Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][N:10]=1.[Cl:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Cl)=[CH:47][CH:46]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:17]=[CH:18]/[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:49][C:48]2[CH:51]=[CH:52][C:45]([Cl:44])=[CH:46][CH:47]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(O)cn5)c(Cl)c4)CC3)cc2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCc2ccc(CN3CCN(C(=O)/C=C/c4cc(C)c(Oc5ccc(OCc6ccc(Cl)cc6)cn5)c(Cl)c4)CC3)cc2)cc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
To a solution of (E)-3-{3-chloro-4-[(5-hydroxypyridin-2-yl)oxy]-5-methylphenyl}-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (479 mg) and p-chlorobenzyl chloride (129 mg) in DMF (5.0 mL) was added NaH (41.6 mg, 60% in mineral oil) at 0° C. Then the reaction mixture was stirred over night at room temperature. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/0 to 9/1) to afford (E)-3-[3-chloro-4-({5-[(4-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-methylphenoxy)-ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one (507 mg) as a colorless amorphous. To a solution of that amorphous (507 mg) in EtOH (10 mL) was added 6 M aqueous HCl (0.129 mL) at room temperature, then the reaction mixture was stirred for 3 hours. The reaction mixture was filtered off, and the precipitate was dried at 50° C. under reduced pressure to afford (E)-3-[3-chloro-4-({5-[(4-chlorobenzyl)oxy]pyridin-2-yl}oxy)-5-methylphenyl]-1-(4-{4-[2-(4-methylphenoxy)ethyl]benzyl}piperazin-1-yl)prop-2-en-1-one hydrochloride (486 mg) as a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:16]([CH:6]1[C:5](=[O:15])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[C:7]21[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:17]=[CH:18][CH3:19]
Reactant: Cc1ccc2c(c1)C(=O)CC21CCCC1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(C)ccc2C12CCCC2
Yield: 59 %

Procedure:
A solution of 17.0 g of 5'-methyl-2',3'-dihydro-spiro[cyclo-pentane-1,1'-[1H]indene]-3'-one, 17.5 ml of 3-buten-2-ol and 170 mg of p-toluenesulfonic acid in 170 ml of 2,2-dimethoxy-propane was boiled under reflux for 71 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). In addition to 4.0 g of educt, there were obtained 12.7 g (59%) of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([SH:35])[NH:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C)C=O.[Cu]>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[N:25]=[C:24]([S:35][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[F:1])[NH:23][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:28][CH:29]=1
Reactant: Nc1ccccc1F
Reactant: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1
Agent: [Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(Sc3ccccc3F)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 3 h
Yield: 33.3 %

Procedure:
At 0° a diazonium salt solution prepared from 2.5 g of 2-fluoroaniline, 1.58 g of sodium nitrite, and 10 ml of 6 N hydrochloric acid is added dropwise to a solution of 6.25 g of 4,5-bis(4-methoxyphenyl)-2-mercaptoimidazole in a mixture of 240 ml of dimethylformamide, 10 ml of 2 N sodium hydroxide solution, and 1.45 g of powdered copper. The solution develops a reddish brown color under nitrogen evolution. The mixture is further stirred for 3 hours, concentrated under vacuum, and the residue is distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is subjected to column chromatography on 500 g of silica gel. Elution with acetone/hexane 2:3 yields 2.71 g of 4,5-bis(4-methoxyphenyl)-2-(2-fluorophenylthio)imidazole having a melting point of 195° after recrystallization from hot diisopropyl ether.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.C1C[O:21][CH2:20]C1>>[C:1]1([CH:20]=[O:21])[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12
Reactant: C1CCOC1
Reactant: c1ccc2c(c1)c1ccccc1c1cscc21
Product: O=Cc1scc2c3ccccc3c3ccccc3c12
Yield: 85.9 %

Procedure:
Phenanthro[9,10-c]thiophene (H. C. Pars Pharmaceutical Laboratories, Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give a 85.9% yield of phenanthro[9,10-c]thiophene-1-carbaldehyde, mp 198°-199°, (C,H,S), (THF/95% EtOH).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CS(=O)(=O)Nc1ccc(F)cc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 70 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
(Step 3) A suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.77 g), N-[2-(aminomethyl)-4-fluorophenyl]methanesulfonamide hydrochloride obtained in Step 2 (1.0 g) and potassium carbonate (1.36 g) in ethanol (15 ml) was stirred overnight at 70° C. The reaction solution was filtered through celite, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.04 g).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=1)[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=1)[C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 211.5 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (20 mL) was added to tert-butyl N′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (1.35 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (1.18 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (552 mg) and triethylamine (0.95 mL) in ethanol (10 mL) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (500 mg) and triethylamine (1 mL) in ethanol (10 mL) at room temperature, and the reaction solution was stirred at 80° C. for 21 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 131 mg of the title compound as a racemate. The property values of the compound are as follows.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][C:27]([C:35]#[N:36])=[C:26]2[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Br:44])[CH:39]=1>O1CCCC1>[Br:44][C:40]1[CH:39]=[C:38]([NH:37][C:26]2[C:25]3[C:30](=[CH:31][C:32]([O:33][CH3:34])=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:35]#[N:36])[CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1N
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cc1OC
Yield: 53.3 %

Procedure:
To a solution of 1.44 g (17.14 mmol) of 2-butynoic acid and 2.26 g (16.5 mmol) of isobutyl chloroformate in 30 ml of tetrahydrofuran at 0° C., with stirring , was added 3. 1 g (3.4 mmol) of N-methyl morpholine. This solution of the mixed anhydride was added to a stirred solution of 1.13 g (3.06 mmol) of 6-amino-4-[(3-bromophenyl)amino]-7-methoxy-3-quinolinecarbonitrile in 30 ml tetrahydrofuran in three portions over a 24 hour period. The solvent was removed. The residue was stirred with dilute sodium bicarbonate solution. Solid was collected and washed with water and ether. This was recrystallized from 1-butanol. The resulting solid was taken up in hot tetrahydrofuran and filtered through silica gel. The filtrate was concentrated and diluted with hexanes to give 0.71 g of N-[4-[(3-bromophenyl)amino]-3-cyano-7-methoxy -6-quinolinyl]-2-butynamide as a yellow powder: mass spectrum (electrospray, m/e): M+H 437.1,438.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[S:23][C:24]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)=[CH:25][C:26]=3[CH2:27][CH2:28]O)=[O:21])=[CH:15][C:14]=2[O:37][CH3:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:28][CH2:27][C:26]4[CH:25]=[C:24]([C:30]5[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=5)[S:23][C:22]=4[C:20]3=[O:21])=[CH:15][C:14]=2[O:37][CH3:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2CCO)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1cc(N2CCc3cc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 67.8 %

Procedure:
Dissolve 3-(4-{[5-(4-chloro-phenyl)-3-(2-hydroxy-ethyl)-thiophene-2-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (840 mg, 1.50 mmol) and tri-n-butylphosphine (2.25 mmol, 562 μL) in tetrahydrofuran (15 mL) and add slowly dropwise diisopropyl azodicarboxylate (2.25 mmol, 447 μL). Stir the mixture overnight and concentrate in vacuo. Triturate the residue with Et2O, filter, and dry in vacuo to afford 550 mg (62%) of the title compound as a white solid. LC-MS/ES m/z (35Cl) 441.0 [M-tBuCO2+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[C:7]=1[F:16])(=O)C.[OH-].[Na+]>CO>[F:16][C:7]1[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: COc1ccc(COC(C)=O)c(F)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CO)c(F)c1OC

Procedure:
5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate are heated to 80° for 1.5 hours together with 50 ml of methanol and 50 ml of 1N sodium hydroxide solution. After evaporation of the methanol the residue is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 50 g of silica gel with methylene chloride/methanol (95:5). 2-fluoro-3,4-dimethoxybenzyl alcohol is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:12]2[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[C:14]([CH:20]=O)[C:13]=2[O:22][CH3:23])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.[OH-].[NH4+:25].II>C1COCC1>[Cl:1][C:2]1[N:3]([C:12]2[C:17](=[O:18])[N:16]([CH3:19])[N:15]=[C:14]([C:20]#[N:25])[C:13]=2[O:22][CH3:23])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: [NH4+]
Reactant: COc1c(C=O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Agent: II
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(C#N)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 5-(2,3-dichloroindol-1-yl)-4-methoxy-1-methyl-6-oxo-pyridazine-3-carbaldehyde (98 mg, 0.278 mmol) in THF (1.5 mL) is added ammonium hydroxide (30% aq. solution, 1.5 mL), followed by iodine (92 mg, 0.362 mmol), which caused a dark brown colour to appear. The resulting reaction mixture was stirred for 1 h and then quenched with NaHCO3 solution (5 mL) and Na2S2O3 solution (5 mL). This caused the reaction to change from dark brown to a clear pale yellow mixture. After stirring for 10 min the reaction was extracted with DCM (20 mL×2), dried (MgSO4) and concentrated under reduced pressure to afford the desired pro duct 5-(2,3-dichloroindol-1-yl)-4-methoxy-1-methyl-6-oxo-pyridazine-3-carbonitrile (82 mg, 0.235 mmol, 85%) as a yellow foam that crushed into a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:44]([N+:48]1[N:52]=[C:51]([CH3:53])[S:50][C:49]=1[CH3:54])[CH2:45][CH2:46][CH3:47]>>[CH2:44]([N:48]1[N:52]=[C:51]([CH3:53])[S:50]/[C:49]/1=[CH:54]\[C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])=[O:9])[CH2:45][CH2:46][CH3:47]
Reactant: Cc1ccsc1C(=O)O
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-methylthiophene-2-carboxylic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3H) 1.28-1.39 (m, 2 H) 1.69-1.79 (m, 2 H) 2.45-2.48 (m, 3 H) 4.15 (t, 2 H) 6.18-6.22 (m, 1 H) 6.97 (d, 1 H) 7.55 (d, 1 H); MS (ESI) m/z 295 (M+H)+.
Reaction SMILES: [N+](C1C=C([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([CH3:20])[CH:19]=2)[NH:16][C:15](C)(C)[CH:14]=[C:13]3C)C=CC=1)([O-])=O.[Br:24]C1C=CC(N)=C(C)C=1.II>CC(C)=O>[Br:24][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([CH3:20])[CH:19]=1)[NH:16][CH2:15][CH:14]=[CH:13]2
Reactant: Cc1cc(Br)ccc1N
Reactant: CC1=CC(C)(C)Nc2c(C)cc(-c3cccc([N+](=O)[O-])c3)cc21
Agent: II
Solvent: CC(C)=O
Product: Cc1cc(Br)cc2c1NCC=C2

Procedure:
1,2-Dihydro-6-(3-nitrophenyl)-2,2,4,8-tetramethylquinoline (Compound 292, structure 86 of Scheme XXII, where R1 =R3-5 =H, R2 =nitro) 4-Bromo-2-methylaniline (5.58 g, 30 mmol) was treated with iodine (0.2 g, 0.9 mmol) and acetone (150 mL) in a sealed tube at 80° C. for 24 h to provide 6-bromo-1,2-dihydro-8-methylquinoline (Compound 85 of Scheme XXII) in 9% yield as a yellow oil (0.70 g). Most of the aniline (>80%) was recovered. A mixture of the 6-bromo-1,2-dihydro-8-methylquinoline (90 mg, 0.33 mmol), 3-nitrobenzeneboronic acid (167 mg, 1.0 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol), K2CO3 (190 mg, 1.38 mmol) in toluene (7 mL) and water (1.5 mL) was heated at 70° C. for 16 h. Standard work-up followed by chromatography afforded 23 mg (23%) of Compound 292 as a yellow oil. Data for Compound 292: IR (neat) 3412, 2966, 1602, 1530, 1348; 1H NMR (400 MHz, CDCl3) 8.38 (t, J=2.0, 1 H), 8.08 (dd, J=7.8 and 2.0, 1 H), 7.85 (d, J=7.8, 1 H), 7.52 (t, J=7.8, 1 H), 7.24 (d, J=117, 1 H), 7.21 (d, J=1.9, 1 H), 5.39 (s, 1 H), 3.72 (bs, 1 H), 2.18 (s, 3 H), 2.07 (s, 3 H), 1.34 (s, 6 H); 13C NMR (100 MHz, CDCl3) 148.9, 143.7, 142.0, 132.2, 129.6, 128.8, 128.7, 128.6, 126.5, 121.3, 121.0, 120.7, 120.6, 120.3, 52.3, 319.9, 19.2, 17.3.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10]([C:11]1[CH:16]=[CH:15][C:14]([S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:13][CH:12]=1)=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(S(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 11.4 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (1.00 g, 3.40 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.61 g, 6.79 mmol). Purification on :2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.185 g (11%) of the title compound as an off white solid, mp 143-145° C. 1H NMR (DMISO-d6) δ0.76 (t, 3 H), 1.12-1.22 (m, 2 H), 1.60 (quintet, 2 H), 2.69 (t, 2 H), 7.21-7.38 (m, 7 H), 7.61 (d, 1 H), 7.76 (d, 2 H), 7.98 (d, 1 H). IR (KBr) 2950, 1690, 1600, 1380 and 1150 cm−1. mass spectrum (+ESI) m/z 495 (M+H). Anal. Calcd. for C26H22O8S. 0.2H2O: C, 62.24; H, 4.58; N, 0.00. Found: C, 62.38; H, 4.59; N, 0.13.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][C:15]1[O:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][CH:26]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=4)[C:24]=3[CH:36]=2)=[N:18][N:19]=1.[Sb](Cl)(Cl)Cl>ClCCl.C(OCC)(=O)C>[F:11][CH2:35][S:34][C:31]1[CH:30]=[CH:29][C:28]([C:25]2[C:24]3[CH:36]=[C:20]([C:17]4[O:16][C:15]([CH3:14])=[N:19][N:18]=4)[CH:21]=[CH:22][C:23]=3[O:27][CH:26]=2)=[CH:33][CH:32]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: Cl[Sb](Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(SCF)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To a solution of [bis(2-methoxyethyl)amino]sulfur trifluoride (1.38 mL, 7.50 mmol) in dichloromethane (10 mL) was added dropwise a solution of 2-methyl-5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (1.61 g, 5.00 mmol) in dichloromethane (15 mL) at room temperature. Antimony (III) chloride (0.0570 g, 0.250 mmol) was added to the solution, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/tetrahydrofuran=1/1) and recrystallized from hexane/ethyl acetate to give the title compound (517 mg, yield 30%) as pale-yellow crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[NH:25][C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.ClCCl>CN(C)C=O>[Br:1][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:9]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[NH:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]1)=[O:27])[CH2:10][CH2:11]2
Reactant: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCc3cc(Br)ccc32)CC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
N-Bromosuccinimide (2.6 g, 14.5 mmoles) was added to a solution of N-[2-(indolin-1-yl)-5-bromophenyl]-4-methyl-1-piperazinecarboxamide (5.0 g, 12.0 mmoles) in dimethylformamide (50 ml). The solution was stirred at room temperature for 15 minutes and at 60° C. for 15 minutes. The solution was cooled and poured into dichloromethane (500 ml). The layers were separated and the organic phase was washed with water (3×500 ml), brine (500 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography over silica gel (60 g, eluted with 4% methanol:96% dichloromethane, 1 l). The appropriate fractions were pooled and concentrated to give 4.8 g (84%) of product. Recrystallization from chloroform and hexane gave the analytical sample, mp 118°-119.5° C.
Reaction SMILES: C([O:4][CH2:5][C@@H:6]1[C@@H:10]([O:11]C(=O)C)[CH2:9][CH:8]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[O:7]1)(=O)C.C[O-].[Na+].Cl>CO>[OH:11][C@@H:10]1[C@@H:6]([CH2:5][OH:4])[O:7][CH:8]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[CH2:9]1
Reactant: CC(=O)OC[C@H]1OC(n2ccnc(C(N)=O)c2=O)C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1nccn(C2C[C@H](O)[C@@H](CO)O2)c1=O
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
In 2 ml of methanol was dissolved 0.20 g of {(2R,3S)-3-(acetyloxy)-5-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]tetrahydro-2-furanyl}methyl acetate. While cooling the solution with ice, 0.23 g of 28% methanol solution of sodium methoxide was added, and stirred for 20 minutes. Then, 1.2 ml of 1 mol/L hydrochloric acid was added to the reaction mixture, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: chloroform:methanol=10:1] to obtain 90 mg of 4-[(4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a yellow oily product.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]([C:25](O)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>>[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:26]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C27H24N4O, 420.52; m/z found, 421.3 [M+H]+.