Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][C:25]=5[CH:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[C:25]([CH:31]([NH:33][CH3:34])[CH3:32])=[CH:26][N:27]=[C:28]([Cl:30])[CH:29]=5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(c1cnc(Cl)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)c1cnc(Cl)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Combine tert-butyl 1-(4-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)pyrimidin-4-yl)benzo[b]thiophen-7-yl)-6-chloropyridin-3-yl)ethyl(methyl)carbamate (300 mg, 0.5 mmol) and dry TFA (2.0 mL) in dry DCM (6 mL). Stir the solution at RT for 1 h. Dilute the resulting residue with DCM and wash with saturated sodium bicarbonate solution, water, and saturated aqueous sodium chloride. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo to give a residue. Purify the residue by column chromatography [0.1% to 2% 2 M ammonia in methanol/DCM] to afford the title compound (175 mg, 70%). MS (ES) m/z 491 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32]1[C:33](=O)[C:34](=[O:38])[C:35]=1[O:36]C)([CH3:30])([CH3:29])[CH3:28]>CO>[C:27]([O:31][C:32]1[C:35](=[O:36])[C:34](=[O:38])[C:33]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][C:18]([CH3:26])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])[CH:11]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(N)c2)cc1
Reactant: COc1c(OC(C)(C)C)c(=O)c1=O
Solvent: CO
Product: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc(Nc3c(OC(C)(C)C)c(=O)c3=O)c2)cc1
Yield: 82.9 %

Procedure:
Following a similar procedure to that described in Example (94c), 1.19 g of 3-[(4-methoxyphenyl)-(1-methyl-1-phenylethylamino)methyl]phenylamine [prepared as described in step (b) above], 886 mg of 3-t-butoxy-4-methoxy-3-cyclobutene-1,2-dione and 40 ml of methanol were reacted, to obtain 1.42 g of the title compound as a white foamy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:10][CH3:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(I)cn1
Reactant: C[O-]
Agent: [Cu]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N)nc1

Procedure:
2-Amino-5-methoxypyridine is prepared by combining 55 g. of 2-amino-5-iodopyridine, 20 g. of sodium methoxide, 5 g. of copper powder, 500 ml. of methanol in a glass lined bomb and rocking at 150° C. for 12 hours. Upon concentration to dryness, an extraction with chloroform extracts are dried and evaporated to dryness in vacuo. The residue is chromatographed on 1200 g. of silica gel eluting with 50% ethylacetate and methylenechloride affording 2-amino-5-methoxy pyridine.
Reaction SMILES: [NH2:1][C:2](=NO)[C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH2:27]C(=NO)C1C=C(C(NCC2C=CC(CCC(OCC)=O)=CC=2)=O)C=CC=1>>[NH2:27][N:1]=[CH:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2cccc(C(N)=NO)c2)cc1
Reactant: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C(N)=NO)c2)cc1
Product: CCOC(=O)CCc1ccc(NC(=O)c2cccc(C=NN)c2)cc1

Procedure:
The compound of Example 14 was reduced under conditions similar to the conditions described in Example 15, replacing the compound of Example 13 with the compound of Example 14.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH2:4].Br[CH2:12][CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH:4][CH2:12][CH:13]=[O:14]
Reactant: COc1cccc(C)c1N
Reactant: O=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-6-methoxyaniline (100 grams), the dipropyl acetal of 2-bromoacetaldehyde (59.1 grams) and sodium carbonate (31.8 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is heated at a temperature of about 150°C for a period of about 30 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then distilled under vacuum to yield the desired product the dipropyl acetal of 2-(2-methyl-6-methoxyanilino)acetaldehyde as the residue.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH2:9][CH2:10][O:11]C2CCCCO2)[CH:2]=1.Cl>CO.O.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:2]=1
Reactant: C(=Cc1cccnc1)CCOC1CCCCO1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: OCCCCc1cccnc1
Yield: 241.5 %

Procedure:
10 g (43 mmol) of 2-[4-(3-pyridyl)but-3-enoxy]tetrahydropyran in 200 ml of methanol/water 1:1 (v/v) is acidified by 2N hydrochloric acid and hydrogenated for 16 hours over 2 g 10% palladium on carbon. After filtration, the solvent is removed, the remaining residue is neutralized by saturated aqueous bicarbonate, and the product is extraced with several portions of ether. Purification of the crude product by column chromatography on silica gel yields 15.7 g (87%) of 4-(3-pyridyl)but-Anol as colourless viscous oil. (C9H13NO; F.W. 151.2).
Reaction SMILES: [C:1]([C:3]1[C:11]([Cl:12])=[C:10]([Cl:13])[C:6]([C:7](N)=[O:8])=[C:5]([Cl:14])[C:4]=1[Cl:15])#[N:2].Cl[O-].[Na+].S(=O)(=O)(O)[OH:20]>O>[C:1]([C:3]1[C:11]([Cl:12])=[C:10]([Cl:13])[C:6]([C:7]([OH:20])=[O:8])=[C:5]([Cl:14])[C:4]=1[Cl:15])#[N:2]
Reactant: N#Cc1c(Cl)c(Cl)c(C(N)=O)c(Cl)c1Cl
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: N#Cc1c(Cl)c(Cl)c(C(=O)O)c(Cl)c1Cl
Temperature: 15 °C
Yield: 92 %

Procedure:
4-Cyano-2,3,5,6-tetrachlorobenzamide (284 g) which had been synthesized separately and water (2556 g) were placed in a four-neck flask, and the mixture was cooled to 15° C. with stirring. Subsequently, an aqueous solution (2360 g) of sodium hypochlorite (effective chlorine 12%) was added to the reaction mixture over six hours while a 50% aqueous solution of sulfuric acid was added so as to maintain the pH of the mixture at 5-6. Liquid chromatographic analysis revealed that the reaction mixture contained 262.2 g of 4-cyano-2,3,5,6-tetrachlorobenzoic acid (yield 92%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:25].[CH3:26][O:27][CH2:28]Cl>C1COCC1.O>[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]2)=[CH:8][CH:7]=[CH:6][C:5]=1[O:25][CH2:26][O:27][CH3:28]
Reactant: CCCC1CCC(c2ccccc2-c2cccc(O)c2F)CC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(c2ccccc2-c2cccc(OCOC)c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.6 %

Procedure:
Under a nitrogen atmosphere, 1.52 g of sodium hydride was added to 9.45 g of 2-fluoro-3-((4-propylcyclohexyl)phenyl)phenol (5) dissolved in 60 mL of THF cooling with iced water, and the mixture was stirred at ambient temperature for 30 minutes. 3.07 g of chloromethyl methyl ether was added to the solution under cooling with iced water, followed by stirring at ambient temperature for 4 hours. After terminating the reaction by pouring water into the reaction solution, the aqueous layer was extracted with toluene, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 11.6 g of 2-fluoro-3-((4-propylcyclohexyl)phenyl)-1-methoxymethoxybenzene (6).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1.[CH3:20][C:21]([O:23][CH2:24][C@H:25]1[O:30][C@H:29](Br)[C@H:28]([O:32][C:33]([CH3:35])=[O:34])[C@@H:27]([O:36][C:37]([CH3:39])=[O:38])[C@@H:26]1[O:40][C:41]([CH3:43])=[O:42])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:19][C@@H:29]3[O:30][C@H:25]([CH2:24][O:23][C:21](=[O:22])[CH3:20])[C@@H:26]([O:40][C:41](=[O:42])[CH3:43])[C@H:27]([O:36][C:37](=[O:38])[CH3:39])[C@H:28]3[O:32][C:33](=[O:34])[CH3:35])=[N:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CSc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a solution of 1,2-dihydro-4-[(4-methylthiophenyl)-methyl]-5-trifluoromethyl-3H-pyrazol-3-one (2.0 g) in acetonitrile (100 mL) were added acetobromo-α-D-glucose (3.1 g) and potassium carbonate (1.1 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole (2.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([NH:6][C:21](=[O:22])[O:23][CH2:24][CH3:25])[CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.5 %

Procedure:
To a solution of 3,4,5-trimethoxyaniline (6 g) in tetrahydrofuran (125 ml) at room temperature was added potassium carbonate (5.42 g) followed by ethyl chloroformate (3.55 g). The mixture was stirred at room temperature for 48 hours, then solvent removed under reduced pressure. The residue was stirred with diethyl ether and filtered. The solid material remaining on the filter was extracted with acetone, the organic extracts combined, and solvent removed from the combined extracts under reduced pressure, to give a residue of ethyl 3,4,5-trimethoxyphenylcarbamate (6.05 g)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[F:12].[CH3:13]CN(CC)CC.CN(C=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:11]=[CH:13][NH:8]2)=[CH:4][C:3]=1[F:12]
Reactant: CCN(CC)CC
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cc2cc[nH]c2cc1Br
Temperature: 130 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 2 L dry round bottom flask was charged with 1-bromo-2-fluoro-4-methyl-5-nitrobenzene (24.5 g, 0.1 mol, 97%), DMF-DIPA (39 g, 0.22 mol), Et3N (16 mL, 0.11 mol) and dry DMF (100 mL). The mixture was stirred at 130° C. for 2 h. After removal of the volatiles the residue was dissolved in a mixture of toluene (650 mL) and acetic acid (390 mL) followed by addition of iron powder (55 g) and silica gel (50 g). The dark red mixture was heated to 100° C. with vigorous stirring. The dark color disappeared after refluxing for 20 min indicating completion of reaction. The mixture was then cooled to 25° C., diluted with EtOAc and filtered. The cake was washed thoroughly with EtOAc. The combined filtrates were washed with sat. aq. Na2S2O5, sat. aq. NaHCO3, and brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with 5/1 hexanes/CH2Cl2 to provide 6-bromo-5-fluoro-1H-indole as a white crystalline solid (16.2 g, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[CH3:24][O:25][C:26]([CH:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:27].Cl.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:24][O:25][C:26](=[O:27])[CH:28]([NH:37][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]3[C:5]([CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=3[N:8]=2)=[CH:19][CH:18]=1)[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: COC(=O)C(N)Cc1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Cl)cc1)NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
At room temperature, a 2-dram vial, equipped with a magnetic stirrer was charged with 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (153 mg, 0.5 mmol, INTERMEDIATE 2), DL-4-chlorophenylalanine methyl ester hydrochloride (125 mg, 0.5 mmol), bromotrispyrrolidinophosphonium hexafluorophosphate (233 mg, 0.5 mmol) and 5 ml of dimethylformamide. To this was added diisopropylethylamine (524 μl, 3 mmol) dropwise, during which addition the reaction turned a reddish-orange. After a few minutes the reaction mixture faded to a pale yellow clear solution. The reaction mixture was allowed to stir at room temperature for 3 d. The residue was purified by chromatography using a Biotage SP1, 40M silica cartridge, eluting with a linear gradient of hexanes in ethyl acetate from 20% to 100% over 15 column volumes to provide the title compound as a white solid (150 mg). Mass spectrum (ESI) 502.2 (M+1). 1H NMR (600 MHz, CDCl3): δ 8.31 (d, J=8.2 Hz, 2H), 7.93 (d, J=1.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.5 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.1 (d, J=8.3 Hz, 2H), 6.66 (d, J=7.3 Hz, 1H), 3.79 (s, 1H), 3.46 (m, 1H), 3.3 (dd, J=5.9, 5.9 Hz, 1H), 3.21 (dd, J=5.2, 5.0 Hz, 1H), 1.44 (J=6.9 Hz, 6H).
Reaction SMILES: C(O)(=O)C.CC1(C)[O:13][CH2:12][CH2:11][CH:10]2[N:7]1[C:8](=[O:17])[CH:9]2[N:14]=[N+:15]=[N-:16]>O>[N:14]([CH:9]1[CH:10]([CH2:11][CH2:12][OH:13])[NH:7][C:8]1=[O:17])=[N+:15]=[N-:16]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=NC1C(=O)NC1CCO
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
To a mixture of 8 ml of acetic acid and 2 ml of water is added 1.0 g of 2,2-dimethyl-7-azido-1-aza-3-oxa-bicyclo[4,2,0]octane-8-one (1:4 cis-trans mixture) and the mixture is stirred at 60° C. for 4 hours and concentrated to dryness. Tetrahydrofuran (15 ml) is added and the insoluble matter is filtered off. The filtrate is concentrated to dryness and the residue is dissolved in a small amount of chloroform and subjected to column chromatography using silica gel (20 g), elution being carried out with chloroform-ethyl acetate (1:1) and ethyl acetate in that order to give 179 mg of 3-azido-4-hydroxyethyl-2-azetidinone as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH3:9][O:10][C:11]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=1>>[CH3:59][O:58][C:52]1[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=[C:11]([O:10][CH3:9])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:41]([O:50][CH3:51])=[CH:42][C:43]([O:48][CH3:49])=[CH:44][C:45]=1[O:46][CH3:47])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][C:6](=[O:7])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:17]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)COC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)COC(C)=O)c2)c(OC)c1
Yield: 90 %

Procedure:
A solution of acetoxyacetyl chloride (10 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxy benzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified column chromatography to give a 90% yield of the desired product. (m.p. 192-1 94° C.)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].ClCCl>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][CH:32]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([C:11]3[C:12]([O:14][CH3:15])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:17])[CH2:38][CH2:37]2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCNCC2)CC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1c(N2CCC(NC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 62.5 °C
Yield: 17.9 %

Procedure:
To a stirred solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (295 mg, 1.0 mmol) in acetonitrile (5 mL) was added 4-(piperidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (339 mg, 1.2 mmol) followed by the addition of 8-diazabicyclo[5.4.0]undec-7-ene (DBU, 182 mg, 1.2 mmol). The resulting stirred solution was then heated in a 60-65° C. oil bath for two days. The cooled reaction mixture was filtered through a fritted funnel. The filtrate was condensed to dryness. Dichloromethane was added into this residue and washed with water twice. The resulting organic layer was washed one more time with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give crude material as light brown syrup. This crude product was further purified with 10% methanol in dichloromethane by preparative TLC plate to afford pure title product as yellow solid (100 mg). ESI MS m/z 559 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.76 (d, J=12.4 Hz, 1H), 3.98 (m, 3H), 3.71 (s, 3H), 3.51 (d, J=12.1 Hz, 2H), 3.17 (t, J=12.3 Hz, 2H), 2.76 (br s, 1H), 1.92 (d, J=11.8 Hz, 2H), 1.83 (d, J=11.6 Hz, 2H), 1.49 (q, J=8.6 Hz, 2H), 1.38 (s, 9H), 1.20 (q, J=7.9 Hz, 2H), 1.15 (d, J=7.1 Hz, 2H), 0.94 (d, J=5.6 Hz, 2H).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N+:11]([O-:27])[C:12]([O:25][CH3:26])=[C:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[N:14]=1)C1C=CC=CC=1.[H][H].ClCCl>CO.[C].[Pd]>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C:13]2[NH:14][C:9](=[O:8])[C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N+:11]([O-:27])[C:12]=2[O:25][CH3:26])=[CH:17]1
Reactant: [H][H]
Reactant: COc1c(Cc2c[nH]c3ccccc23)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1c(Cc2c[nH]c3ccccc23)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Reaction time: 0.33 h
Yield: 92 %

Procedure:
In 140 ml of methanol was dissolved 2.69 g of 3-benzyloxy-5-(indol-3-yl)methyl-2-isobutyl-6-methoxypyrazine 1-oxide, thereto was added 10% palladium-carbon, and the mixture was stirred for 1 hour at room temperature in a hydrogen gas atmosphere. 150 Milliliters of dichloromethane was added, and the mixture was stirred for 20 minutes, then the catalyst was removed by filtration, and the filtrate was subjected to recrystallization from methanol-chloroform to obtain 1.94 g of the title compound as pale yellow prism-like crystals having a melting point of 222°-224° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[C:23]([C:29]#[N:30])=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH:21]=1>>[F:28][C:25]1[CH:24]=[C:23]([C:29]#[N:30])[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:31])=[CH:27][CH:26]=1
Reactant: N#Cc1cc(F)ccc1-c1cc(Br)ccc1F
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 44.6 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (102 mg, 0.5 mmol) and 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (221 mg, 0.75 mmol) were coupled following the procedure given in Example 6 to afford 4,2′-difluoro-5′-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)-biphenyl-2-carbonitrile (93 mg, 45%) as an off-white solid: δH (360 MHz, CDCl3) 7.00 (1H, dd, J 7 and 6), 7.40-7.47 (2H, m), 7.55 (1H, dd, J 8 and 3), 7.57-7.65 (3H, m), 7.86 (1H, s), 8.34 (1H, d, J 7); m/z (ES+) 418 (100%, [MH]+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]([NH:17][C:18]([C:20]2[C:21]3[CH:28]=[N:27][N:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:22]=3[CH:23]=[N:24][CH:25]=2)=[O:19])[CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]([NH:17][C:18]([C:20]2[C:21]3[CH:28]=[N:27][N:26]([C:29]4[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=4)[C:22]=3[CH:23]=[N:24][CH:25]=2)=[O:19])[CH2:15][CH3:16])[CH2:9]1
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.3 mmol) was added a 10% solution of trifluoroacetic acid in dichloromethane (10 mL). The mixture was stirred at room temperature overnight and the reaction was monitored by HPLC-MS indicating incomplete conversion. Additional trifluoroacetic acid (1 mL) was added. The mixture stirred until HPLC-MS indicated starting material was consumed. The mixture was concentrated in vacuo and the residue was diluted with EtOAc (100 mL), made basic with saturated aqueous sodium bicarbonate (pH=10), washed with brine, and dried over sodium sulfate, filtered and concentrated. A portion of the crude material was purified by reversed-phase HPLC (Sunfire PrepC18 OBD 5 mM 30×150 mm column) eluting with a gradient of 15-85% acetonitrile in water (0.1% TFA). The fractions from the column were concentrated to remove acetonitrile made basic with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layers were dried and concentrated to afford the title compound as a white foam.