Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[NH:7].C(NC1N=[C:17]([C:19]2[C:20]([CH:28]([CH3:30])[CH3:29])=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=23)[CH:16]=[CH:15]N=1)(C)C>>[CH:28]([C:20]1[C:19]([C:17]2[CH:16]=[CH:15][N:8]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[N:7]=2)=[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]2[N:21]=1)([CH3:30])[CH3:29]
Reactant: N=C(N)NCCCO
Reactant: CC(C)Nc1nccc(-c2c(C(C)C)nn3ccccc23)n1
Product: CC(C)c1nn2ccccc2c1-c1ccnc(NCCCO)n1

Procedure:
3-[4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-ylamino]-propan-1-ol was prepared from 3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone and N-(3-hydroxy-propyl)-guanidine following the method used in Step 4 of the synthesis of Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine (Example 66), except preparative-HPLC purification was used in the place of recrystallization (166 mg, 18%). 1H-NMR (250 MHz, DMSO-d6) δ 8.85 (d, J=7.0 Hz, 1H), 8.44-8.22 (m, 3H), 7.59 (t, J=7.0 Hz, 1H), 7.18-7.05 (m, 2H), 4.07 (broad s, 1H), 3.79 (sept, J=6.9 Hz, 1H), 3.58-3.33 (m, 4H), 1.77 (pent, J=6.6 Hz, 2H), 1.37 (d, J=6.5 Hz, 6H); LC/MS 312.3 m/z (M+H+). Compound 1134.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:25][NH2:26]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=[C:2]1[NH:26][CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:30])=[C:22]([F:21])[CH:23]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: Fc1ccc(CBr)cc1F
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(CNc2nc3ccccc3n2Cc2ccc(F)c(F)c2)cc1F

Procedure:
The title compound was prepared by Procedure B in two steps from 2-chloro-benzimidazole, 3,4-difluorobenzyl bromide and 3,4-difluorobenzylamine. The product was isolated by column chromatography to give the title compound as the free base (oil). MS(ES+) m/z 386 ([M+1]+, 100). 1NMR (DMSO-d6) δ 4.59 (d, 2H), 5.30 (s, 2H), 6.87-6.97 (m, 3H), 7.16-7.49 (m, 8H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[F:28]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][C:20]=1[F:28]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, light brown solid (64 mg, 75%), MS (ISP) m/z=340.3 [(M+H)+], mp 309° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].[Br:24]N1C(=O)CCC1=O>ClC1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:24][CH:16]1[CH2:15][CH2:14][CH:13]([S:10](=[O:11])(=[O:12])[NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]1
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: CCOC(=O)C1=CC(Br)CCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 90 °C
Reaction time: 7 h
Yield: 22 %

Procedure:
To a solution -of ethyl 6-(N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (100 mg) obtained in Example 3 in chlorobenzene (2 ml), N-bromosuccinimide (56.7 mg) and 2,2′-azobisisobutyronitrile (0.5 mg) were added and the mixture was stirred at 90° C. for 7 hours. The reaction mixture was combined with an ice-water (20 ml), extracted with ethyl acetate (20 ml), washed with saturated brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off and the resultant residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/hexane=1/20→ethyl acetate/hexane=1/10) and crystallized from hexane to yield ethyl 3-bromo-6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 85, 27 mg) as colorless powdery crystals.
Reaction SMILES: [N+:1]([C:4]1[C:9](O)=[C:8]([NH2:11])[CH:7]=[C:6](C)[CH:5]=1)([O-:3])=[O:2].C1(N2C(=[O:24])C=C(CS(O)(=O)=O)N2)C=CC=CC=1>[Cr].O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:24])=[C:8]([NH2:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1cc(CS(=O)(=O)O)[nH]n1-c1ccccc1
Reactant: Cc1cc(N)c(O)c([N+](=O)[O-])c1
Agent: [Cr]
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1O

Procedure:
45.4 Parts of the 1:1 chromium complex (obtained by the known process and containing 1 atom of chromium for each molecule of monoazo dyestuff) of the azo dyestuff from diazotised 6-nitro-4-methyl-2-amino-1-hydroxybenzene and 1-phenyl-3-sulphomethyl-5-pyrazolone are stirred in 1000 parts of hot water together with 33.9 parts of the monoazo dyestuff obtained by the known process from diazotised 4-nitro-2-amino-1-hydroxybenzene. The suspension is adjusted to pH 7 to 8 by addition of 20 parts vy volume of concentrated sodium hydroxide solution and subsequently stirred at 90°-95° C. until both starting dyestuffs can no longer be detected. The unitary chromium mixed complex present in clear solution is precipitated by the addition of sodium chloride, isolated by filtration, washed with sodium chloride solution, and then dried in vacuo. After it has been ground, the dyestuff is in the form of a dark red, readily water-soluble powder from a bath containing ammonium sulphate dyes wool or polyamide fibres in full scarlet shades with good fastness properties. It has the following constitution: ##STR15##
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.CN(C=O)C.[C:18](=[O:20])=[O:19]>O>[C:18]([C:4]1[C:3]([OH:2])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([OH:20])=[O:19]
Reactant: O=C=O
Reactant: Oc1cccc2cccnc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2cccnc2c1O
Yield: 30.4 %

Procedure:
Potassium salt of 8-hydroxyquinoline (25 mmol, 4.58 g), DMF (50 mL) and an excess of dry ice were heated in a pressure reactor at 120° C. for 12 hours. After cooling, water (150 mL) was added to the reaction mixture. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. To the residue, water was added again, and additional insoluble material was collected by filtration. The filtrate was acidified to pH 4 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 7-carboxy-8-hydroxyquinoline in 30.4% yield (1.44 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:19])([CH3:20])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
2,2-dimethyl-3-(N-Boc-piperidine-4-yl)-propionic acid methyl ester (598 mg) from above was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated. The mixture was partitioned between ether and sodium hydroxide solution (1N). The organic layer was washed with brine and dried. Evaporation of solvents gave 2,2-dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (370 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:29][C:30]([OH:32])=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)C[C@H](c1ccccc1)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@H](CC(=O)O)c4ccccc4)cc3)ccc2C(C)(C)C)c1
Reaction time: 21 h
Yield: 71.5 %

Procedure:
To a stirred solution of 42.3 (0.048 g, 0.09 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting mixture was stirred for 21 hours and then concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 42 (33 mg, 73% yield) as a colorless oil. MS ESI (neg.) m/e: 511.3 (M−H)+.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate(0.29 g, 1.0 mmol) and 1-(2-methoxyphenyl)piperazine(0.19 g, 1.0 mmol) were dissolved in tetrahydrofuran(10 ml) and DBU(0.15 g, 1.0 mol) was added thereto and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated and chromatographed to obtain 0.33 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.O[O:26][S:27]([O-:29])=O.[K+].[CH2:31]1COCC1>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:27]([CH3:31])(=[O:29])=[O:26])=[CH:16][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C1CCOC1
Reactant: CSc1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)C(C)(C)O2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cc(F)cc(F)c2)C1=O

Procedure:
Alternatively, 18 g of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{4-(methylthio)-phenyl}-3(2H)-furanone (Example 173) was reacted with 45 g of OXONE in 300 ml THF, 300 ml ethanol and 300 ml water according to a procedure similar to the alternative procedure of Example 4 to afford 19.5 g of 4-(3,5-difluorophenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=[O:14].[N:25]1([CH2:30][CH:31]2[CH2:36][O:35][CH2:34][CH2:33][NH:32]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[C:10]([OH:12])(=[O:11])/[CH:30]=[CH:31]\[C:36]([OH:35])=[O:14].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:31]2[CH2:30][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCN(CC2COCCN2)C1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCOCC1CN1CCCC1
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100.7 %

Procedure:
To a solution of 3,4-dichlorophenylacetic acid (410 mg) in acetonitrile (10 ml) was added a solution of 1,1'-carbonyldiimidazole (340 mg) in warm acetonitrile (10 ml). After 10 min a solution of the product of stage (iii) (330 mg) was added and the mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (40 ml) and 2N sodium carbonate (30 ml). The organic phase was separated and washed with water (20 ml). The dried organic layer was evaporated and the oily residue (0.77 g) was purified by column chromatography on alumina (Type UGI), eluting with ethyl acetate, to give the free base of the title compound as a gum (462 mg) a portion of which (452 mg) was treated with maleic acid (147 mg) and crystallised from ethyl acetate to give the title compound (365 mg), m.p. 129°-131°.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.[OH-].[Na+].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>O1CCCC1.CN(C)C=O>[O:19]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=2)[N:15]1[CH2:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one, prepared as described above (90 mg, 0.31 mmol) in anhydrous tetrahydrofuran (3 mL) was added at room temperature 20-40 mesh beads of sodium hydroxide (48 mg, 1.20 mmol) and ethyl acrylate (1.200 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 4 hours under an atmosphere of dry N2, followed by addition of a second portion of sodium hydroxide (96 mg, 2.40 mmol). The reaction was followed by LCMS and stirring was continued until all of the starting material had disappeared. Solvent was removed from the reaction mixture under reduced pressure, diluted with ethyl acetate (20 mL), and aqueous Na2SO3 (10 mL) added. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent gave a crude mixture that was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford ethyl 3-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate (65 mg, 0.18 mmol, 58%). LCMS mz 364.0 (M+H), 386.0 (M+Na), anal HPLC >99% in purity. 1H NMR (400 MHz; CD3CN) δ7.87 (d, J=8.2 Hz, 2H); 7.81 (d, J=8.6 Hz, 2H); 7.66 (d, J=2.3 Hz, 1H); 7.63 (m, 1H); 7.26 (d, J=8.6 Hz, 1H); 4.25 (m, 2H); 3.02 (m, 2H); 2.67 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.[C:21]1([CH2:27][C:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:31]1([C:30]2[C:28](=[O:29])[C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Product: COc1ccc(C2=C(c3ccccc3)C(=O)C(c3ccccc3)=C2c2ccc(OC)cc2)cc1

Procedure:
The tetracyclone is prepared from 4,4'-dimethoxybenzil and 1,3-diphenylacetone (XV) by the procedure described in "Organic Syntheses," Coll., Vol. 3, E. C. Horning, Ed., Wiley, N.Y., 1955, pp 806-807: mp 227°-228° C. (mp 226.8-227.2° C. reported in Coan et al J. Am. Chem. Soc., 77, 60 (1955).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]2[CH2:20][CH2:19][Si:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.[F:30][C:31]([F:41])([F:40])[O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>CN(C)C=O>[F:30][C:31]([F:40])([F:41])[O:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]3[CH2:20][CH2:19][Si:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:37][CH:38]=1
Reactant: CCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](CBr)CC2)CC1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[Si]1(c2ccccc2)CCC([C@H]2CC[C@H](COc3ccc(OC(F)(F)F)cc3)CC2)CC1

Procedure:
8.3 g (60 mmols) of potassium carbonate was added to a mixture of 7.9 g (20 mmols) of 4-(trans-4-bromomethylcyclohexyl)-1-phenyl-1-n-propyl-1-silacyclohexane, 3.6 g (20 mmols) of 4-trifluoromethoxyphenol and 50 ml of dimethylformamide, followed by heating under reflux for 10 hours. The reaction mixture was after-treated by a usual manner and purified through chromatography to obtain 7.0 g (yield: 71%) of 4-(trans-4-(4-trifluoromethoxyphenyloxymethyl)cyclohexyl)-1-phenyl-1-n-propyl-1-silacyclohexane. The results of IR and NMR analyses are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18][C:17]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:32]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[O:18][C:17]([C:19]3[C:20]([C:25]([F:28])([F:27])[F:26])=[N+:21]([O-:32])[CH:22]=[CH:23][CH:24]=3)=[N:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(-c2nnc(-c3cccnc3C(F)(F)F)o2)cc([N+](=O)[O-])c1OC
Solvent: ClCCl
Product: COc1cc(-c2nnc(-c3ccc[n+]([O-])c3C(F)(F)F)o2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine (0.45 g, 1.13 mmol) in dichloromethane (10 mL)) cooled in an ice-water bath was added urea hydrogen peroxide complex (0.23 g, 2.45 mmol) in one portion followed by trifluoroacetic anhydride (0.47 g, 2.24 mmol) dropwise. The resulting mixture was allowed to stir at room temperature overnight and then the insoluble material was filtered off. The filtrate was washed with water and brine, then dried over anhydrous sodium sulphate, filtered and evaporated to leave an off-white solid. Recrystallisation from ethanol afforded 3-[5-(3,4-dimethoxy-5-nitro-phenyl)-[1,3,4]oxadiazol-2-yl]-2-trifluoromethyl-pyridine 1-oxide, 0.39 g (83%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[O:15][C@@H:16]([CH3:23])[C:17]([O:19]CC=C)=[O:18])=[CH:8][C:7]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:6][CH:5]=2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:42](Cl)(=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1>O1CCCC1>[CH3:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([C:42]([N:3]2[C:4]3[C:9](=[CH:8][C:7]([O:27][C:28]([F:30])([F:29])[F:31])=[CH:6][CH:5]=3)[C:10]([CH2:11][C:12]3[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=3)[O:15][C@@H:16]([CH3:23])[C:17]([OH:19])=[O:18])=[C:2]2[CH3:1])=[O:51])=[CH:44][CH:45]=1
Reactant: C=CCOC(=O)[C@H](C)Oc1cccc(Cc2c(C)[nH]c3ccc(OC(F)(F)F)cc23)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)n2c(C)c(Cc3cccc(O[C@@H](C)C(=O)O)c3)c3cc(OC(F)(F)F)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Compound 5 (467 mg, 1.1 mmole) was dissolved in tetrahydrofuran (11 mL) and cooled to −78° C. Sodium bis(trimethylsilyl)amide 1.3 mL of a 1.0N solution in THF) was added and the reaction mixture was stirred for 10 minutes. p-Anisoyl chloride (221 mg, 1.3 mmole) was then added. The reaction was warmed to 0° C. then quenched with saturated ammonium chloride and diluted with ether (100 ml). The ether layer was washed with water (2×), brine (1×) and dried over sodium sulfate followed by filtration and evaporation of the filtrate giving the title compound after silica gel chromatography (490 mg, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]#[C:26][C:27](OC)=[O:28])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH2:31][OH:32].[OH-].[Na+].Cl>CO.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[O:32][N:31]=[C:27]([OH:28])[CH:26]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C#Cc1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2c(Cc3cccc(-c4cc(O)no4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 45.1 %

Procedure:
To a solution of methyl [6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridin-2-yl]propynoate (73 mg) and hydroxylamine (50% aqueous solution, 18.2 mg) in methanol (1 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.166 mL), and this mixture was stirred at room temperature for 64 hours. To the reaction mixture were added water, ethyl acetate, and 2 mol/L hydrochloric acid (0.230 mL). The organic layer was separated. This organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (33 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.34 (2H, s), 6.51 (1H, s), 6.60-6.68 (1H, m), 6.87 (1H, d, J=2.3 Hz), 7.24-7.43 (3H, m), 7.44-7.54 (2H, m), 7.64-7.73 (1H, m), 7.76-7.87 (3H, m), 11.16 (1H, s), 11.47 (1H, s).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:7]([CH:21]=[CH:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:28])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:16][CH:17]=2)[C:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:26]([CH3:27])[CH3:28])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(C(C)C)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-isopropylphenyl)-5-(pent-1-enyl)pyridine (Example 133) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl 3): δ 0.74 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 25 H), 2.25 (m, 2 H), 2.95 (m, 1 H), 3.25 (m, 1 H), 3.40 (m, 1 H), 4.35 (d, J=6.0 Hz, 2 H), 7.1, (d, J=8.5 Hz, 2 H), 7.25 (d, J=8.5 Hz, 2 H). FAB-MS: calculated for C26H39NO 382; found 382 (M+H, 100%). Rf=0.40 (10% ethyl acetate/n-hexane). mp 42-44° C.