Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:20])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:8]=1.[NH2:23][C:24]1[NH:28][N:27]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:25]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[C:29]([C:26]1[CH:25]=[C:24]([NH:23][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:8]=2)=[O:20])[NH:28][N:27]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(Nc1cccc(Oc2cccnc2)c1)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)[nH]n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3cccnc3)c2)[nH]n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 2,2,2-trichloroethyl-3-(pyridin-3-yloxy)phenylcarbamate (0.040 g, 0.11 mmol), 5-amino-3-t-butylpyrazole (0.031 g, 0.22 mmol) and i-Pr2NEt (0.029 g, 0.22 mmol) in DMF (2 mL) was stirred at 100° C. overnight. Water (20 mL) was added and the mixture was extracted with EtOAc (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 1-(3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (26 mg, 67% yield) of the desired product as a red-brown oil. 1H-NMR (400 MHz, CDCl3): δ 10.1 (brs, 1H), 8.40 (s, 1H), 8.35 (d, J=3.6 Hz, 1H), 8.02 (s, 1H), 7.35-7.28 (m, 4H), 6.71 (dt, J=6.4, and 2.2 Hz, 1H), 5.67 (brs, 1H), 1.32 (s, 9H), urea protons not visible; MS (EI) m/z: 352.3 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9]CC)=O)=[CH:3][CH:2]=1.[CH3:12][C:13]([CH3:15])=[O:14].C[O-].[Na+]>C1COCC1>[OH:14]/[C:13](/[CH3:15])=[CH:12]\[C:7]([C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:9]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C(O)=C/C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-pyridinecarboxylate (30 g, 198 mmol) and acetone (34.58 g, 595 mmol) in THF (150 mL) was slowly added NaOMe (12.87 g, 238 mmol) at 35-40° C. The mixture was stirred at room temperature for 0.5 h, and then heated at reflux for 3 h. The mixture was cooled to room temperature and filtered to give a solid, which was washed with t-BuOMe, and dissolved in H2O. The solution was acidified with acetic acid and the resulting oily product was extracted with CHCl3. The solvent was removed in vacuo, and the crude product was obtained (12 g, 37%) and used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, 2H), 7.76 (d, 2H), 6.63 (s, 1H), 2.21 (s, 3H); note: enolic OH does not appear.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]([Si:43]([CH3:46])([CH3:45])[CH3:44])#[CH:42]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:42]#[C:41][Si:43]([CH3:46])([CH3:45])[CH3:44])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCOc1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C

Procedure:
To a 500 mL N2 filled round bottom flask was added 1-bromo-4-(hexyloxy)benzene (20.5 g, 80.0 mmol, 1 equiv.) and DMF (160 mL, 0.5 M). The mixture was then sparged with bubbling N2. To this mixture was added N2-sparged triethylamine (39.0 mL, 280 mmol, 3.5 equiv.) via syringe. Finally, copper (I) iodide (254.0 mg, 1.33 mmol, 1.7%), triphenylphosphine (603.0 mg, 2.67 mmol, 3.3%) and PdCl2(PPh3)2 (933.0 mg, 1.33 mmol, 1.7%) were added as a single portion and the head space was flushed with N2. Ethynyltrimethylsilane (16.9 mL, 120.0 mmol, 1.5 equiv.) was added via syringe to the mixture. The flask was sealed with a ground glass stopper, Teflon tape, and then electrical tape and heated to 90° C. for 48 hours. After 48 hours the mixture was diluted with hexanes and extracted with 10% H3PO4 then 5% K2CO3. The organic layer was then dried with MgSO4 and filtered through a plug of SiO2 with 100% hexanes. Upon evaporation, ((4-(hexyloxy)phenyl)ethynyl)trimethylsilane was isolated as a clear oil (16.45 g, 60.2 mmol, 75%). 1H NMR (400 MHz, CDCl3) δ7.42 (d, J=9.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 3.98 (t, J=6.4 Hz, 2H), 1.85-1.73 (m, 2H), 1.52-1.42 (m, 2H), 1.41-1.26 (m, 4H), 0.94 (t, J=7.6 Hz, 3H), 0.27 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[CH3:20][C:21]1[N:22]=[N:23][S:24][C:25]=1[C:26]([NH:28][NH2:29])=O>>[CH3:20][C:21]1[N:22]=[N:23][S:24][C:25]=1[C:26]1[O:15][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[N:29][N:28]=1
Reactant: Cc1nnsc1C(=O)NN
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Product: Cc1nnsc1-c1nnc(Cn2ccc3c(C(F)(F)F)c(C#N)ccc32)o1

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 4-methyl-1,2,3-thiadiazole-5-carbohydrazide: MS (ES) m/z 391 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[C:7]([Cl:19])=[CH:6][C:5]=1[Cl:20].[C:22]([O:26][C:27](=[O:40])[NH:28][CH2:29][CH2:30][S:31][C:32]1[CH:37]=[C:36](Cl)[N:35]=[C:34]([NH2:39])[N:33]=1)([CH3:25])([CH3:24])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(COC)OC>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:36]2[CH:37]=[C:32]([S:31][CH2:30][CH2:29][NH:28][C:27]([O:26][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:40])[N:33]=[C:34]([NH2:39])[N:35]=2)[C:7]([Cl:19])=[CH:6][C:5]=1[Cl:20]
Reactant: CC(C)(C)OC(=O)NCCSc1cc(Cl)nc(N)n1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of the crude product of 2,4-dichloro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzoic acid methyl ester (320 mg) obtained in Step 3 of Example 2-8, [2-(2-amino-6-chloropyrimidin-4-ylsulfanyl)ethyl]carbamic acid tert-butyl ester (177 mg, 0.58 mmol) obtained in Step 1 above, palladium acetate (5 mg, 0.02 mmol), triphenylphosphine (19 mg, 0.07 mmol), 1N aqueous sodium bicarbonate solution (725 μl), and dimethoxyethane (4.4 ml) was stirred at 80° C. for 2 hours. After the reaction solution was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=3:1 to 1:1) to yield 5-[2-amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2,4-dichlorobenzoic acid methyl ester (96 mg).
Reaction SMILES: O[CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[N+:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17].CCCCCC.[OH-].[K+]>O.C(O)C.CC(O)C>[N+:16]([CH:19]([CH:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:18])=[O:17]
Reactant: OC1c2ccccc2Sc2ccccc21
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C1c2ccccc2Sc2ccccc21)[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Crude 9-hydroxythioxanthene (9.58 g, 45 mmol) is mixed with ethyl nitroacetate (5.5 mL, 49 mmol) and heated at 100° C. for 1 hour. TLC (SiO2, hexane:2-propanol/3:l) after 45 minutes shows no starting material. The cooled reaction mixture is treated with 100 mL of ethanol and 39 mL of 1.25M ethanolic potassium hydroxide solution. Ethanol is stripped and the residue taken up in water and extracted with diethyl ether. The aqueous layer is acidified to pH 2 to 3 with 85% phosphoric acid solution and refrigerated overnight. A crystalline solid is collected by filtration and dried at 50° C./10 mm Hg. A total of 8.4 g of the title compound is collected in three crops; mp 111°-115° C.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:11][F:12])[O:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][O:4]1.[H-].[Na+].Cl[C:16]1[CH:21]=[CH:20][N+:19]([O-:22])=[C:18]([CH3:23])[C:17]=1[CH3:24]>CS(C)=O>[F:1][CH2:2][C:3]1([CH2:11][F:12])[O:4][CH2:5][CH:6]([CH2:9][O:10][C:16]2[CH:21]=[CH:20][N+:19]([O-:22])=[C:18]([CH3:23])[C:17]=2[CH3:24])[CH2:7][O:8]1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCC1COC(CF)(CF)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2COC(CF)(CF)OC2)cc[n+]([O-])c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a dimethylsulfoxide (10 ml) solution of the (2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methanol (1.6 g, 8.98 mmol) obtained in the step (7a), sodium hydride, in oil (431 mg, 9.88 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (1.42 g, 8.98 mmol) was added and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to obtain the title compound (1.63 g, yield: 60.6%) as a yellow oil.
Reaction SMILES: [C:1]([C:6]1([CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[NH:23][NH2:24].C([O-])(=O)C.[Na+]>CO>[CH2:4]([O:3][C:1]([C:6]1([CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]1=[N:24][NH:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[Cl:15])=[O:2])[CH3:5]
Reactant: C=CCC1(C(=O)OCC)CCCC1=O
Reactant: NNc1cc(Cl)ccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCC1(C(=O)OCC)CCCC1=NNc1cc(Cl)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-carbethoxy-2-allylcyclopentanone (110 mg, 0.55 mmol) in 1 mL of methanol was added (2,5-dichloro-phenyl)-hydrazine (89 mg, 0.50 mmol) and sodium acetate (62 mg, 0.75 mmol). The reaction mixture was stirred at room temperature over night. The reaction mixture was concentrated and adding 10 mL of ethyl acetate diluted the residue. The organic solution was washed with 5 mL of water and 5 mL of brine. The organic layer was dried over sodium sulfate and concentrated to give the crude product, which was directly used in next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH2:20]O)[CH:17]=[CH:18][CH:19]=3)[S:13][C:6]=12.S(Cl)([Cl:31])=O>>[Cl:31][CH2:20][C:16]1[CH:15]=[C:14]([C:12]2[S:13][C:6]3[C:7](=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=3[F:1])[CH:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(CO)c4)sc23)c(F)c1
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4cccc(CCl)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
The hydroxy-compound 147 (685 mg, 1.73 mmol) was suspended in thionyl chloride (8.6 mL) and the reaction mixture was refluxed for about one hour. The mixture was cooled to RT then poured into an ice/water mixture. The resultant solid was collected by filtration, washed with water and well dried to afford title compound 148 as a yellow solid (730 mg, 93% yield). MS (m/z): 415.0 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:36][N:37]([CH:46]=[O:47])[O:38]CC2C=CC=CC=2)[C:8]([N:10]2[CH:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N+:19]=3[O-:25])=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:36][N:37]([CH:46]=[O:47])[OH:38])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N+:19]=3[O-:25])=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1C(C(=O)Nc2ccc(F)c[n+]2[O-])CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1ccc(F)c[n+]1[O-]
Reaction time: 1 h
Yield: 17.4 %

Procedure:
To a solution of phenylmethyl 2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-{[(5-fluoro-1-oxido-2-pyridinyl)amino]carbonyl}-1-pyrazolidinecarboxylate (104 mg, 0.161 mmol) in methanol (4 ml) was added 20% palladium hydroxide on carbon (50 mg, 0.161 mmol). The mixture was hydrogenated under balloon pressure for 1 h and then filtered. The filtrate was purified by reverse-phase HPLC to yield (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-(5-fluoro-1-oxido-2-pyridinyl)-3-pyrazolidinecarboxamide (13 mg, 0.028 mmol, 18% yield). LC/MS: (M+H)+: 423.8. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.00-1.27 (m, 2H) 1.39-1.69 (m, 5H) 1.70-1.99 (m, 4H) 2.25-2.45 (m, 1H) 2.45-2.64 (m, 1H) 2.84-3.03 (m, 1H) 3.18-3.30 (m, 1H) 3.53 (dd, J=14.02, 4.42 Hz, 1H) 3.74-3.88 (m, 1H) 3.98 (td, J=9.28, 4.93 Hz, 1H) 4.74-4.87 (m, 1H) 7.37-7.54 (m, 1H) 7.89 (s, 1H) 8.37-8.60 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17]C3C=CC=CC=3)[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[S-2].[Na+].[Na+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([SH:17])[C:10]=2[C:24]#[N:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C#N)cnc(Sc3ccccc3)c2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(C#N)cnc(S)c2C#N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.3 g (3.028 mmol) of 4-(4-methoxyphenyl)-2-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 48A) were initially charged in 11 ml of DMF. 284 mg (3.634 mmol) of sodium sulfide were added, and the mixture was then stirred at 80° C. for 2 h and stirred further at RT overnight. 6 ml of 1N hydrochloric acid were added to the reaction mixture, and the reaction solution was evaporated. The residue was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:24])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16])([CH3:14])[CH2:6][CH2:5]2.[O:25]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:8][C:7]([CH3:14])([C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16])[CH2:6][CH2:5][C:4]1[C:9](=[O:25])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:24]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCN(C)CC1)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)N2CCN(C)CC2)=C(C)C1=O

Procedure:
Oxidation as described in protocol B, using 122 mg (0.368 mmol) of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-methylpiperazin-1-yl)methanone and 444 mg CAN (0.811 mmol) yielded 2-(3-hydroxy-3-methyl-4-(4-methylpiperazin-1-yl)-4-oxobutyl)-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione as an orange oil, 67.9 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:27]([C:29]1[C:30](F)=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28])[CH:20]=[CH:19]2.C([O-])([O-])=O.[K+].[K+].[CH3:42][N:43]([CH3:47])[CH2:44][CH2:45][OH:46]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26][C:27]([C:29]1[C:30]([O:46][CH2:45][CH2:44][N:43]([CH3:47])[CH3:42])=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28])[CH:20]=[CH:19]2
Reactant: CN(C)CCO
Reactant: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5F)ccc4c3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(Oc3ccc4cc(NC(=O)c5cccnc5OCCN(C)C)ccc4c3)c2cc1OC
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a mixture of N-[6-(6,7-dimethoxy-(4-quinolyloxy)) (2-naphthyl)](2-fluoro-(3-pyridyl))carboxamide (Step a, 62 mg, 0.13 mmol) and K2CO3 (166 mg, 1.3 mmol) in dry NMP (5 mL, Aldrich) was added N,N-dimethylethanolamine (35 mg, 0.36 mmol, Aldrich) at RT. The reaction was stirred at 110° C. for 16 h. The mixture was cooled and diluted with 60 mL of EtOAc, then washed with water and brine. The organic phase was dried over MgSO4 and concentrated. The residue was purified by prep-HPLC to give title compound as a white solid. MS (ESI, pos. ion) m/z: 539 (M+1). Mass Calc'd for C31H30N4O5: 538.22.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][NH:31][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: Cc1ccc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCC3=O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(2-oxopyrrolidin-1-yl)biphenyl-3-carboxylic acid (53.0 mg, 0.000152 mol) in N,N-dimethylformamide (1 mL, 0.01 mol) was added (6-methylpyridin-3-yl)methanamine (45.0 mg, 0.000368 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150.0 mg, 0.0003945 mol) and N,N-diisopropylethylamine (150.0 uL, 0.0008612 mol). The reaction mixture was stirred for 16 hours at 25° C. Checked LC/MS, the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC. The final product was yield a light color foam.
Reaction SMILES: [C:1]([O:7][C@H:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][NH:10][C:11]([C@@H:13]([CH2:22][CH:23]=[CH2:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])(=[O:6])[CH2:2][CH2:3]C=C>C1(C)C=CC=CC=1.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[O:12]=[C:11]1[C@H:13]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:22][CH:23]=[CH:24][CH2:3][CH2:2][C:1](=[O:6])[O:7][C@H:8]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][NH:10]1
Reactant: C=CCCC(=O)O[C@@H](CNC(=O)[C@@H](CC=C)CC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: CC(C)(C)OC(=O)C[C@@H]1C/C=C/CCC(=O)O[C@H](c2ccccc2)CNC1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H]1CC=CCCC(=O)O[C@H](c2ccccc2)CNC1=O
Temperature: 65 °C
Reaction time: 7 h

Procedure:
To a solution of (S)-tert-butyl 3-((R)-2-(pent-4-enoyloxy)-2-phenylethylcarbamoyl)hex-5-enoate (470 mg, 1.13 mmol) in toluene (113 mL) was added Grubbs 2nd Generation catalyst (96 mg, 0.113 mmol) and the reaction mixture was heated to 65° C. Upon stirring 7 h with continued heating, TLC analysis indicated complete consumption of starting material. The reaction mixture was cooled to rt, diluted with degassed CH2Cl2 (11 ml) and Pb(OAc)4 (251 mg, 0.566 mmol) was added. The resulting mixture was stirred for 12 h at which point the mixture was passed through a short plug of silica then concentrated using rotary evaporation. The resulting purple solid was triturated with methanol to further remove ruthenium complexes. The off white solid that remained was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 320 mg of desired product as a white solid in 73% yield. LRMS (M+Na)+: 410.4.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N,N-dimethylethylenediamine (0.5 g) in dichloromethane (10 ml) at 0° C. was added triethylamine (0.87 ml) and methane sulphonyl chloride. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution, the combined organics were dried (MgSO4) and the solvents removed in vacuo to yield a crude product. This was purified by flash chromatography to yield N-(2-dimethylamino-ethyl)-methanesulfonamide (0.46 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1B(O)O.Br[C:25]1[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH:26]=1>C(O)C.C(COC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[C:25]1[CH2:30][CH2:29][CH2:28][C:27](=[O:31])[CH:26]=1
Reactant: COCOc1ccc(B(O)O)c(OCOC)c1
Reactant: O=C1C=C(Br)CCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Reaction time: 6 h
Yield: 82.8 %

Procedure:
Aqueous sodium carbonate (2 ml of a 6M solution) and 2,4-bis(methoxymethoxy)phenylboronic acid (120 mg) in ethanol (2 ml) were added to a solution of palladium tetrakis(triphenylphosphine) (57 mg) and 3-bromo-2-cyclohexen-1-one (87 mg) in dimethoxyethane (3 ml) and the mixture was heated under reflux. After 6 hr, the mixture was partitioned between water (50 ml) and ethyl acetate (100 ml). The organic layer was dried over magnesium sulfate and evaporated in vacuo to furnish an oil that was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:3, v/v) to furnish the title compound as an oil (120 mg, 83%). δH (CDCl3) 2.10 (2H, quintet), 2.47 (2H, t), 2.74 (2H, m), 3.476 (3H, s), 3.484 (3H, s), 5.185 (2H, s), 5.190 (2H, s), 6.21 (1H, m), 6.71 (1H, dd), 6.85 (1H, d), 7.16 (1H, d).