Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccnc(-c2ccc(Cl)cc2)c1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccnc(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-methoxypyridin-2-yl)chlorobenzene (500 mg) in sulfuric acid (4 ml) was added fuming nitric acid (0.2 ml) dropwise at 0° C., and the mixture was stirred at 5° C. for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered, washed with diisopropyl ether and dried under reduced pressure to give 1-chloro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (601 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][O:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1B(O)O>O1CCOCC1.O>[CH3:20][C:3]1[C:2]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][C:33]=2[O:35][CH3:36])=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:6]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COC(=O)CCCCCNC(=O)c1cccc(Br)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CCCCCNC(=O)c1cccc(-c2ccc(OC)cc2OC)c1C
Yield: 77.6 %

Procedure:
The procedure of the step 1 in Example 92 was repeated except that the methyl 6-(3-bromo-2-methylbenzamido)hexanoate (34 mg, 0.10 mmol), tetrakis(triphenylphosphin)palladium (12 mg, 0.010 mmol), sodium carbonate (21 mg, 0.20 mmol), and 2,4-dimethoxyphenyl boronic acid (27 mg, 0.15 mmol) instead of phenyl boronic acid were dissolved in 3 mL of dioxane/H2O (4:1, v/v) to obtain the title compound (31 mg, 80%).
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([C:14]2[CH2:15][CH2:16][C:17]3[C:22]([C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=[C:19]([O:30]C)[CH:18]=3)=[O:13])=[CH:10][CH:9]=1.Cl>CN(C=O)C>[OH:7][C:8]1[CH:33]=[CH:32][C:11]([C:12]([C:14]2[CH2:15][CH2:16][C:17]3[C:22]([C:23]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][CH:20]=[C:19]([OH:30])[CH:18]=3)=[O:13])=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3CC2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: O=C(C1=C(c2ccccc2)c2ccc(O)cc2CC1)c1ccc(O)cc1
Temperature: 60 °C

Procedure:
To 300 ml. of DMF were added under nitrogen and with ice bath cooling, 9.3 gms. of ethyl mercaptan. To the mixture then were added 7.2 gms. of 50 percent sodium hydride-oil mixture. The mixture represents 0.15 mole of sodium hydride. To the resulting mixture then were added 11.1 gms. (0.03 mole) of the product from Example 4. The mixture was heated at 60° C. for 1 hour. Analysis of the reaction mixture by TLC indicated the presence of starting material plus another component, probably the mono-hydroxy compound. The temperature of the reaction mixture was raised to 110° C., and this temperature was maintained for 1 hour. TLC showed no starting material; however, the presence of two components was noted. The reaction mixture therefore was heated for an additional 1 hour at 125° C. after which a single spot was noted by TLC analysis. The reaction mixture then was acidified by addition of cold 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate was washed with water and evaporated. The resulting residue was recrystallized from a mixture of methanol and acetone to give 8 g. of the title compound, m.p. 205°-207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>C(O)C>[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1]2)=[CH:21][CH:20]=1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: CCO
Product: CN(C)c1ccc(C2Nc3ccccc3C(=O)N2c2ccccc2)cc1

Procedure:
9.6 g (0.4 mol) Magnesium, 0.1 g iodine and 180 ml anhydrous (sodium dried) diethyl ether were placed in a 2 liter flask equipped with magnetic stirrer, condenser, dropping funnel containing 62.4 g (0.4 mol) ethyl iodide and drying (CaCl2) tubes. The ethyl iodide was added dropwise slowly until the reaction started. The magnetic stirrer was then started and the remaining ethyl iodide added over a period of about 3/4 hr. It was not found necessary to apply external cooling. Stirring was continued for a further 1/2 hr at ambient temperature to ensure completion of reaction. To the resulting solution 18.6 g (0.2 mol) of aniline were added dropwise over a period of about 1/2 hr. and stirring was again continued at ambient temperature for a further 1/2 hr. To this mixture 15.1 g (0.1 mol) methyl 2-aminobenzoate were added dropwise over a period of about 1/2 hr. The reaction mixture became relatively viscous (a quantity e.g. 80 ml anhydrous diethyl ether can be added to this mixture and the stirring can be supplemented by manual agitation). Stirring, or manual agitation, was continued for about one hour. A saturated aqueous solution of ammonium chloride was then added to quench the reaction, about 300 to 350 ml is usually adequate. This mixture was thoroughly stirred and the aqueous and organic phases were separated. The aqueous phase was washed with fresh diethyl ether (ca 100 ml.) and the ethereal solutions were combined, washed with water and dried over anhydrous magnesium sulphate. The intermediate, 2-amino-N-phenylbenzamide was isolated by evaporating off the ether solvent. This crude 2-amino-N-phenylbenzamide (21 g; 0.1 mol; 99% theory based on methyl 2-aminobenzoate) had a melting point of 95° C. 10.6 g (0.05 mol) of the 2-amino-N-phenylbenzamide and 7.46 g (0.05 mol) of 4-dimethylaminobenzaldehyde were heated under reflux in 100 ml ethanol for 5 hrs. The reaction mixture was allowed to cool and the product slowly crystallised out. The crystals were filtered off to give 13 g (0.038 mol; 76% theory) of a pale yellow solid. The title compound, recrystyallised from methanol, had a melting point of 195° C. The IR and NMR spectra of this purified product were taken, as described above. The compound was also imaged onto CF paper to give an intense yellow-gold colour. The UV-visible reflectance spectrum of this colouration was measured. The results of spectral analysis were as follows:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:44][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])[CH:19]=2)[C:15]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:16]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3-(methylsulfonyl)phenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-(3-(methylsulfonyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.91 (s, 3 H) 7.57 (dd, J=8.48, 1.49 Hz, 1 H) 7.71 (t, J=7.73 Hz, 1 H) 7.77 (d, J=8.02 Hz, 1 H) 7.84-7.95 (m, 3 H) 8.02 (d, J=7.90 Hz, 2 H) 8.05 (s, 1 H) 8.13 (s, 1 H). m/z (ESI) 448.0 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[Cl:30][CH2:31][C:32]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20])=[O:33]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.08 h
Yield: 83.6 %

Procedure:
Triethylamine (0.6 g, 6 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.8 g, 2.5 mmol) in THF (70 ml). After stirring for 5 min, chloroacetyl chloride (0.34 g, 3 mmol) was added and the resulting mixture was heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (70 ml), washed with water (20 ml), 2N HCl (30 ml), water (2×30 ml), brine (30 ml) and dried. Solvent was removed in vacuo and the resulting solid was slurried in dichloromethane (10 ml) and ether (10 ml) and filtered to give 0.76 g (84%) of the product: 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 8.87 (t, J=5.9 Hz, 1H), 7.88-7.68 (m, 3H), 5.19-5.12 (dd, J=5.3 and 12.6 Hz, 1H), 4.77 (d, J=5.9 Hz, 2H), 4.19 (s, 2H), 2.96-2.83 (m, 1H), 2.65-2.51 (m, 2H), 2.11-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.88, 169.90, 167.53, 167.01, 166,67, 138.46, 134.90, 133.22, 131.63, 127.26, 122.14, 48.94, 42.61, 38.27, 30.99, 22.05.
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:13])([F:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.C1(C)C=CC=CC=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1>O>[F:3][C:4]([F:12])([F:13])[C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Brc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cccc(Oc2ccc(Br)cc2)c1
Reaction time: 18 h
Yield: 45 %

Procedure:
The reaction is performed in a 1 L 3-necked flask equipped with a mechanical stirrer, a Dean-Stark trap topped with a condenser and a nitrogen bubbler, and a stopper. The flask is flushed with nitrogen and charged firstly with potassium hydroxide (22.4 g, 0.4 mol), α,α,α-trifluoro-m-cresol (64.8 g, 0.4 mol), and toluene (500 mL). The mixture is stirred and heated at reflux for 2 h, during which water collected in the trap (ca. 6 mL). 1,4-Dibromobenzene (94.4 g, 0.42 mol) and cuprous chloride (39.6 g, 0.4 mol) are added, and heating a reflux is continued for another 18 h. The reaction mixture is analyzed by capillary GC which shows ca.45% of the title product along with ca.10% of the dialkylation product, with the rest being starting materials. The mixture is filtered with the aid of ether (200 mL), and washed successively with 2×100 mL portions of 5% HCl (to remove any residual copper impurities), water, and brine. It is then dried (MgSO4) and concentrated on the rotary evaporator to a red oily residue. TLC (silica gel) shows four components (Rf =0.00, 0.15, 0.35, 0.70, CH2Cl2). Fractional distillation afforded 42.9 g (34%) of the title compound, distilling at 112-116° C. @ 1 mm. Also obtained was 12.1 g (10.5%) of the dialkylation product, distilling at 160-165° C. @ 1 mm.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)nc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Reaction time: 4 h

Procedure:
To a solution of 1.16 g (2.53 mmol) benzyl 4-[(1R,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate in 15 ml anhydrous methanol at ambient temperature was added 0.12 g (1.13 mmol) palladium on carbon, 10% by weight. The solution was stirred under hydrogen for 4 hours and filtered. The crude product was concentrated to give the title compound as white solid and used for the next step. LC/MS 325.5 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[CH3:28][S:27][C:23]1[N:24]=[C:25]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[CH:26]=[CH:21][N:22]=1
Reactant: CSc1nccc(I)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of t-butyl (4-hydroxy-1-naphthyl)carbamate (5.0 g, 19.3 mmol), 4-iodo-2-methylthiopyrimidine (4.86 g, 19.3 mmol) and cesium carbonate (7.52 g, 23.1 mmol) in DMF (25 ml) is heated at 70° C. for 20 h. The resulting mixture is diluted with CH2Cl2 (50 ml), washed with water (25 ml×3), dried over Na2SO4 and concentrated. This residue is dissolved in minimum volume of EtOAc at 70° C. and then hexane (20 ml) is added. The resulting solution is left at room temperature overnight, filtered and washed with hexane to obtain t-butyl (4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)carbamate as a pink solid (4.2 g); Mp: 173-174° C.; 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9 H), 2.30 (s, 3H), 6.45 (d, J=5.7 Hz, 1H), 6.86 (s, 1H), 7.27 (d, J=8.1Hz, 1H), 7.47-7.60 (m, 2H), 7.87-7.94 (m, 3H), 8.32 (d, J=5.7 Hz, 1H); MS: 384 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[C:7]([Br:14])=[C:6]([OH:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][C:3]1=2.[CH3:20][O:21][CH2:22]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:14][C:7]1[C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:19])([CH3:1])[C:3]=2[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[C:6]=1[O:15][CH2:20][O:21][CH3:22]
Reactant: COCCl
Reactant: CC1(C)CCC(C)(C)c2c1cc(C(=O)O)c(O)c2Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(C(=O)O)cc2c(c1Br)C(C)(C)CCC2(C)C
Temperature: 45 °C

Procedure:
To a solution of 4-bromo-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl acid (Compound M), 233 mg, 0.71 mmol) in 6 ml of CH2Cl2 was added chloromethyl methyl ether (0.162 ml, 2.1 mmol), diisopropylethyl amine (0.764 ml, 4.2 mmol) and a catalytic amount of tetrabutylammonium bromide. The reaction mixture was heated to 45° C. for 2 h. The reaction mixture was concentrated and the residue was purified by column chromatography (ethyl acetate/hexane 1/9) to yield the methoxymethyl ester of the title compound as a white solid (200 mg). This white solid was further dissolved in 20 ml of EtOH. An aqueous solution of NaOH (0.5 ml, 1M) was added. The reaction mixture was stirred at room temperature for over night. The EtOH was removed and the residue was added 2 ml of ethyl acetate and 3 ml of water. This mixture was very slowly acidified with 10% HCl to PH=7. The ethyl acetate layer was separated and washed with brine, dried over Na2SO4. After filtration of the drying agent and removal of solvent, the reaction yielded the title compound as a white solid (155 mg). 1H NMR δ7.99 (s, 1H), 5.20 (s, 2H), 3.66 (s, 3H), 1.74 (m, 2H), 1.67 (m, 2H), 1.60 (s, 6H), 1.32 (s, 6H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[O:10]=[C:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1COCC1>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:11](=[O:10])[CH2:15][CH2:14][CH2:13][NH:12][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:4][CH:5]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
A thoroughly dried three-necked round-bottom flask was equipped with reflux condenser, addition funnel and argon inlet. Then magnesium powder (7.5 g, 311 mmol, activated by iodine) and dry THF (300 mL) were placed into this apparatus. A solution of 1,4-dibromobenzene (73.5 g, 311 mmol) in dry THF (200 mL) was slowly added at such a rate that the mixture maintained at reflux. When the addition was completed the mixture was refluxed for additional 2 hrs. After cooling to room temperature, the solution was added into a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (48 g, 260 mmol) in THF (320 mL) at −78° C. and the mixture was stirred at −78° C. for 2 hrs. The solution was warmed to ambient temperature and stirred for another 10 hrs before quenching with water. Hydrochloric acid (1 N, 100 mL) was added and the mixture was stirred at ambient temperature for 10 minutes. The mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo to afforded the crude product, which was purified by column chromatography (EtOAc: DCM:hexane=1:1:15) to give the title compound as a white solid (53 g, yield 60%). LC-MS (ESI) m/z: 342 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(=[CH:30][C:31]([O:33][CH3:34])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:34][O:33][C:31](=[O:32])[CH:30]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[OH:1]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1O
Product: COC(=O)C=Cc1ccc(F)cc1O
Yield: 85.6 %

Procedure:
2-Hydroxy-4-fluoro-benzaldehyde (306 mg, 1.99 mmol) was reacted with methyl (triphenylphosphoranylidene)acetate (681 g, 2.044 mmol) at 110° C. overnight as described above to yield title compound (334 mg, 85%).
Reaction SMILES: [C:1]([C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[C:17]3=[N:18][CH:19]=[CH:20][C:21]([CH3:22])=[C:16]3[N:15]=[C:14]2[CH2:23][CH2:24][CH3:25])=[CH:10][CH:9]=1)#[N:2].C[Sn]([N:32]=[N+:33]=[N-:34])(C)C>C1(C)C(C)=CC=CC=1>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH2:12][C:11]3[CH:10]=[CH:9][C:8]([C:7]4[CH:6]=[CH:5][O:4][C:3]=4[C:1]4[NH:34][N:33]=[N:32][N:2]=4)=[CH:27][CH:26]=3)[C:14]([CH2:23][CH2:24][CH3:25])=[N:15][C:16]=12
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccoc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccoc2-c2nnn[nH]2)cc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
A mixture of 3-[4-(2-cyano-3-furyl)benzyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (540 mg) and trimethyltin azide (1.095 g) in xylene (10 ml) was stirred at 125° C. for 24 hours. The mixture was concentrated in vacuo. The residue was dissolved in methanol (15 ml) and the methanolic solution was treated with 8.9N methanolic hydrogen chloride (1 ml) for one hour at ambient temperature. The mixture was adjusted to pH 5 with aqueous 1N sodium hydroxide solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (elution by dichloromethane/methanol=15/1-8/1) to yield 7-methyl-2-propyl-3-[4-[2-(1H-tetrazol-5-yl)-3-furyl]benzyl]-3H-imidazo[4,5-b]pyridine (525 mg) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH2:16][O:17][CH3:18])=[N:13][N:12]([CH:19]4[CH2:21][CH2:20]4)[C:11]=3[C:10](=[O:22])[NH:9]2)=[CH:4][CH:3]=1.Br[C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH2:16][O:17][CH3:18])=[N:13][N:12]([CH:19]4[CH2:20][CH2:21]4)[C:11]=3[C:10](=[O:22])[N:9]2[C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)=[CH:4][CH:3]=1
Reactant: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cc1cc(Br)cn(C)c1=O
Product: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared using an analogous procedure to that described in Example but using 4-(4-chlorophenyl)-1-cyclopropyl-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 130.4) and 5-bromo-1,3-dimethyl-2-pyridone. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 0.5-3.5%) to provide the title compound (286 mg) as a colorless solid. tR: 0.95 min (LC-MS 2); ESI-MS: 439.1 [M+H]+ (LC-MS 2); Rf=0.48 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.07 (m, 2H) 1.20-1.27 (m, 2H) 1.91 (s, 3H) 3.02 (s, 3H) 3.34 (s, 3H) 3.81-3.89 (m, 1H) 3.97 (d, J=12.51 Hz, 1H) 4.20 (d, J=12.51 Hz, 1H) 6.09 (s, 1H) 7.20-7.28 (m, 2H) 7.31-7.37 (m, 2H) 7.40-7.45 (m, 1H) 7.76 (d, J=2.74 Hz, 1H).
Reaction SMILES: [CH2:1]([Si:3]([C:8]#[CH:9])([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].I[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH2:8]([Si:3]([C:6]#[C:7][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:9]
Reactant: Oc1ccc(I)cc1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1ccc(O)cc1)(CC)CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylsilylacetylene 108 (3 eq.) was coupled to 4-iodophenol 107 (1 eq.) in the presence of CuI (0.05 eq.), Pd[PPh3]4 (0.05 eq.), and triethylamine (2 eq.) in DMF. The mixture was stirred at ambient temperature for 5 hours after which it was concentrated under vacuum to afford a crude black oil. The oil was purified by flash column chromatography to afford pure p-(triethylsilyl)ethynyl phenol 109.
Reaction SMILES: [CH3:1][C:2]1[N:3]([SeH:16])[C:4]([C:10]2[CH:15]=CC=C[CH:11]=2)=C(C(C)C)[N:6]=1.[H-].[Na+].[CH2:19](OCCl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]([SeH:16])[C:4]([CH:10]([CH3:15])[CH3:11])=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1nc(C(C)C)c(-c2ccccc2)n1[SeH]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(C(C)C)n1[SeH]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a solution of 400 mg of 2-methyl-4-isopropyl-5-phenylselenyl-imidazole (1.4 mmol) in 4 ml of dry dimethylformamide is added 70 mg of 60% oil suspension of sodium hydride (1.8 mmol) under ice cooling and the mixture is allowed to stand for 5 minutes followed by the addition of 270 mg of benzyloxymethyl chloride (1.7 mmol). The mixture is stirred for 30 minutes under ice cooling, mixed with ice water and extracted with diethyl ether. The extract is washed with water, dried over sodium sulfate and filtered. The filtrate is concentrated in vacuo. The crude product is chromatographed on a column of silica gel, eluting with ethyl acetate/n-hexane (1:1). The product is recrystallized from n-hexane to give 297 mg of the objective 2-methyl-4-phenylselenyl-5-isopropyl-imidazole (I-87) and 1-benzyloxymethyl-4-isopropyl-2-methyl-5-phenylselenyl-imidazole (I-37). Yield, 52%; mp. 94°-96° C.