 g of water and 25 g of sulfuric acid (96%). The aqueous phase is separated off. The organic phase is washed three times with a mixture of 1000 g of water and 15 g of sulfuric acid (96%) in each case. After washing three times, it is allowed to cool to approximately 20° C. and the colorless product is then filtered off with suction. This is then washed three times with 150 g of ethanol (96%) in each case. The product is dried at 60° C. and about 100 mbar until free of solvent and water. 148 g (0.49 mol) of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid (70%) are obtained as a colorless, finely crystalline powder. By working up the mother liquor, as described in Example 1, the yield is increased to 83%. (HPLC purity 99.6-99.8%)
Reaction SMILES: C(O)CCC.[OH-].[Na+].[CH2:8]([P:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:16])[O:11]CCCC)[CH3:9].S(=O)(=O)(O)O>O>[CH2:8]([P:10]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])(=[O:11])[OH:16])[CH3:9]
Reactant: CCCCOP(=O)(CC)CCOCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCOCCP(=O)(O)CC
Temperature: 120 °C
Yield: 78.5 %

Procedure:
A stirred apparatus is initially charged with 150 g of butanol, 65 g of water, 150 g (3.75 mol) of sodium hydroxide and 278 g (1.25 mol) of butyl ethyl(2-ethoxyethyl)-phosphinate (produced as in Example 7). The efficiently stirred mixture is heated to about 120° C. and reacted at that temperature for about 6 hours. Then, 250 ml of water were added and the butanol was removed from the reaction mixture by distillation. Following the addition of a further 500 ml of water, the mixture is neutralized by addition of about 184 g (1.88 mol) of concentrated sulfuric acid. The water is then distilled off in vacua. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to obtain 163 g (98% of theory) of ethyl(2-ethoxyethyl)phosphinic acid as oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O(C1C=C(C=CCC(C2C=CC(C)=CC=2)(C)C)C=CC=1)C1C=CC=CC=1.[H][H]>[Pd].C([O-])(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)([CH3:18])[CH3:19])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(C)(C)C=CCc2cccc(Oc3ccccc3)c2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cc1ccc(C(C)(C)CC=Cc2cccc(Oc3ccccc3)c2)cc1
Product: Cc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 3 h

Procedure:
To 30 ml of ethyle acetate, 1.9 g of a mixture of 50% 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-2-pentene and 50% 1-(3-phenoxyphenyl)-4-(4-methylphenyl)-4-methyl-1-pentene was added and dissolved, and thereto 0.4 g of 5% Pd-C was added, and the mixture was stirred under a pressure of 20 kg/cm2G with hydrogen gas at room temperature. After three hours, Pd-C was removed by filtration, and ethyl acetate was evaporated under reduced pressure.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:13]([C:15]([CH2:22][OH:23])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:16]=[O:17])[CH3:14]>>[CH2:13]([C:15]([CH2:22][O:23][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:16]=[O:17])[CH3:14]
Reactant: CCCCC(C=O)(CC)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCC(C=O)(CC)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
To a cold (10° C.) solution of 12.6 g (0.11 mole) of methanesulfonyl chloride and 10.3 g (0.13 mole) of triethylamine was added dropwise 15.8 g of 2-ethyl-2-(hydroxymethyl)hexanal, prepared according to the procedure described in Chem. Ber. 98, 728-734 (1965), while maintaining the reaction temperature below 30° C. The reaction mixture was stirred at room temperature for 18 h, quenched with dilute HCl and extracted with methylene chloride. The methylene chloride extract was dried over MgSO4 and concentrated in vacuo to give 24.4 g of brown oil.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:12][CH:13]=1)[O:6][CH2:7][CH2:8][C:9]2=[O:11]
Reactant: O=C(O)CCOc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=C1CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
A mixture of 30.0 g (163.0 mmol) of 3-(4-fluorophenoxy)propionic acid and 180 ml of concentrated sulfuric acid was stirred for 1 hour at room temperature and then the reaction mixture was poured into 700 g of ice to deposit immediately a white crystal. The white crystal was collected by filtration, washed with water and dried in air, and the resultant was recrystallized from ethanol to give 20.55 g of 6-fluoro-4-chromanone as a white crystal (yield: 76%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.C(O)C.[Cl-].[NH4+]>[Zn].C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:14]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc([N+](=O)[O-])c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc(N)c2)cc1
Yield: 102.5 %

Procedure:
To a flask containing 4,5-difluoro-2-methoxy-4′-(3-nitro-benzyloxy)-biphenyl (1.49 g, 4.0 mmol) was added ethanol (40 ml), zinc (2.5 g, 40 mmol) and ammonium chloride (3.2 g, 60.2 mmol). Additional solvent was added over time, ethanol (30 mL at 15 min) and ethyl acetate (10 mL at 45 min). After 1 hr the reaction was filtered through Celite, concentrated, diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL), dried over magnesium sulfate, concentrated and dried from hexanes/methylene chloride mixtures to yield 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-phenylamine as a yellow oil (1.4 g, 100%). LC-MS (ES) calculated for C20H17F2NO2, 341.12; found m/z 342 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[CH:6]=1)=[O:4].Cl>CO.[Fe]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2cc(N)ccc2s1

Procedure:
A suspension of 584 (3.52 g, 14.8 mmol) in methanol (100 ml) was treated with Fe powder (6.63 g, 118.7 mmol). The resulting suspension was heated to reflux, and 12M HCl (8.5 ml) was slowly added over 15 min. The resulting green dark suspension was refluxed for an additional 3 h, then cooled and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3, then brine, dried over MgSO4, filtered and concentrated to afford (2.57 g, 84%). 1H NMR: (DMSO) δ (ppm): 7.92 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.88 (dd, J=1.8, 8.4 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H). LRMS: 207.0 (Calc.). 208.1 (found).