Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8](O)[CH:7]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]1)[CH2:6]2.[ClH:30]>C(O)C>[ClH:30].[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[C:7]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]1)[CH2:8]2
Reactant: COc1cc2c(cc1OC)C(O)C(CN1CCN(c3ccccc3OC)CC1)C2
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(CN1CCN(c3ccccc3OC)CC1)=C2

Procedure:
2,3-Dihydro-5,6-dimethoxy-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]-1H-inden-1-ol (5.2g, prepared as described in Example 8) is dissolved in ethanol, chilled and treated with an excess of ethereal hydrogen chloride.
Reaction SMILES: C(O)(=[O:3])C.[C:5]1([S:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OO.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[C:14]1([S:13][CH2:12][S:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:3])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O
Reactant: c1ccc(SCSc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=S(CSc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
5 ml of acetic acid was added to 1.538 g of bis(phenylthio)methane, 0.75 ml of an aqueous solution of hydrogen peroxide (concentration: 30%) was added thereto, and then the mixture was stirred for 1 hour at room temperature. After 100 ml of methylene chloride, 6 g of potassium carbonate and a small amount of water were thereto, the resultant mixture was dried with anhydrous sodium sulfate. The product was concentrated under reduced pressure, and then the leavings were separated by means of column-chromatography (silica gel, methylene chloride). Thus 1.585 g of phenyl phenylthiomethyl sulfoxide was obtained as a colorless liquid. The yield was 96.6%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:20]([OH:32])[C@@H:19]([CH2:33][OH:34])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].N1C=CN=C1>CN(C=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C@@H:20]([OH:32])[C@@H:19]([CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[O:18][C@H:10]1[O:11][CH2:12][CH2:13][Si:14]([CH3:16])([CH3:15])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](OCC[Si](C)(C)C)[C@@H]2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of 5.05 (8.90 g, 18 mmol) in DMF (60 mL) was treated with tert-butyldimethylsilyl chloride (6.8 g, 45.2 mmol) and imidazole (3.1 g, 45.2 mmol). After stirring for 8 h, the reaction was concentrated in vacuo. The residue was redissolved in CH2Cl2 then washed with H2O. The organic layer was dried over Na2SO4, decanted, and concentrated in vacuo. The residue was purified by silica gel chromatography (10% EtOAc/petroleum ether) to afford the title compound (10.5 g, 17.4 mmol, 96%). 1H NMR (600 MHz, CDCl3): δ ppm 7.38 (d, J=7.0 Hz, 2H, PhH), 7.33 (t, J=7.6 Hz, 2H, PhH), 7.30-7.26 (m, 3H, PhH, PMPH), 6.85 (d, J=8.2 Hz, 2H, PMPH), 4.92, 4.73 (ABq, J=11.1 Hz, 1H each, OCH2Ph), 4.68, 4.64 (ABq, J=11.4 Hz, 1H each, OCH2PMP), 4.34 (d, J=7.9 Hz, 1H, H-1), 4.04-3.98 (m, 1H, OCHHCH2SiMe3), 3.94 (br s, 1H, H-4), 3.89 (dd, J=10.3, 6.2 Hz, 1H, H-6), 3.82 (dd, J=10.4, 5.7 Hz, 1H, H-6), 3.80 (s, 3H, OMe), 3.64-3.54 (m, 2H, H-2, OCHHCH2SiMe3), 3.45 (dd, J=9.4, 3.2 Hz, 1H, H-3), 3.38 (t, J=6.0 Hz, 1H, H-5), 2.50 (br s, 1H, OH), 1.03 (t, J=8.5 Hz, 2H, OCH2CH2SiMe3), 0.90 (s, 9H, SiCMe3), 0.082, 0.078 (s, 3H each, SiMe2), 0.02 (s, 9H, SiMe3); 13C NMR (125 MHz, CDCl3): δ ppm 159.41, 138.99, 130.26, 129.56, 128.35, 128.14, 127.62, 113.93, 103.33, 80.55, 79.34, 75.23, 74.56, 72.18, 67.24, 66.75, 62.50, 55.33, 25.97, 18.59, 18.41, −1.32, −5.23, −5.28; HRMS calcd for C32H56NO7Si2 [M+NH4]+: 622.3595. found 622.3580.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:21][CH:22]1CCCN(C2C=CC(C3CCC(=O)NN=3)=CC=2)[CH2:23]1>>[O:21]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=4)=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[O:1][CH2:23][CH2:22]1
Reactant: O=C1CCC(c2ccc(N3CCCC(O)C3)cc2)=NN1
Reactant: O=C1CCC(c2ccc(N3CCC(O)CC3)cc2)=NN1
Product: O=C1CCC(c2ccc(N3CCC4(CC3)OCCO4)cc2)=NN1

Procedure:
Following the procedure described in Example 38 but using a molar equivalent quantity of the appropriate 3- and 4-hydroxypiperidine in place of 1,4-dioxa-8-azaspiro[4,5]decane one obtains the suitably substituted γ-oxobenzenebutanoic acids which upon cyclization with hydrazine gives the following compounds: 37b. 4,5-dihydro-6-[4-(4-hydroxy-1-piperidinyl)phenyl]-3(2H)-pyridazinone, mp 262°-263° C. 37c. 4,5-Dihydro-6-[4-(3-hydroxy-1-piperdinyl)phenyl)-3(2H)-pyridazinone, mp 211°-212° C.
Reaction SMILES: C[O-].[Na+].Cl.Cl.[NH:6]([C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH2:19])[N:14]=1)[C:7]([NH2:9])=[NH:8].CO[C:22]1[C:26](OC)=[N:25][S:24](=[O:29])[N:23]=1>CO>[NH:6]([C:10]1[S:11][CH:12]=[C:13]([CH2:15][S:16][CH2:17][CH2:18][NH:19][C:22]2[C:26]([NH:19][CH2:18][CH2:17][S:16][CH2:15][C:13]3[N:14]=[C:10]([NH:6][C:7]([NH2:9])=[NH:8])[S:11][CH:12]=3)=[N:25][S:24](=[O:29])[N:23]=2)[N:14]=1)[C:7]([NH2:9])=[NH:8]
Reactant: COC1=NS(=O)N=C1OC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2NCCSCc2csc(NC(=N)N)n2)cs1
Reaction time: 0.33 h

Procedure:
To a solution of sodium methoxide (2.16 g; 40.0 mmoles) in 100 ml of CH3OH that was cooled to 0° in an ice-water bath was added 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine dihydrochloride (6.09 g; 20.0 mmoles) and, after 20 minutes of stirring, the solution was treated with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g; 10 mmoles). The reaction mixture was stirred at ambient temperature for 65 hours and evaporated under reduced pressure. The residue was chromatographed on 100 g of silica gel (230-400 mesh) by flash chromatography using a gradient elution of acetonitrile-methanol. The appropriate fractions were combined, evaporated and the residue chromatographed on a Preparative HPLC system using μ-porasil silica gel. The appropriate fractions were combined, and evaporated under reduced pressure to give the title compound as an amorphous solid; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of approximately 0.11 mole of ethanol.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([CH2:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:6]=2)[CH2:3][CH2:2]1.C(O)C.[NH:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[O:30].N1CCCCC1>O>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:34]4[C:32](=[O:33])[NH:31][C:29](=[O:30])[NH:28]4)=[C:9]3[N:8]=[C:7]([CH2:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1cccc(Cc2cc(NC3CC3)n3ncc(C=O)c3n2)c1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cccc(Cc2cc(NC3CC3)n3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 80 °C
Yield: 34 %

Procedure:
To the reaction flask, 3-((7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (28 mg, 0.09 mmol) was added to ethanol (0.5 mL) along with hydantoin (9 mg, 0.09 mmol) and piperidine (9 μL, 0.09 mmol). The reaction was heated at 80° C. for 30 minutes in the microwave then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, 3-((7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was recovered as a solid in 34% yield. LCMS (M+1=400)
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=c1cccc[nH]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=c1ccccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 110 °C
Yield: 86 %

Procedure:
A solution of 1H-pyridin-2-one (950 mg, 10 mmol), 1-bromo-4-nitro-benzene (2.4 g, 12 mmol) and CuI (400 mg, 2 mmol) in dioxane (15 mL) was stirred for 15 minutes. N,N′-dimethyl ethylenediamine (363 mg, 4 mmol) was then added, followed by the addition of K3PO4 (4.25 g, 20 mmol). The resulting mixture was heated to reflux at 110° C. for 2 hours under an atmosphere of nitrogen. The reaction mixture was then cooled to room temperature and poured onto ice. The resulting precipitate was filtered and purified by column chromatography using silica gel 60-120 mesh (50-100% ethyl acetate in hexane) to afford 1.86 g (89%) of 1-(4-nitro-phenyl)-1H-pyridin-2-one. 1H NMR: (DMSO-d6): δ 8.46 (d, 2H), 7.8 (m, 3H), 7.6 (t, 1H), 6.6 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.CO.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16](/[CH:18]=[N:8]/[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: COC(OC)N(C)C
Solvent: CO
Product: CN(C)/C=N/C(=O)c1ccc(O)cc1

Procedure:
A solution of 4-hydroxybenzamide (5.58 g, 40 mmol) in 15 mL of dimethylformamide dimethyl acetal was stirred at 120° C. for 1.5 h with distillation of the product methanol. After cooling, the solid was collected and tritrarated with diethyl ether, DCM to give desired product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].[CH3:18][Si](Cl)(C)C.[I-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:18])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:15])[CH3:16]
Reactant: CC(C)C(=O)c1cnc2ccc(O)nc2c1O
Reactant: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2ncc(C(=O)C(C)C)c(O)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 1-(4,6-dihydroxy-1,5-naphthyridin-3-yl)-2-methylpropan-1-one (15.5 g, 63.0 mmol) in acetonitrile (250 ml) was added trimethylsilylchloride (20.5 g, 189 mmol) and sodium iodide (28.3 g, 189 mmol) and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and satd. aq. sodium thiosulfate was added. The mixture was concentrated to remove acetonitrile, diluted with brine and the solids were filtered and dried to provide the intermediate 1-(4-hydroxy-6-methoxy-1,5-naphthyridin-3-yl)-2-methylpropan-1-one. This intermediate was suspended in phosphorus oxychloride (60 mL) and catalytic N,N-dimethylformamide and the reaction mixture was stirred with heat at 70° C. for 30 min. The reaction mixture was cooled to room temperature and quenched by pouring slowly into ice-cold satd. aq. sodium bicarbonate or 3 N sodium hydroxide. The quenched reaction mixture was concentrated to remove the dichloroethane and the resulting solids were collected by filtration and purified by chromatography (silica, hexanes/ethyl acetate) to provide the desired product (12.0 g, 75% over 2 steps) as a yellow solid: ESI MS m/z 255 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH2:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[CH2:22]([N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)[CH3:23]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CCNc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CCN(c1ccccc1)c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 22 °C
Yield: 40 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 24 mg, 0.085 mmol), N-ethylaniline (75 μl, 0.595 mmol, Alfa Aesar, Ward Hill, Mass.), and NaHMDS (1.0M in THF; 595 μl, 0.595 mmol) and heating at 22° C. for 30 min. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(ethyl(phenyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (40% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (t, J=7.14 Hz, 3H) 2.80 (t, J=6.85 Hz, 2H) 3.61 (td, J=6.90, 2.45 Hz, 2H) 4.10 (q, J=7.24 Hz, 2H) 5.35 (br. s., 1H) 7.14 (d, J=2.15 Hz, 1H) 7.33-7.37 (m, 2H) 7.39-7.45 (m, 2H) 7.51-7.56 (m, 2H) 7.72 (dd, J=8.02, 1.17 Hz, 1H) 7.99 (dd, J=7.63, 1.37 Hz, 1H) 8.35 (s, 1H) 12.12 (br. s., 1H). MS (ESI, pos. ion) m/z: 384.4 (M+1).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([S:24][CH3:25])[C:19]([C:20]#[N:21])=[C:18](F)[CH:17]=2)[CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:36][NH2:37]>CCO>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:19]([C:20]([NH2:21])=[N:36][NH:37]3)=[C:22]([S:24][CH3:25])[CH:23]=2)[CH:9]=1)[CH3:2]
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(SC)c2)nc(NC)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC[C@@H]1CCCN1c1cc(-c2cc(SC)c3c(N)n[nH]c3c2)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
In a microwave tube, 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methylthio)benzonitrile (136 mg, 0.366 mmol), 5 mL of EtOH, Hunig's base (0.064 mL, 0.366 mmol), and hydrazine anhydrous (0.069 mL, 2.197 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), dried under reduced pressure to afford the title compound (90 mg). LC-MS (ES) m/z=370 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.91 (t, J=7.3 Hz, 3H), 1.36 (m, 1H), 1.80 (m, 2H), 1.93 (m, 3H), 2.59 (s, 3H), 2.83 (d, J=4.6 Hz, 3H), 3.53 (m, 1H), 4.06 (m, 1H), 5.08 (s, 2H), 6.22 (s, 1H), 6.44 (s, 1H), 7.38 (s, 1H), 7.71 (s, 1H), 11.75 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:24])[C@@H:13]2C(=O)[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(CC(N(C)[C@@H]2C(=O)CCC[C@H]2N2CCCC2)=O)C=CC=1Cl.C(O[CH:53]([O:57][CH2:58][CH3:59])[O:54][CH2:55][CH3:56])C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]([CH3:24])[C@@H:13]2[C:53]([O:54][CH2:55][CH3:56])([O:57][CH2:58][CH3:59])[CH2:17][CH2:16][CH2:15][C@H:14]2[N:20]2[CH2:23][CH2:22][CH2:21]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(OCC)OCC
Reactant: CN(C(=O)Cc1ccc(F)c(F)c1)[C@@H]1C(=O)CCC[C@H]1N1CCC1
Agent: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)[C@@H]1C(=O)CCC[C@H]1N1CCCC1
Solvent: CCO
Product: CCOC1(OCC)CCC[C@@H](N2CCC2)[C@@H]1N(C)C(=O)Cc1ccc(F)c(F)c1

Procedure:
Following the procedure of Example 3, substituting trans-(±)-3,4-difluoro-N-methyl-N-[6-oxo-2-(1-azetidinyl)cyclohexyl]benzeneacetamide for the trans-(±)-3,4-dichloro-N-methyl-N-[6-oxo-2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide in 50 ml of dry ethanol instead of methanol and 5.0 ml of triethylorthoformate instead of trimethylorthoformate, there is formed as product trans-(±)-3,4-difluoro-N-methyl-N-[6,6-diethoxy-2-(1-azetidinyl)cyclohexyl]benzeneacetamide, which is converted to a hydrochloride salt.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: C1COCCN1
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To the solution of 5-fluoro-N-methyl-2-nitrobenzamide (178 mg, 0.9 mmol) and morpholine (94 mg, 1.2 eq) in anhydrous DMF (3.0 mL) was added Cs2CO3 (350 mg, 1.2 eq). The mixture was stirred at 100° C. in an oil bath overnight. The mixture was cooled and the solvent was removed to obtain the crude which was purified by silica gel chromatography to obtain the desired compound N-methyl-5-morpholino-2-nitrobenzamide (206 mg, isolated yield 86%).
Reaction SMILES: [CH:1](=NO)CCC.C(=NO)CC.ClN1C(=O)CCC1=O.O1C=NC=N1.[CH3:25][C:26]1[CH:42]=[C:41]([C:43]2[N:47]=[C:46]([CH3:48])[O:45][N:44]=2)[CH:40]=[C:39]([CH3:49])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([CH2:37][CH3:38])[CH:33]=1>N1C=CC=CC=1.C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C.CN1CCCC1=O>[CH3:49][C:39]1[CH:40]=[C:41]([C:43]2[N:47]=[C:46]([CH3:48])[O:45][N:44]=2)[CH:42]=[C:26]([CH3:25])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([CH2:37][CH2:38][CH3:1])[CH:33]=1
Reactant: CCc1cc(CCCOc2c(C)cc(-c3noc(C)n3)cc2C)on1
Reactant: CCCC=NO
Agent: CCC=NO
Agent: O=C1CCC(=O)N1Cl
Agent: c1ncon1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCc1cc(CCCOc2c(C)cc(-c3noc(C)n3)cc2C)on1
Yield: 58 %

Procedure:
Following a procedure similar to that of Example 8(c) but substituting 2.6 g butyraldehyde oxime for the propionaldehyde oxime and using 3.99 g N-chlorosuccinimide, 2 drops pyridine, 50 ml N-methylpyrrolidinone, 2.7 g of the 1,2,4-oxadiazole of part (b) of Example 8 and 4.2 ml triethylamine, there was obtained after chromatography (MPLC, silica gel, 30:70 ethyl acetate/hexane) 2.06 g (58%) of the title compound as white needles, m.p. 69.0°-70.0° C. when recrystallized from methyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]=[CH:13][N:14](C)C)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:17][CH3:18])[CH:8]=2)[N:3]=1.NOS(O)(=O)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]#[N:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:17][CH3:18])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)cc(C=CN(C)C)c2c1
Agent: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2nc(Cl)cc(CC#N)c2c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 77.8 %

Procedure:
[2-(2-Chloro-6-methoxyquinolin-4-yl)ethenyl]dimethylamine (28.3 g, 0.11 mol) and hydroxylamine-O-sulfonic acid (40.2 g, 0.36 mol) were suspended in water (1.2 L), and the mixture was stirred at room temperature for 70 hours. The reaction mixture was neutralized with an aqueous solution of sodium hydroxide, and the organic materials were extracted with a mixed solvent of 5% methanol/ethyl acetate. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to obtain the title compound (19.9 g, 79%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1([C:23]2[C:31]3[C:26](=[C:27]([OH:32])[CH:28]=[CH:29][CH:30]=3)[CH2:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1N(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C1(C)C=CC=CC=1>[C:11]1([C:7]2[C:6]3[C:10](=[C:2]([O:32][C:27]4[CH:28]=[CH:29][CH:30]=[C:31]5[C:26]=4[CH2:25][CH:24]=[C:23]5[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:3]=[CH:4][CH:5]=3)[CH2:9][CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1cccc2c1CC=C2c1ccccc1
Reactant: Brc1cccc2c1CC=C2c1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=C(c2ccccc2)c2cccc(Oc3cccc4c3CC=C4c3ccccc3)c2C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a mixture of 6.90 g (25.5 mmol) of 7-bromo-3-phenyl-1H-indene, 5.30 g (25.5 mmol) of 3-phenyl-1H-inden-7-ol, 10.8 g (51 mmol) K3PO4, and 100 ml of toluene, a mixture of 300 mg (0.52 mmol) Pd(dba)2 and 348 mg (1.02 mmol) of N-{2′-[di(tert-butyl)phosphino][1,1′-biphenyl]-2-yl}-N,N-dimethylamine was added. This mixture was stirred for 8 hours at 100° C. Then, 300 ml of water was added, the organic layer was separated, and the aqueous layer was extracted with 3×75 ml of CH2Cl2. The combined extract was washed with 2×100 ml of water, dried over K2CO3, and evaporated to dryness. The analytically pure product, bis(3-phenyl-1H-inden-7-yl)ether, was obtained using flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, 1250 mm, eluant: CH2Cl2). Yield, 3.56 g (35%) of a white solid.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:34][C:32]1[CH:33]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])[CH:29]=[C:30]([Cl:35])[CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3cc(Cl)cc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.9 %

Procedure:
Lithium hydroxide monohydrate (0.013 g, 0.30 mmol) was added to a stirred solution of {4-[4-(3,5-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.039 g, 0.075 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3,5-dichlorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.026 g, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s, 1 H) 8.25 (d, J=8.31 Hz, 2 H) 8.15 (s, 2 H) 8.07 (s, 1 H) 8.00 (dd, J=8.80, 6.20 Hz, 1H) 7.90 (s, 1 H) 7.55 (d, J=8.31 Hz, 2 H) 7.38 (t, J=9.00 Hz, 1 H) 6.66 (d, J=11.74 Hz, 1 H) 3.83 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C25H16Cl2FO4S [(M−H)−] 501, obsd. 501.0.