Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.N1C=CC=CC=1>C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:21]4[CH2:24][CH2:23][CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CNC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC3)c(F)cc2c1=O
Yield: 89.2 %

Procedure:
A mixture of 0.6 g (2.1 mmoles) of 1-cyclopropyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid with 0.25 g (4.4 mmoles) of azetidine, 8 ml of pyridine and 1 ml of triethylamine is maintained at 110°-120° C. for 2 hours in a closed vessel. After cooling, evaporating under vacuum, filtering and washing, 0.6 g (88%) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 289°-93° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[C:12]=1[F:27])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[C:12]=1[F:27])=[O:8]
Reactant: Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (73.0 mg, 0.131 mmol) in DCM (5 ml) was added TFA (1.5 mL) and the reaction mixture was stirred for 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (32 mg, 0.075 mmol, 57% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 12.74-13.45 (m, 1H), 7.97-8.44 (m, 1H), 7.73 (s, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 6.98 (s, 1H), 6.69 (d, 2H), 4.27-4.76 (m, 2 H), 2.23 (s, 3H). LC-MS (ES+) m/z 427.91, [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][C:3]=1[N+:12]([O-])=O.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[O:6][CH2:7][C:8]#[N:9]
Reactant: Cc1ccc(OCC#N)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(OCC#N)cc1N
Temperature: 70 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
(4-Methyl-3-nitrophenoxy)-acetonitrile (6.0 g) was dissolved in 120 ml of ethyl acetate and treated with 21.8 g of tin (II) chloride dihydrate; and the mixture was stirred at 70° C. for 2 hours. The mixture was cooled, poured into a saturated solution of sodium bicarbonate, extracted with ethyl acetate, dried, and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexane (7:3) to give 2.7 g of (3-amino-4-methylphenoxy)-acetonitrile. ##STR75##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CCCCCCN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), hexylamine (0.330 g, 3.26 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.06 g, 83.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[C:4]([F:11])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]=3[N:26]=2)=[C:4]([F:11])[CH:3]=1
Reactant: NC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3F)nc12
Temperature: 45 °C
Reaction time: 1 h

Procedure:
4-Bromo-2-fluorobenzoic acid (5 g) in a mixture of pyridine (50 mL) and DMF (50 mL) at 45° C. was treated with CDI (0.856 g), stirred at 45° C. for 1 hour, treated with 2,3-diaminobenzamide dihydrochloride (5.1 g), stirred at ambient temperature for 18 hours and concentrated. The concentrate was dissolved in acetic acid (100 mL), heated at 70° C. for 1 hour and concentrated. The concentrate was partitioned between ethyl acetate and sodium bicarbonate solution and the organic phase was isolated, washed with brine and concentrated. The concentrate was flash chromatographed on silica gel with ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[C:7]([CH3:24])[C:6]=2[C:5]([OH:25])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>C(OCC)(=O)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-ol (0.31 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.46 g) and bromoacetic acid methyl ester (0.35 g) was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate and this solution washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 and 0:1:1 by volume) gave title compound as a white solid, 0.20 g.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12]([O:14]C)=O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:22]([Li])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:11]=2[C:12](=[O:14])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(CO)ccc1-c1cc(OC)ncc1F
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(CO)cc2C(=O)C(C)(C)C)c(F)cn1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of methyl 2-(5-fluoro-2-methoxypyridin-4-yl)-5-(hydroxymethyl)benzoate T37.3 (0.307 g, 1 mmol) in THF (11 mL) at −78° C. was added tert-butyl lithium (2 mL, 3 mmol). The reaction mixture was stirred for one hour and then quenched with a saturated solution of ammonium chloride and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield T37.4 as a colorless solid (0.28 g, 84% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.[H-].[Na+].I[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1.ClCCl>[O:1]=[C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCN1C(=O)CN=C(c2ccccc2)c2ccccc21
Temperature: 0 °C
Yield: 47.8 %

Procedure:
10 g of 2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine were dissolved in 100 ml of tetrahydrofuran under a nitrogen atmosphere. 1.4 g of sodium hydride in the form of an 80% oily suspension were added in portions to the solution under the nitrogen atmosphere, and the reaction mixture was heated to reflux for 30 minutes. 9.2 g (=5.5 ml) of iodopentane were slowly added dropwise, the mixture was heated to reflux for a further 1.5 hours and then another 0.3 g of sodium hydride in the form of an oily suspension was added and, after a further 10 minutes, another 5.5 ml of iodopentane were added dropwise, and the mixture was heated to reflux for a further hour. To work up the reaction mixture, ice-water was added to the reaction mixture and it was diluted with dichloromethane, the aqueous phase was separated, and the organic phase was washed to neutrality with water, dried over sodium sulfate, filtered and evaporated. 13.5 g of crude product were obtained and were purified by flash chromatography on about 300 g of silica gel using cyclohexane/ethyl acetate 1:1 as the eluent. The purified product was crystallized from cyclohexane and dried. 6.2 g of pure 2-oxo-1-n-pentyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine having a melting point of 93-95° C. were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[Si:8](Cl)([CH3:11])([CH3:10])[CH3:9]>CCOCC>[Si:8]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C)CCCN
Solvent: CCOCC
Product: CN(C)CCCN[Si](C)(C)C
Temperature: 10 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Under argon, in a 500 ml Schlenk flask containing a magnetic stir bar, 49.38 g (0.480 mol) of 3-dimethylaminopropylamine (99%, Aldrich) was added to 120 ml of anhydrous hexanes (distilled from Na). This mixture was stirred and cooled with a constant temperature bath at 10° C. From a dropping funnel, 25 g of TMS—Cl (0.230 mol) were added dropwise to the mixture over a period of two hours. A white precipitate formed, and later redissolved forming a separate layer at the bottom of the flask. Once the TMS—Cl addition was complete, 200 ml of anhydrous ether (distilled from Na/K) was added to the flask. The mixture then was rapidly stirred overnight causing the two layers to merge into a homogeneous solution over a white precipitate. The solution was separated from the white solid by cannulation and distilled at ambient pressure to give TMS—NH—CH2CH2CH2NMe2 at 160° C. Yield: 85%. Characterization: 1H NMR: (400 MHz, positive δ downfield referenced to Si(CH3)4=0 ppm utilizing residual CDCl3=7.24 ppm in solvent CDCl3) 2.72 [m, 2H, —CH2NMe2], 2.24 [(m, 2H, TMS—NH—CH2—], 2.20 [s, 6H, —NCH3], 1.54 [m, 4H, TMS—NH—CH2CH2—], 0.02 [s, 18H, CH3Si—]. 13C{1H} NMR: (75 MHz, positive δ downfield referenced to Si(CH3)4=0 ppm utilizing residual C6D5H=128.0 ppm in solvent C6D6) 57.45 [—CH2NMe2], 45.40 [—NCH3], 40.00 [TMS—N—CH2—], 32.66 [TMS—N—CH2CH2—], −0.20 [(CH3)3Si—N—]. Mass Spectrum: (EI, 70 eV) 174 [TMS—NHCH2CH2CH2NMe2]+, 159 (M—Me), 129, 114, 100, 85, 72, 58.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([C:12]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:32][CH2:31][C:30]6[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:29]=6[NH:28][C:27]5=[O:39])[CH2:22][CH2:21]4)[CH:15]=3)=[O:13])[CH2:9][C:10]=2[CH:11]=1.[H][H]>[Pd].CO>[N:4]1[C:5]2[CH2:6][CH2:7][N:8]([C:12]([C:14]3[N:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][CH:23]([N:26]5[CH2:32][CH2:31][C:30]6[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:29]=6[NH:28][C:27]5=[O:39])[CH2:22][CH2:21]4)[CH:15]=3)=[O:13])[CH2:9][C:10]=2[CH:11]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ncc(Br)cc5C4)ncn3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5ncccc5C4)ncn3)CC1)C(=O)N2

Procedure:
Under a hydrogen atmosphere 77 mg (0.12 mmol) 3-{1-[6-(3-bromo-7,8-dihydro-5H-1,6-naphthyridin-6-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 40 mg palladium on charcoal (10%) were hydrogenated in 10 mL methanol at 50° C. under 50 psi hydrogen pressure. Then the catalyst was removed by suction filtering and the filtrate was evaporated down i. vac. The residue was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]([CH3:25])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:25][N:22]1[C:21]2[CH:26]=[CH:27][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:28])[C:20]=2[N:24]=[CH:23]1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2c1ncn2C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1ncn2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (494 mg) and 4-dimethylaminopyridine (0.01 g) in methylene chloride (40 mL) is added dropwise over 30 minutes, a solution of 5-amino-1,4-dimethylbenzimidazole (176 mg) in methylene chloride (20 mL). The mixture is stirred for 3 hours at room temperature, then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 50% ethyl acetate/hexane, to afford 1,4-dimethyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [CH:1]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:11])[CH:2]=1.Cl.[CH3:13][NH:14][CH3:15]>>[I:11][C:3]1[CH:4]=[CH:5][C:6]([S:7]([N:14]([CH3:15])[CH3:13])(=[O:9])=[O:8])=[CH:1][CH:2]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Product: CN(C)S(=O)(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared from pipsyl chloride and dimethylamine hydrochloride using a similar procedure to that used for Description 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].BrC1C(O)=CC=C(C)[N:20]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[C:10]([Br:16])=[N:20][C:12]([CH3:11])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: Cc1ccc(O)c(Br)n1
Product: Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)n1
Yield: 79 %

Procedure:
Following the general method as outlined in Intermediate 1, starting from 2-Bromo-6-methylpyridin-3-ol (Activate Scientific), the title compound was obtained in 79% yield as a yellow liquid after purification by flash column chromatography (silica), eluting with chloroform and methanol (98:2).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([OH:14])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[C:1]([O:4][CH2:5][CH2:6][CH:7]([CH3:15])[CH:8]([O:14][CH:16]([O:18][CH2:19][CH3:20])[CH3:17])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: C=COCC
Reactant: CC(=O)OCCC(C)C(O)CC=C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCOC(C)OC(CC=C(C)C)C(C)CCOC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-5-hydroxy-2-octene (2.27 g, 10.6 mmole), ethyl vinylether (0.82 g. 11.4 mmole), p-toluenesulfonic acid monohydrate (catalytic amount) and ether (50 ml) is stirred at room temperature for 16 hours. The resulting mixture is treated with ether (150 ml) and washed with 5% sodium bicarbonate solution (2×100 ml). The organic phase is dried (Na2SO4), and evaporated in vacuo to give the crude product. The crude material is further purified by column chromatography on silica gel (25 g, 5% ethyl acetate in hexane) to give 8-acetoxy-2,6-dimethyl-5-[(1-ethoxyethoxy)]-2-octene as a colorless oil.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]=2[C:4]([NH:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][CH:17]=2)=[N:3][CH:2]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1>>[C:18]([C:15]1[N:14]=[CH:13][C:12]([NH:11][C:4]2[C:5]3[CH2:10][N:9]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:8][CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:17][CH:16]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)c1ccc(Nc2ncnc3c2CNCC3)cn1
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cn1

Procedure:
The title compound was prepared according to the procedure given for Compound 1C by reacting (5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(6-tert-butyl-pyridin-3-yl)-amine with 2,3-dichloropyridine to give the desired compound as an off-white powder.
Reaction SMILES: NCCC[Si]([O:12][CH2:13][CH3:14])(OCC)OCC.Cl.[OH2:16]>>[O:16]=[CH:14][C@@H:13]([C@H:14]([C@@H:13]([C@@H:14]([CH2:13][OH:12])[OH:16])[OH:12])[OH:16])[OH:12]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O
Agent: Cl
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3 h

Procedure:
The three wafers with porous silicon and a wafer of polished silicon introduced for comparative purposes were silanised in a cup containing 3-aminopropyltriethoxysilane (Sigma Chemical Co, St Louis, US) and 1 g of APTES in 9 ml of water, the pH value being adjusted to 3.5 with the aid of 6 M HCl. The silanisation was performed in a water bath at 75° C. for 3 h and was followed by abundant washing with water for 30 min. Careful agitation took place during each stage of the immobilisation process. Then, the wafers were placed in a solution of 2.5% glutaraldehyde (GA) (grade II, Sigma Chemical Co, St Louis, US) in 0.1 M phosphate buffer (PBS) for 2 h. The GA activation was followed by washing with PBS for 30 min. Finally, glucose oxidase (GOD) was associated with the wafers as a result of a treatment with 10 mg of glucose oxidase (EC 1.1.3.4, type X-S, Aspergillus niger) in 2 ml of PBS overnight (8 h), which was followed by washing in PBS for 1 h.
Reaction SMILES: [CH:1]1([N:4]=[C:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([C:15]([F:32])([F:31])[C@@H:16]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH2:17][CH2:18]2)=[CH:13][CH2:12]4)[CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C>[CH:1]1([NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([C:15]([F:32])([F:31])[C@@H:16]([O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[CH2:17][CH2:18]2)=[CH:13][CH2:12]4)[CH2:3][CH2:2]1
Reactant: C[C@]12CC[C@H](OC3CCCCO3)C(F)(F)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NC3CC3)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C(F)(F)[C@@H](OC5CCCCO5)CC[C@@]43C)[C@@H]1CC[C@@H]2NC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.1 g of 17-(cyclopropylimino)-4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-ene in 200 ml of dry ethanol is added 2 g of sodium borohydride. The reaction mixture is stirred at room temperature for 3 hours and then 100 ml of solvent is removed from the mixture under reduced pressure. The reaction mixture is then quenched with dilute acetic acid, diluted with 600 ml of water, and the pH is adjusted to 14 by the addition of sodium hydroxide. The aqueous mixture is extracted 3 times with 600 ml potions of ethyl acetate and the combined organic extracts are dried over magnesium sulfate. Removal of the solvent under reduced pressure gives the desired 17β-(cyclopropylamino)-4,4-difluoro-3β-(2-tetrahydropyranyloxy)androst-5-ene as a white solid. This material is treated with a catalytic amount of hydrochloric acid in dioxane to remove the tetrahydropyranyl protecting group. This compound has the following structural formula: ##STR4##
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C(c1ccccc1)C(O)Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)C(O)Cc1cccc(OCc2ccccc2)c1

Procedure:
20.8 g (86 mmole) 2,5-dihydroxy-β-phenylpropiophenone, 15.4 ml (130 mmole) benzyl bromide and 12.5 g (90 mmole) potassium carbonate were heated under reflux for 3 hours with 200 ml acetone. After distilling off the solvent, the residue was dissolved in ethylacetate and extracted three times with 150 ml each of 2N sodium hydroxide solution. Subsequently the organic phase was extracted with 150 ml 2N hydrochloric acid and then washed with water to neutrality. After that, the organic phase was separated, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol/acetone (2:1).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[NH:7]1[CH:11]=[C:10]([C:12]23CCC(=O)[CH:13]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[CH2:20]3)[N:9]=[CH:8]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]=[C:2]1[CH:5]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][C:12]2([C:10]2[N:9]=[CH:8][NH:7][CH:11]=2)[CH2:20][CH2:3]1
Reactant: O=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Yield: 44 %

Procedure:
A mixture of potassium tert-butoxide (0.38 g) and methyltriphenyl-phosphonium bromide (1.2 g) in dry toluene (20 ml) was heated at reflux for 0.5 hour. To the mixture was then added 0.55 g of 8a-(1H-imidazol-4-yl)-1,3a,8,8a-tetrahydro-2H-cyclo-penta[a]inden-3-one and the resulting mixture was heated at reflux for 4 hours. After the removal of toluene, the residue was suspended in water and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified by flash chromatography using methylene chloride/methanol (95:5) as eluent. Recrystallization from ethyl acetate afforded 240 mg of the product, m.p. 167-174° C.