Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[N:8](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]#[N:13])[OH:9]
Reactant: ON=Cc1ccccc1
Reactant: [C-]#N
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 9.07 g (75 mmol) of benzaldoxime in 25 ml of carbon tetrachloride is added dropwise, at 5°, a solution of 45 ml of carbon tetrachloride saturated with 5.6 g (79 mmol) of chlorine gas. The mixture is stirred for 1 hour in an ice bath and then excess HCl is removed by vacuum. A saturated solution of 7.35 g (150 mmol) of sodium cyanide in water is added dropwise, at 0°. The mixture is stirred for 2 hours as it is allowed to warm to RT. An excess of aqueous sodium hydroxide is added and then the carbon tetrachloride layer is discarded. The aqueous layer is acidified and filtered, and the resulting solid is washed with water and dried to give α-oximinophenylacetonitrile, m.p.=120°-125°.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].C(N(CC)C(C)C)(C)C.[F:27][C:28]1[CH:29]=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][C:33]=1F>C(#N)C>[F:27][C:28]1[CH:29]=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][C:33]=1[N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][F:8])[C:12](=[O:17])[CH2:13]1
Reactant: O=C1CNCCN1CCF
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2F)CCN1CCF

Procedure:
1-(2-Fluoroethyl)-2-oxopiperazine trifluoroacetate (6.1 g) is dissolved in acetonitrile (100 ml). N,N-Diisopropylethylamine (13 ml) is added to the mixture, followed by 3,4-difluoronitrobenzene (3.39 g) and the mixture heated to reflux for 18 hours. The solvent is removed and the residue chromatographed (silica; eluting with a gradient increasing in polarity from 0 to 4% methanol in dichloromethane) to give 3-fluoro-4-(4-{2-fluoroethyl}-3-oxopiperazin-1-yl)nitrobenzene.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]([N:20]1[C:24]2[NH:25][C:26](=O)[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]=2[C:22]([CH3:35])=[N:21]1)([CH3:19])[CH3:18]>N1C=CC=CC=1.CCOC(C)=O>[CH3:19][C:17]([N:20]1[C:24]2[N:25]=[C:26]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23]=2[C:22]([CH3:35])=[N:21]1)([CH3:16])[CH3:18]
Reactant: CCOC(=O)c1cc(=O)[nH]c2c1c(C)nn2C(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1c(C)nn2C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (0.457 mL, 2.70 mmol) was added dropwise to a solution of ethyl 1-(1,1-dimethylethyl)-3-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (500 mg, 1.803 mmol) in pyridine (10 mL), and the reaction mixture was stirred at room temperature for 16 h. The contents were diluted with EtOAc and washed with saturated NaHCO3, and then brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0% to 100% DCM:Hex) to afford the final product as a solid, 670 mg (91%). LCMS E-S (M+H)=410.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.07 Hz, 3H), 1.71 (s, 9H), 2.58 (s, 3H), 4.46 (q, J=7.07 Hz, 2H), 7.63 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[F:1][C:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][C:18]3[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(C=C2c3ccccc3CCc3c(F)cccc32)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(CC2c3ccccc3CCc3c(F)cccc32)c1
Reaction time: 18 h
Yield: 57 %

Procedure:
Dissolve 3-(1-fluoro-10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (170 mg, 0.54 mmol) in EtOH (5 mL) and add 10% Pd/C (50 mg). Stir for 18 h under an atmosphere of hydrogen. Filter and concentrate. Purify the crude product using column chromatography (10% EtOAc/hexane→25% EtOAc/hexane) to give 98 mg (57%) product as a colorless oil. MS (ES) 317 (M−1). HPLC shows 99% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].Br[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C)C=O>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CCBr
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNc1cc(Cl)cc(Cl)c1
Yield: 49.2 %

Procedure:
In 20 ml of dimethylformamide was dissolved 5.0 g of 3,5-dichloroaniline. To the solution was added 6.16 g of ethyl 3-bromopropionate, followed by heating under reflux for 6 hours. The reaction mixture was concentrated and the concentrate was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was subjected-to silica gel column chromatography (eluent: chloroform:hexane=1:1) to yield 3.98 g of the titled compound as a white crystal.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[OH:36][C@@H:37]([CH3:41])[C:38]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:6][CH2:7]1)=[O:39]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example D.f12) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:14])[CH:11]=2)[CH2:6]1.CS(C)=O.N1C=CC=CC=1.[CH3:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([C:43](Cl)=[O:44])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:43]([C:31]3[C:32]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:35][CH:34]=4)=[C:27]([CH3:26])[CH:28]=[CH:29][CH:30]=3)=[O:44])[CH:11]=2)[CH2:6]1)=[O:15]
Reactant: COC(=O)N[C@@H]1Cc2ccc(N)cc2C1
Reactant: Cc1cccc(C(=O)Cl)c1-c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)N[C@@H]1Cc2ccc(NC(=O)c3cccc(C)c3-c3ccc(C(F)(F)F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice bath cooled solution of (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester (9.5 g, 46.1 mmol), ([α]D=−26.29° (c=9.87 mg/mL, DMSO); mp 144-145° C.) and pyridine (4.48 mL, 55.5 mmol) in 200 mL of methylene chloride is added 6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid chloride (80.5 mL of a 0.63 M solution in methylene chloride, 50.7 mmol). The reaction is stirred for 15 minutes at room temperature. The mixture is washed with 1N HCl, bicarbonate and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate/hexanes (1:2) to give (R)-6-methyl-4′-trifluoromethyl-1,1′-biphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl)-amide as crystalline solid, mp 112-114° C. [α]D=−12.85°, c=11.36 mg/mL DMSO.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: COc1cccc(CCc2ccccc2O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 45.8 %

Procedure:
Following a procedure similar to that described in Example 40(a), 2.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 3.74 g of (S)-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine and 0.983 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.65 g (yield 45%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>C(C(C)=O)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccccc1NCc1ccc(F)cc1

Procedure:
56 g N-(4-fluorobenzyl) 2-nitroaniline are reduced in the presence of 34 g of 5% palladized charcoal into methanol (560 ml) using a stream of hydrogen at room temperature and normal pression. After achievement of the reaction, the mixture is washed with nitrogen, filtered on clay (Trade Mark Celite) and concentrated to dryness. The residue is recrystallized from isopropyl ether. The desired N-substituted phenylene diamine, is thus obtained recovered weight: 38.5 g. The starting material N-(4-fluorobenzyl) 2-nitroaniline is prepared by alkylating the 2-nitroaniline by means of 4-fluorobenzyl chloride in the methyl ethyl ketone.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][O:24]C2CCCCO2)[N:9]=1>CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH2:23][OH:24])[N:9]=1
Reactant: COc1ccc(CNc2nn(CCCOC3CCCCO3)c(=O)c3ccc(C#N)cc23)cc1Cl
Agent: Cl
Solvent: CO
Product: COc1ccc(CNc2nn(CCCO)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanol (20 ml) and 1N hydrochloric acid (2 ml) were added to the 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-2-[3-(tetrahydropyran-2-yloxy)propyl]-1(2H)-phthalazinone (0.20 g) prepared in Example 24. The obtained mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].[Li]CCCC.[CH2:23]=[O:24]>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH2:23][OH:24]
Reactant: C#CCCCc1nc(-c2ccccc2)oc1C
Reactant: C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCCC#CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Alkyne 1-7 (1.44 g, 6.4 mmol) was dissolved in THF (100 mL) at −78° C. under N2 atmosphere. nBuLi (5.6 mL, 9.0 mmol) was then added and the reaction stirred at −78° C. for 1 hour. Paraformaldehyde (320 mg, 9.6 mmol) was then added in one portion and the reaction stirred while allowing equilibration to 23° C. over 16 hours. Reaction was washed with dilute aqueous HCl, water, brine, and dried over MgSO4. After removing solvent in vacuo chromatography of the residue with 25% EtOAc/Hexanes gave 1.5 g of the product 1-8 as a clear yellowish oil (92%). NMR CDCl3 (δ): 7.97 (@H, m); 7.43 (3H, m); 4.25 (2H, t, J=2.2, 4.4 Hz); 2.60 (2H, t, J=7.3, 14.6 Hz); 2.33 (3H, s); 2.27 (2H, m); 1.89 (2H, m). M+1=256.2.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].S(=O)(=O)(O)O.C(N(CC)[C:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[Cl:28])=[CH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)C.[OH-].[Na+]>O>[CH3:2][O:3][N:4]=[C:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[Cl:28])[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCN(CC)C(=Cc1cccnc1)c1ccc(F)cc1Cl
Reactant: CON
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CON=C(Cc1cccnc1)c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 1.2 g of O-methylhydroxylamine hydrochloride in 2.4 ml of distilled water is slowly treated with concentrated sulfuric acid with stirring in such a way that the reaction temperature does not rise above 60° C. 4.0 g of 3-[β-(diethylamino)-2-chloro-4-fluorostyryl]pyridine are then added rapidly in such a way that the internal temperature is exactly 70° C. at the end of the addition. The mixture is then stirred at 70° C. for 5 hours, cooled to room temperature and poured into ice-water. The aqueous phase is adjusted to pH=8.0 with sodium hydroxide solution and the mixture is extracted with diethyl ether. The organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2'-Chloro-4'-fluoro-2-(3-pyridyl)acetophenone O-methyloxime is obtained as an E/Z isomer mixture in the form of a brownish oil. Column chromatographic separation on silica gel using n-hexane/ethyl acetate (4:1) first gives the E isomer [1H-NMR (CDCl3, 200 MHz): 4.03 ppm (s, CH3O--N=)] and then the Z isomer [1H-NMR (CDCl3, 200 MHz): 3.84 ppm (s, CH3O--N=)].
Reaction SMILES: [C:1]([C:5]1[C@@H:6]2[O:12][CH:9]([CH2:10][CH:11]=1)[CH2:8][CH2:7]2)([O:3][CH3:4])=[O:2].C12(C)C(C)(C)C(CC1)[C@@H](C([O-])=[O:23])C2.CO.[OH-].[Li+].Cl>C1COCC1.CCOCC.O>[C:1]([CH:5]1[C:11](=[O:23])[CH2:10][CH:9]2[O:12][C@@H:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: CC12CCC([C@@H](C(=O)[O-])C1)C2(C)C
Reactant: COC(=O)C1=CCC2CC[C@H]1O2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)C1C(=O)CC2CC[C@H]1O2
Yield: 94 %

Procedure:
(1R)-2-Carbomethoxy-8-oxabicyclo(3.2.1)octa-2-ene-3-(S)-camphanate, (1R, 1′S)-19 (1.76 g, 4.8 mmol) was dissolved in THF (15 mL) and then methanol (5 mL) and water (5 mL) were added. The resulting solution was cooled in an ice bath and lithium hydroxide (325 mg, 7.7 mmol) was added in one portion. After 20 min no (1R, 1′S)-19 remained. The solution was neutralized with 1 M hydrochloric acid. Ether (200 mL) was then added and the ethereal solution was washed with brine and dried (MgSO4). Evaporation gave 1.38 g of the crude reaction product. This was chromatographed (SiO2, 50 g, eluent: 20% ether in hexanes) to yield 833 mg (94%) of the pure title compound. 1H-NMR and TLC were identical with the racemic ketone 13. Under chiral HPLC conditions (Chiralcel OC column, eluent: 10% isopropanol in hexanes 1 mL/min.) tR (1S)-13=6.99 min (1.78%); tR (1R)-13=10.92 min (98.21%, ee=96.4%).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2cc(OC)c(OC)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)C(=O)C(CC=O)C2
Reaction time: 0.5 h
Yield: 73 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 30 minutes through a solution, cooled to -70°, of 6.8 g of (RS)-2-(2-buten-1-yl)-5,6-dimethoxy-1-indanone in 100 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 250 ml of dichloromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 1.5 hours. The mixture was subsequently poured into 100 ml of water and neutralized while stirring by the spatula-wise addition of sodium hydrogen carbonate. An additional 70 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 120 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was crystallized from diethyl ether/hexane. 4.7 g (73%) of (RS)-2-(2-oxoethyl)-5,6-dimethoxy-1-indanone were obtained as a light yellow solid with m.p. 122°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]([N:17]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18]3)[CH:15]=2)[NH:10][C:9](=[O:28])[C:8]1=[O:29])=[O:5])[CH3:2].[Cl-].[CH2:31]([O:38][NH3+:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])(=O)C.[Na+]>CCO.O>[CH2:31]([O:38][N:39]=[CH:22][C:19]1[CH:20]=[CH:21][N:17]([C:14]2[CH:15]=[C:16]3[C:11]([NH:10][C:9](=[O:28])[C:8](=[O:29])[N:7]3[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][C:13]=2[C:24]([F:26])([F:27])[F:25])[CH:18]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=O)c3)cc21
Reactant: [NH3+]OCc1ccccc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(-n3ccc(C=NOCc4ccccc4)c3)cc21
Yield: 82.8 %

Procedure:
1.1 g (2.7 mmol) of the compound of Example 70, 0.86 g (5.4 mmol) of O-benzylhydroxylammonium chloride and 0.44 g (5.4 mmol) of sodium acetate in 4.5 ml of EtOH/H2O (1:2) were refluxed for 30 minutes. The ethanol was then removed under reduced pressure, and the precipitate was filtered off with suction and recrystallized from ethanol to yield 1.15 g (84%) of the product. The 1H-NMR shows that an E/Z mixture is present. Melting point 142°-147° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[S:11](Cl)([Cl:14])(=[O:13])=[O:12]>C(#N)C>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][S:11]([Cl:14])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](NS(=O)(=O)Cl)C(C)C

Procedure:
A suspension of 15.3 g (90 mmol) of L-valine methyl ester hydrochloride in 45 ml of acetonitrile was treated with 22 ml (270 mmol) of sulfuryl chloride and heated at reflux for 16 h. The resulting light yellow solution was allowed to cool and concentrated in vacuo to a viscous oil. The oil was treated two times with acetonitrile followed each time by concentration in vacuo. The crude desired product was thus obtained as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:16][S:17]([O:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Yield: 100 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (compound [6]; 108.6 g) obtained in Example 3 was dissolved in toluene (600 mL), and methanesulfonyl chloride (45.4 mL) was added, which was followed by stirring under ice-cooling. To this solution was added dropwise triethylamine (81.7 mL) under ice-cooling. After stirring for 1 hr, toluene (1 L) was added and 1N hydrochloric acid (1 L) was added for partitioning. The aqueous layer was extracted again with toluene (0.5 L). The combined organic layers were washed successively with water (1 L), saturated sodium hydrogencarbonate solution (1 L) and saturated brine (1 L), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (compound [7]; 150 g, yield 100%) as crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([OH:38])[CH:35]=[C:34]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:33]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:49]([O:56][C:57](=[O:62])[CH2:58][CH2:59][CH2:60]Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.O>CN(C=O)C>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C:20](=[O:28])[CH2:21][CH2:22]1)[CH2:17][C@H:16]3[CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([O:38][CH2:60][CH2:59][CH2:58][C:57]([O:56][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:62])[CH:35]=[C:34]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:33]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCc4cc(O)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCc4cc(OCCCC(=O)OCc5ccccc5)cc(OCc5ccccc5)c4)C[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A solution of 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3-benzyloxy-5-hydroxyphenyl)propyl)-5α-androstan-3-one (21.0 mg) in DMF (0.3 ml) was cooled on ice, followed by addition of sodium hydride (1.6 mg) and 15-crown-5-ether (7.8 μl). After the reaction mixture was stirred for 30 minutes, 4-bromo-n-butyric acid benzyl ester (10 mg) was added and stirred on ice for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After evaporation under reduced pressure to remove the solvent, the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4) to give 17β-(tert-butyldimethylsilyloxy)-7α-(3-(3-benzyloxy-5-(3-(benzyloxycarbonyl)propoxy)phenyl)propyl)-5α-androstan-3-one.