Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[O:22]COC)[C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.O1CCOCC1.Cl.[OH-].[Na+]>>[OH:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[CH:8]1[CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]([CH3:13])([CH3:14])[C:9]1=[O:15]
Reactant: COCOc1cnccc1C1Cc2ccc(OC)cc2C(C)(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(C)(C)C(=O)C(c1ccncc1O)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
Mixture of 7-methoxy-3-(3-methoxymethoxy-pyridin-4-yl)-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound GT15-8, 430 mg) and 4 N hydrochloric acid dioxane solution (5 ml) was heated and stirred at room temperature for 1.5 hrs. The reaction mixture was neutralized with 2 N aqueous solution of sodium hydroxide. The resulting mixture was extracted with the mixture of DCM and MeOH (DCM:MeOH=9:1). The residues obtained after concentration under reduced pressure were purified by silica gel column (DCM/MeOH) to obtain the title compound (280 mg, 75%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O)[CH3:2].[OH2:10]>>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:10])[CH:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O
Reactant: CCc1ccccc1O
Product: CCc1cccc(O)c1

Procedure:
This Mg-P-ZSM-5/Al2O3 (5 g) was packed in a quartz fixed-bed flow reactor, and the ethylphenol mixture containing m- and p-ethylphenols obtained in Example 1 (Table 4; raw material) was charged as the raw material together with water (raw material/water weight ratio=1/1) at a reaction temperature of 450° C. and with WHSV=8 hr-1. The products were separated into gaseous and liquid products, the quantities of each product was measured and compositions were determined by gas chromatography. The total product composition was calculated from the quantities and compositions of the gaseous and liquid products. The compositions of the reaction products are shown in Table 4. The liquid product thus obtained was distilled with an Oldershow type distillation column with 25 plates, and the m-and p-ethylphenol fraction was collected to give m-ethylphenol with a purity of 98.6 wt%. The impurities were mainly of p-ethylphenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[F:10][CH:11]([F:14])[CH2:12][NH2:13].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:13][CH2:12][CH:11]([F:14])[F:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NCC(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)CNCc1ccc(Cl)nc1
Yield: 53.9 %

Procedure:
41.57 g (256.6 mmol) of 2-chloro-5-chloromethylpyridine, 20.80 g (256.6 mmol) of 2,2-difluoroethane-1-amine and 35.8 ml (256.6 mmol) of triethylamine in 500 ml of acetonitrile are stirred at 45° C. for 21 hours. The reaction mixture is concentrated under reduced pressure and the residue is then taken up in 1 N aqueous hydrochloric acid and the mixture is washed with ethyl acetate. The aqueous phase is made alkaline using 2.5 N aqueous sodium hydroxide solution and extracted repeatedly with ethyl acetate. Concentration of the organic phase under reduced pressure gives 28.6 g (53% of theory) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethane-1-amine.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[C:14]=2[C:13](C(OC)=O)([C:27]([O:29][CH3:30])=[O:28])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].FC(F)(F)C(O)=O>CO.C1COCC1.[Na+].[Cl-]>[C:4]([O:8][C:9]([N:11]1[C:19]2[CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[C:14]=2[CH:13]([C:27]([O:29][CH3:30])=[O:28])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)C1(C(=O)OC)CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])c3ccccc3c21
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)c2cc([N+](=O)[O-])c3ccccc3c21
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
NaOMe (5.61 mL of a 0.62 M solution in MeOH, 3.48 mmol) was added dropwise to a stirred solution of 10 (1.00 g, 2.32 mmol) in THF (20 mL) at 10° C. After 15 min at 20° C., trifluoroacetic acid (0.29 mL, 3.8 mmol) was added in one portion, causing dissipation of the deep purple colour of the solution. The reaction was diluted with saturated NaCl, extracted with CH2Cl2 and the extract was washed twice with water and dried (Na2SO4). The CH2Cl2 solution was filtered through a short column of silica gel, eluting with additional CH2Cl2, and the solvent was evaporated under reduced pressure below 30° C. to give crude 3-(tert-butyloxycarbonyl)-1-methoxycarbonyl-5-nitro-1,2-dihydro-3H-benz[e]indole (11) (0.85 g, 98%), which was used without further purification. 1H NMR (CDCl3) δ8.89 (br s, 1 H, H-9), 8.38 (br s, 1 H, H-7), 7.87 (d, J=8.3 Hz, 1 H, H-4), 7.63-7.51 (m, 2 H, H-5,6), 4.61 (dd, J=10.5, 3.9 Hz, 1 H, NCH2CH), 4.50 (br s, 1 H, NCH2CH), 4.32 (t, J=11.1 Hz, 1 H, HCH2CH), 3.72 (s, 3 H, CO2CH3), 1.61 (s, 9 H, C(CH3)3).
Reaction SMILES: [O:1]([C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:18]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[O:1]([C:8]1[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(F)(F)F)c1Oc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(C(F)(F)F)c1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
A −78° C. solution of the crude 2-phenoxy-3-trifluoromethyl-anisole (3.47 g, 12.9 mmol) in CH2Cl2 (35 mL) is treated with BBr3 (12.99 g, 51.8 mmol), and the mixture is warmed to 0° C. and stirred for 1.5 h under N2. The reaction is poured into ice water and then extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude material that is absorbed on silica gel and columned with 96/4 chloroform/methyl tert-butyl ether to afford 1.51 g (24%) of 2-phenoxy-3-trifluoromethyl-phenol. Rf=0.34 (96/4 chloroform/methyl tert-butyl ether). 1H NMR (400 MHz, CDCl3); MS (ES−+) m/z mass calculated for C13H9O2F3 254, found 253 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 105 °C
Yield: 65.2 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (220 mg, 0.57 mmol), 4-(trifluoromethyl)phenylboronic acid (161 mg, 0.85 mmol), K3PO4 (240 mg, 1.13 mmol), H2O (20 mg, 1.13 mmol), SPhos (12 mg, 0.028 mmol) and Pd(OAc)2 (12 mg, 0.017 mmol) in toluene (10 mL) was heated at 105° C. under nitrogen atmosphere for 20 h. After the mixture was cooled to r.t., water and EtOAc were added. 1 M HCl was added until pH was about 3, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH) to give 169 mg of the title compound as a yellow solid. MS: (+) m/z 455.34 (M+1).
Reaction SMILES: C[Mg+].[Br-].[NH:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CCOCC>[CH:9]1([C:15]([C:5]2[NH:4][CH:8]=[CH:7][CH:6]=2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1cc[nH]c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: O=C(c1ccc[nH]1)C1CCCCC1
Yield: 18.9 %

Procedure:
To a solution of MeMgBr (99.3 mL, 298 mmol) in Et2O (500 mL) a solution of 1H-pyrrole (20 g, 298 mmol, dissolved in Et2O) was added dropwise at rt under N2. The mixture was heated to reflux for 30 min and cyclohexanecarbonyl chloride (43 g, 298 mmol) was added dropwise at −30° C. The reaction was refluxed for 30 min, quenched by slowly addition of sat. NH4Cl, diluted with EA and water, washed with (3×) water and once with brine. The organic layer was dried over Na2SO4, concentrated and purified by CC to obtain compound 25a (10 g, 20%).
Reaction SMILES: [C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH2:20][CH2:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)([O:3][CH3:4])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1C([N+]([O-])=O)=CC=C(O)C=1>O1CCOCC1>[C:1]([C@H:5]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:6]12[CH2:7][C:8]([OH:10])=[O:9])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH:20]=[CH:21]1)[N:16]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:15]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CN(C(C)(C)C)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12CC(=O)O
Temperature: 0 °C

Procedure:
A solution of 17β-carbomethoxy-6-t-butylcarboxy-6-azaandrost-4-en-3-one (2.00 g, 4.63 mmol), prepared in Example 3, part E, in dioxane (50 mL) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.37 g, 6.02 mmol) and p-nitrophenol (10 mg). The reaction is heated to reflux for 2 hrs, poured into ice water (150 mL), extracted with ethyl acetate (3×100 mL), extracts washed with saturated aqueous NaHSO3, 2N NaOH, saturated aqueous NaCl, dried over MgSO4, concentrated and chromatographed on silica gel (40% ethyl acetate/hexanes) to give crude 17β-carbomethoxy-6-t-butylcarboxy-6-azaandrost-1,4-dien-3-one as a tan solid of sufficient purity to carry on to the following steps; yield: 1.53 g (76%).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:9]=[C:10]([CH:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[OH:16])[CH:11]=[C:12]([F:14])[CH:13]=1>C(Cl)Cl>[F:7][C:8]1[CH:9]=[C:10]([C:15]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:16])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: OC(c1cc(F)cc(F)c1)c1nccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1cc(F)cc(F)c1)c1nccs1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a suspension of CrO3 (1.1 g, 11 mmol) in CH2Cl2 at r.t. was added pyridine (1.8 mL, 22 mmol) and the resulting mixture was stirred for 20 min.. The alcohol from Step 1 in CH2Cl2 was added and the resulting mixture was stirred for 16 h. Then ET2O was added and the resulting mixture was filtered through silica gel and washed with Et2O. After evaporation the residue was chromatographed on silica gel eluting with 7:3 mixture of hexane:EtOAc to give 1.66 g (90%) of the title compound.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](Br)[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CN(C)[CH:33]=[O:34].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH2:33][OH:34])[CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 2.5 M solution (100 ml) of n-butyllithium in hexane was added dropwise at −78° C. into a solution (2 l) of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-bromoindoline (80 g) in tetrahydrofuran over 15 min. After 10 min, dimethylformamide (23.2 ml) was added thereto and the resultant mixture was warmed to room temperature. Next, a saturated aqueous solution of ammonium chloride (400 ml) and ethyl acetate (1 l) were added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting reside were added ethanol (240 ml) and sodium borohydride (7.6 g) and the resultant mixture was stirred at room temperature for 1 hr. After adding ice water (480 ml) to the reaction solution, the resulting crystals were collected by filtration, washed with water and air-dried at 50° C. over day and night to give the title compound (about 71 g) as a yellow powder. A portion of this crude product was purified by silica gel column chromatography (ethyl acetate/methanol system) followed by conversion into a hydrochloride in a conventional manner to give the hydrochloride of the title compound as a pale purple powder.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH2:7].[CH:17]([O:20][C:21]([N:23]1[C:29]2[C:30]3[CH2:31][CH2:32][CH2:33][C:34]=3[CH:35]=[CH:36][C:28]=2[C:27](=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])[CH3:18].[BH4-].[Na+].[OH-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH:17]([O:20][C:21]([N:23]1[C:29]2[C:30]3[CH2:31][CH2:32][CH2:33][C:34]=3[CH:35]=[CH:36][C:28]=2[CH:27]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])[CH3:18]
Reactant: CC(C)OC(=O)N1CCCC(=O)c2ccc3c(c21)CCC3
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc3c(c21)CCC3
Reaction time: 14 h
Yield: 82.8 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (349 mg, 1.15 mmol) followed by titanium isopropoxide (414 mg, 1.46 mmol) to 6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (300 mg, 1.04 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Add methanol (4.3 mL) and sodium borohydride (59 mg, 1.56 mmol) and stir the mixture under nitrogen at room temperature for 45 min. Add 0.1M NaOH, stir for 30 min. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford (+/−)-6-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester (443 mg, 83%). Add acetic anhydride (0.24 mL, 2.52 mmol) dropwise to a solution of the amine (184 mg, 0.36 mmol) and pyridine (0.25 mL, 3.06 mmol) in dichloromethane (3.1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (149 mg, 74%); MS (ES+): 557 (M+H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](#[N:22])[CH3:21]>>[CH2:1]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)/[C:9]/1=[CH:21]/[C:20]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)C(Cc1ccccc1)C2
Reactant: CC#N
Product: COc1ccc2c(c1)/C(=C/C#N)C(Cc1ccccc1)C2

Procedure:
Starting with 2-benzyl-6-methoxy-1-indanone and acetonitrile, the title compound was synthesized in otherwise the same manner as Reference Example 1 (yield 76%). This compound was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-])=O)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.O.CCO.[NH4+].[OH-]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[NH:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][C:5](=[O:29])[N:6]2[C@H:22]2[CH2:23][CH2:24][C@H:25]([OH:28])[CH2:26][CH2:27]2)=[C:2]([Cl:1])[N:10]=1
Reactant: O=c1[nH]c2c(Cl)nc(Nc3cc(F)ccc3[N+](=O)[O-])nc2n1[C@H]1CC[C@H](O)CC1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n([C@H]3CC[C@H](O)CC3)c2n1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
6-chloro-2-(5-fluoro-2-nitrophenylamino)-9-(trans-4-hydroxycyclohexyl)-7H-purin-8(9H)-one (13.5 mg, 0.03 mmol) was dissolved in CH3COOH:H2O:EtOH (1 mL:2.5 mL:5 mL) and iron powder (18 mg, 0.32 mmol, 10 equiv.) was added. The reaction mixture was then heated to 90° C. with continuous stirring for 15 minutes. Completion of the reaction was monitored by analytical HPLC and MS analysis. The reaction mixture was cooled to room temperature. Saturated NH4OH was added to the cooled solution slowly, with stirring, until pH was 11-12. It was then diluted with EtOAc (15 mL). The organic layer was separated, and the aqueous layer extracted with EtOAc (3×15 mL), the combined organic layers were washed with brine (1×15 mL), dried over MgSO4 and concentrated to give a white solid (12 mg, 96% yield), which was used without purification in the next step. MS (EI) m/z 393 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[I:22]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([I:22])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Brc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(I)n1-2
Temperature: 0 °C

Procedure:
A stirred mixture of 0.339 gm (1 mmol) of 8-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 25 ml of benzene was treated with 0.242 gm (1.1 mmol) of N-iodosuccinimide and refluxed under nitrogen for 12 hr and 40 min. The mixture was cooled and was then mixed with ice water containing sodium bicarbonate and sodium chloride and was finally extracted with methylene chloride. The extract was washed with dilute sodium chloride, dried with sodium sulfate and concentrated in vacuo. The residue was crystallized from methylene chloride-methanol to yield one batch of 0.252 gm, which melted with decomposition between 209° and 212.5° C. and another batch of 0.020 gm which melted with decomposition between 196° and 198.5° C. A portion of the first batch was recrystallized twice by being dissolved in almost pure methylene chloride to which methanol was slowly added during concentration. After this recrystallization, the title product melted with decomposition between 200° and 207° C. Another sample for analysis was prepared by essentially the same procedure and, after recrystallization from methylene chloride-methanol, molded with decomposition between 216° and 219° C. Analysis of the product for carbon, hydrogen and nitrogen showed C: 41.04%, H: 2.11%, N: 12.10%. Calculated values for such an analysis of the product are: C: 41.31%; H: 2.16% and N: 12.05%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:13][C:14](=O)[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(O)(O)(=O)=O.[NH2:23][OH:24].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:13][C:14](=[N:23][OH:24])[CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCC(CC1(c2ccc(Cl)c(Cl)c2)CCC1)=NO
Temperature: 25 °C

Procedure:
A mixture of 1-[1-(3,4-dichlorophenyl)cyclobutyl]butan-2-one (4.3 g) prepared as described above, hydroxylamine sulphate (2.65 g), sodium acetate (4.0 g), industrial methylated spirit (56 ml) and water (23 ml) was stirred at ambient temperature for sixteen hours. The reaction mixture was extracted with ether. The ether extract was washed with water, dried and evaporated to give a solid which was recrystallised from petroleum ether (b.p. 80°-100° C.) to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]butan-2-one oxime (m.p. 106°-110° C.).
Reaction SMILES: [CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CC(C)([O-])C.[K+].[K].C(=O)=O>O.C(O)CCC.CCOCC.CS(C)=O>[CH3:1][C:2]([OH:29])([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C:18](=[O:28])[CH:19]=[CH:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCO
Solvent: O
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.2 h

Procedure:
A reaction vessel was charged with 125 ml of dry dimethylsulfoxide and 2.5 g of cholesta-1,4,6-trien-3-on-25-ol was suspended in the dimethylsulfoxide. The suspension was heated, and 10 ml of dry ether was added to the resulting milky suspension to obtain a transparent solution. The reaction vessel was filled with dry argon gas. Powdery potassium t-butoxide prepared from 1.25 g potassium and 50 ml of butanol was added at one time to the solution under ice cooling and with violent agitation. The reaction mixture liquid was violently agitated for 12 minutes and was then poured into ice water saturated with carbon dioxide gas, which was prepared by adding dry ice to water. The mixture was then extracted with 600 ml of ether cooled to 0° to 5° C. The extract was promptly washed with cooled water saturated with a large quantity of carbon dioxide until the washing liquid became neutral, and the ether was then distilled off to obtain crude cholesta-1,5,7-trien-3-on-25-ol.