Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:25][CH:24]3[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:21]([CH2:22][CH2:23]3)[CH:20]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1OCCOC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH2:20][CH:21]3[N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]([CH2:23][CH2:22]3)[CH:25]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C2C=C(c3ccc([N+](=O)[O-])cc3)CC1CC2
Yield: 60.2 %

Procedure:
A mixture of 1-bromo-4-nitrobenzene (2.0 g; 9.9 mmol; 1.0 eq.), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (4.3 g; 12.9 mmol; 1.30 eq.), PdCl2(dppf) (724 mg; 0.99 mmol; 0.1 eq.) and potassium carbonate (4.1 g; 29.7 mmol; 3.0 eq.) in Dioxane-1,4 (20 mL) and water (10 mL) was heated at 900 under nitrogen atmosphere O/N. The reaction mixture was filtered through a celite pad. The cake was rinsed with dichloromethane, phases were separated and organic phase was washed with water and brine. Organic phase was then dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (heptane/EtOAc, gradient from 90:10 to 80:20) to give the title compound as a yellow solid (1.97 g; 60%). 1H NMR (300 MHz, DMSO-d6-d6) δ: 8.17 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 6.84 (d, J=5.3 Hz, 1H), 4.43 (t, J=5.3 Hz, 1H), 4.35 (m, 1H), 2.97 (d, J=17.5 Hz, 1H), 2.32 (d, J=17.5 Hz, 1H), 2.15 (m, 1H), 1.95-1.88 (m, 2H), 1.71-1.58 (m, 1H), 1.37 (s, 9H). HPLC (max plot) 89.0%; Rt %4.66 min. UPLC/MS: (MS+) 331.3.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)=[N:12][CH:13]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of 7 g of 5-(4-chlorobenzoyl)-2-(1-imidazolyl)pyridine in 60 ml of ethanol plus 10 ml of water is added 1 g of sodium borohydride. After the mixture is stirred at room temperature for an hour, the solvent is distilled off. To the residue is added water and the mixture is extracted with chloroform. After the chloroform is distilled off, the residue is recrystallized from a mixture of toluene and ethanol to give 6.5 g of α-(4-chlorophenyl)-2-(1-imidazolyl)-5-pyridinemethanol as white crystals, melting at 147°-149° C.
Reaction SMILES: [C:1]([CH:3]([OH:33])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)#[N:2].N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[Si:43]([O:33][CH:3]([C:1]#[N:2])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:19][CH2:20][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]4)[C:7]=3[C:6]1=2)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(O)C#N)CC4)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)O[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Reference: For the preparation of the starting material compound 48.1, please refer to the experimental procedure for the synthesis of compound I-57. Into a 50-mL round-bottom flask, a solution of tert-butyl N-(4-[[(3R)-3-(2-cyano-2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (1.9 g, 4.02 mmol, 1.00 equiv) in 10 mL of distilled DMF was added imidazole (544 mg, 8.00 mmol, 2.0 equiv) and tert-butyl(chloro)dimethylsilane (905 mg, 6.00 mmol, 1.49 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at 20° C. After completion, the reaction was then quenched by the addition of 20 mL of water and extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with brine (three times), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with EtOAc/petroleum ether (1:20 to 1:5) to give 2.2 g (93%) of the desired tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]-2-cyanoethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate as a yellow oil. MS: m/z 587 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[CH3:11])[NH2:7].C(O)(=O)C.[CH3:16][C:17]([CH3:19])=O.C([O-])(=O)C.[Na+]>CCCCCC.CCOCC.O.C(O)C>[Br:3][C:4]1[CH:5]=[C:6]([NH:7][CH:17]([CH3:19])[CH3:16])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1ccc(NC(C)C)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (30.5 g, 806.2 mmol) was added slowly over 3 hours to a stirring mixture of 3-bromo-4-methylaniline (30 g, 161.2 mmol), ethanol (110 mL), acetic acid (92 mL, 1.6 mol), water (265 mL), acetone (66 mL, 892.2 mmol), and sodium acetate (29.2 g, 214.9 mmol). The solution was stirred at 0° C. for 1 hour. The reaction mixture was poured into the 1:1 mixture of ether and hexane containing 2N KOH. The layers were separated and aqueous layer was extracted with ether/hexane (1:1). The combined organic layers were washed once with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was used directly for the next reaction without further purification:
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC=CC=1)(=O)C>>[C:1]1([C@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](O)c1ccccc1
Solvent: CC(=O)c1ccccc1
Product: C[C@@H](O)c1ccccc1
Reaction time: 2 h

Procedure:
Analysis showed that (S)-phenylethanol was fully oxidised after 2 h and a corresponding amount of the oxidation product acetophenone could be found by gas chromatography. (R)-phenylethanol remained untouched so an ee value of >99% is obtained for this enantiomer.
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:27])[CH2:10][N:11]1[CH:15]=[CH:14][C:13]([N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[N:12]1)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:27])[CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)Cn1ccc(N2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1ccc(N)n1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
Hydrazine hydrate (0.27 ml, 6.69 mmol) is added to a stirred solution of [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyrazol-1-yl]-acetic acid tert-butyl ester (2.18 g, 6.69 mmol) in ethanol (12 ml). The reaction is stirred at 90° C. for 2.5 hours. When cool, the reaction is diluted with ethanol (50 ml) and the white precipitate is removed by filtration, washing with more ethanol (250 ml). The combined filtrate is evaporated to dryness and dichloromethane (100 ml) is added. After filtering again, the filtrate is evaporated to give the titled compound as a colourless oil.
Reaction SMILES: [C:1]1([C:11]([O:13]C)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[NH2:16][NH2:17]>CO>[C:1]1([C:11]([NH:16][NH2:17])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2ccccc12
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1cccc2ccccc12
Yield: 86 %

Procedure:
A mixture of 21.5 g (0.116 mol) of methyl α-naphthoate, 50 ml of 80% water containing hydrazine, and 30 ml of methanol was refluxed for 3 hours and then the reaction mixture obtained was cooled to form crystals, which were recovered and washed with water to provide 19.0 g (yield 86%) of α-naphthoic acid hydrazide.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:46]([Si:48]([CH2:70][CH3:71])([CH2:68][CH3:69])[O:49][CH2:50][CH2:51][C:52]1[C:53]2[C:62]3[C:61](=[CH:63][CH:64]=1)[S:60](=[O:66])(=[O:65])[NH:59][C:58](=[O:67])[C:57]=3[CH:56]=[CH:55][CH:54]=2)[CH3:47].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:59]3[C:58](=[O:67])[C:57]4[CH:56]=[CH:55][CH:54]=[C:53]5[C:52]([CH2:51][CH2:50][O:49][Si:48]([CH2:68][CH3:69])([CH2:70][CH3:71])[CH2:46][CH3:47])=[CH:64][CH:63]=[C:61]([C:62]=45)[S:60]3(=[O:66])=[O:65])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: CC[Si](CC)(CC)OCCc1ccc2c3c(cccc13)C(=O)NS2(=O)=O
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3C(=O)c4cccc5c(CCO[Si](CC)(CC)CC)ccc(c45)S3(=O)=O)[C@H](C)[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (365 mg, 1.0 mmol), triphenylphosphine (315 mg, 1.2 mmol), and 7-(2-triethylsilanyloxy-ethyl)-1,1-dioxo-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-3-one (431 mg, 1.1 mmol) in anhydrous tetrahydrofuiran (7 mL) is cooled in an ice-bath and stirred under a nitrogen atmosphere while diisopropyl azodicarboxylate (0.24 mL, 1.2 mmol) is added dropwise over a few minutes. The resulting solution is stirred in the cold for 30 minutes, then diluted with chloroform, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated under vacuum. The residue is purified by silica gel flash chromatography, eluting with hexane-ethyl acetate, to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-[1,1,3-trioxo-7-(2-triethylsilanyloxy-ethyl)-2,3-dihydro-naphtho[1,8-de][1,2]thiazin-2-ylmethyl]-carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[Li]CCCC.C[Si](Cl)(C)C.Cl[C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=2[N:24]=1>O1CCCC1.O>[CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:20]1[S:21][C:22]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:23]=2[N:24]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: FC(F)(F)c1ccc2nc(Cl)sc2c1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1CNCC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of cis-2,6-dimethyl piperazine (247 mg) in tetrahydrofuran (5 mL) was added n-BuLi (2.67 M hexane solution, 1.62 mL) at −78° C. The mixture was stirred at room temperature for 30 minutes, and trimethyl silyl chloride (0.27 mL) was added thereto. After stirring for 40 minutes, a solution of 2-chloro-6-trifluoromethyl benzothiazole (500 mg) in tetrahydrofuran (2 mL) was added thereto and the mixture was stirred for 2 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium carbonate. The residue was purified by column chromatograph on silica gel to give the title compound (367 mg). Yield: 54%.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]([O:7][SiH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH3:6].[C:15]1([CH3:22])C(C)=CC=C[CH:20]=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh]>[CH2:1]([NH2:4])[CH:2]=[CH2:3].[NH2:4][CH:15]([CH3:22])[CH2:20][Si:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:7][CH2:5][CH3:6]
Reactant: Cc1ccccc1C
Reactant: CCO[SiH](OCC)OCC
Agent: [Rh]
Agent: [C-]#[O+]
Solvent: C=CCN
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A 200 ml. flask equipped with a stirrer, thermometer, dropping funnel, CO inlet tube and reflux condenser having a CO outlet tube, was flushed with carbon monoxide, charged with 1.9 milligrams of tetrarhodium dodecacarbonyl (2.5×10-6 mole), 14 grams of allylamine (0.25 mole) and 60 ml. of xylene, and heated in an oil bath maintained at a temperature of 110° C. Thereafter, 41 grams of triethoxy silane (0.25 mole) was dropwise added to the mixture from the dropping funnel over 30 minutes. The reaction was continued at a temperature of 110° C. for 2 hours under stirring and CO flush. It was revealed by gas chromatography that gamma-aminopropyl triethoxy silane was obtained in a yield of 58% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 4.9% on an allylamine basis.
Reaction SMILES: ClC1C=CC(CCC(C2C=CC=CC=2)=O)=CC=1F.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][C:21]=1[F:41]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:22][C:21]=1[F:41]
Reactant: CCOC(=O)/C=C(/CCc1ccc(Cl)c(F)c1)c1ccccc1
Agent: O=C(CCc1ccc(Cl)c(F)c1)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc(Cl)c(F)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-chloro-3-fluorophenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(4-chloro-3-fluorophenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(4-chloro-3-fluorophenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: [Cl:1]Cl.[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5]([CH3:10])[CH:4]=1.O>C(Cl)(Cl)(Cl)Cl>[CH:7]1[C:8]([OH:9])=[CH:3][CH:4]=[C:5]([CH3:10])[CH:6]=1.[Cl:1][C:7]1[C:8]([OH:9])=[CH:3][CH:4]=[C:5]([CH3:10])[CH:6]=1
Reactant: ClCl
Agent: Cc1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(O)c(Cl)c1
Reaction time: 16 h
Yield: 3.3 %

Procedure:
Four grams of chlorine was bubbled through a stirred solution of 10.8 g of p-cresol (10 mmoles) in 100 ml of carbon tetrachloride for about 30 minutes. A five-gram sample, removed and analyzed and showed 46.9% p-cresol and 53.1% 2-chloro-p-cresol. Then 0.1 ml of ethanol and 10.00 g powdered anhydrous calcium bromide were added to the chlorinated p-cresol mixture. The mixture was stirred in the absence of atmospheric moisture for about 16 hours. A washed-and-dried solid was obtained weighing 10.40 g. A sample of the solid was hydrolyzed by water and extracted five times with carbon tetrachloride. GC analysis of the combined extract gave 96.6% p-cresol and 3.3% 2-chloro-p-cresol, showing substantially complete separation of p-cresol from its chlorinated derivative by complexation with calcium bromide.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(OCC)(=O)C>[N+:1]1([O-:19])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2c(c1)CCCC2
Solvent: CCOC(C)=O
Product: [O-][n+]1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.3 %

Procedure:
5,6,7,8-Tetrahydroquinoline (3.0 g, 22.5 mmol) was dissolved in ethyl acetate (15 ml), and 3-chloroperbenzoic acid (ca. 70%, 5.6 g, 22.5 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 days, subjected to a silica gel column chromatography and eluted with ethyl acetate-ethanol (5:1, v/v) to give the titled compound (3.4 g, 97%).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: Nc1ccccc1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccccc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with aniline to give the title compound. HR-MS (ES, m/z) calculated for C41H47Cl2N6O3 [(M+H)+] 741.3081, observed 741.3079.
Reaction SMILES: [C:1](#[N:3])C.[CH:4]1([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N+:8]=2[O-])[CH2:6][CH2:5]1.C[Si](C#N)(C)C>C(N(CC)CC)C>[CH:4]1([C:7]2[N:8]=[C:9]([C:1]#[N:3])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH2:6][CH2:5]1
Reactant: CC#N
Reactant: [O-][n+]1ccc(C(F)(F)F)cc1C1CC1
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)cc(C2CC2)n1
Temperature: 25 °C

Procedure:
To 7 ml of acetonitrile were added 0.7 g of 2-cyclopropyl-4-trifluoromethylpyridine N-oxide, 0.96 ml of triethylamine, and 1 g of trimethylsilyl cyanide, and the mixture was heated to reflux for 20 hours. Thereafter, the reaction solution was allowed to cool to room temperature, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.6 g of 6-cyclopropyl-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: Br[CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:6])[CH3:5].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.O>[N:17]([CH2:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:6])[CH3:5])=[N+:18]=[N-:19]
Reactant: COc1cc(C(C)(C)C(=O)CBr)ccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)(C)C(=O)CN=[N+]=[N-])ccc1F
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 1-bromo-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one (125.4 g, 0.44 mol) in DMF (500 mL) was added NaN3 (37.2 g, 0.572 mol) at 0° C., and the mixture was warmed to room temperature over 3 h with stirring. The reaction mixture was diluted with water (2 L) and extracted with EtOAc (1 L×2). Combined extracts were washed with brine, dried over MgSO4, and concentrated to give 1-azido-3-(4-fluoro-3-methoxyphenyl)-3-methylbutan-2-one (99.5 g), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.07 (m, 1H), 6.79 (m, 2H), 3.92 (s, 3H), 3.78 (s, 2H), 1.53 (s, 6H).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29].[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])(=[O:13])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A mixture of 0.62 g (3.6 mmol) of quinaldic acid and 0.61 g (3.76 mmol) of 1,1'-carbonyldiimidazole in 1 ml of dry 1,4-dioxane was stirred for 30 rain at room temperature. To this, a solution of 0.43 g (3.7 mmol) of L-valine and 0.155g (3.7 mmol) of lithium hydroxide in 1 ml of water was added and the resulting mixture was stirred vigorously at room temperature for .about 4 hours; The mixture was diluted to 10 ml with water, cooled (ice-water bath), then acidified with 1N hydrochloric acid to pH about 3 and allowed to stand for 2 hours at 4° C. The crystals which formed were removed by filtration, washed three times with 5 ml of cold water and dried under high vacuum over phosphorus pentoxide to give 0.75 g of the product. Yield=76%, melting point 134°-136° C., NMR (DMSO-d6) 1.03 (d, 6H, val CH3); 2.3 (m, 1H, val CH-J3); 3.35 (broad s, 1H, OH); 4.49 (q, 1 H, val CH-α); 7.5-8.3 (m, 5H, aromatic); 8.5-8.76 (m, 2H, aromatic, NH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH:15]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)cc1

Procedure:
54.3 mg of the target compound (0.16 mmol, 36.4%) was obtained using 1-(4-methylphenyl)piperazine (154.8 mg, 0.88 mmol), biphenyl-3-carbaldehyde (80 mg, 0.44 mmol) and NaBH(OAc)3 (283.8 mg, 1.32 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H](O)CC[C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=CC(O)=C[C:11]=3CC1)[CH2:4][CH2:3]2.CC(O[C@]1(C#C)[C@@]2(C)CC[C@@H]3[C@@H]4C(=CC(CC4)=O)CC[C@H]3[C@@H]2CC1)=[O:23]>>[CH3:1][C@H:2]1[CH2:15][C@@H:14]([OH:23])[C@H:5]([CH:6]([CH3:7])[CH3:11])[CH2:4][CH2:3]1
Reactant: C#C[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
The manufacturing method mentioned above was carried out according to this formulation followed by cutting into a desired size to give a mixed preparation of estradiol and norethisterone acetate.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1.[N+]([O-])(O)=O.[CH3:29][CH2:30][O:31]C(C)=O.CCCCCC>C(O)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:30](=[O:31])[CH3:29])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(Cn2cnc3c(Cl)nc(N)nc32)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: CCCCCC
Product: COc1cc(Cn2cnc3c(Cl)nc(NC(C)=O)nc32)cc(OC)c1OC

Procedure:
A solution of 6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-ylamine in acetic acid was treated with fuming HNO3 at 0° C. for 15 min. Work-up and preparative TLC (EtOAc:hexane 1:1) gave N-[6-chloro-9-(3,4,5-trimethoxy-benzyl)-9H-purin-2-yl]-acetamide. HPLC Rt: 5.744 min. 1H-NMR (CDCl3): δ 8.09 (s, 1H), 6.58 (s, 2H), 5.33 (s, 2H), 3.85 (s, 3H), 3.85 (s, 6H), 2.43 (s, 3H).