Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5]2.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([O:19][C:15](=[O:18])/[CH:16]=[CH:17]/[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7](=[O:12])[C:6]([CH3:14])([CH3:13])[CH2:5][C:4]=2[CH:3]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC1(C)Cc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A suspension of 6-bromo-3,3-dimethyl-3,4-dihydro-1,8-naphthyridin-2(1H)-one (434 mg, 1.7 mmol), tert-butyl acrylate (1.23 mL, 8.5 mmol) and (i-Pr)2EtN (0.9 mL, 5.1 mmol) in DMF (25 mL) was de-oxygenated with Ar for 30 min. The mixture was treated with Pd(OAc)2 (38 mg, 0.17 mmol) and P(o-tol)3 (103 mg, 0.34 mmol) then heated to 110° C. for 22 h. The hot mixture was filtered through a pad of celite and washed with ethyl acetate (50 mL). The filtrate was diluted with H2O (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water, then brine, dried over magnesium sulphate, and concentrated in vacuo. The resulting brown solid was then triturated with a diethyl ether followed by filtration to yield the white solid product. Yield 178 mg (35%); 1H NMR (300 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.52 (d, J=16.1 Hz, 1H), 6.52 (d, J=15.8 Hz, 1H), 2.80 (s, 2H), 1.49 (s, 9H), 1.09 (s, 6H); ESI MS m/z 303 [C17H22N2O3+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].CI.[C:20](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, a dimethylformamide (30 ml) solution of 2-(3-pyridyl)indole (3.07 g) was added to dimethylformamide (20 ml) in which 60% sodium hydride (0.76 g) was suspended and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (1.2 ml) was added at 0° C. and the mixture was stirred at room temperature for one hour. The mixture was reacted at 0° C., then a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, then the solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography to obtain 1-methyl-2-(3-pyridyl)indole (1.72 g).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH3:14])[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:33][C:28]1[CH:27]=[C:26]([CH:10]2[CH:11]([CH:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH3:14])[CH2:12][NH:8][CH2:9]2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (XIV-B-1) 0.99 g (2.00 mmol) dissolved in CH3CN (25 mL) was added 0.40 mL (3.00 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo, and the crude was dissolved in AcOH (20 mL) before a total of 800 mg of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 0.54 g (67%) of the title compound as a colorless oil. ES-MS m/e: 404.2 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[S:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][CH2:7]2
Reactant: BrCCCCCCC(Sc1ccccc1)c1ccccc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccccc1)c1ccccc1)CC2
Yield: 36.4 %

Procedure:
The free base from 4.60 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 3.63 g of [(7-bromo-1-phenylheptyl)thio]benzene, 50 ml of acetonitrile and 2.61 ml of ethyl diisopropylamine is heated at reflux temperature for 29 hours. The solvent is evaporated over night and the residue is partitioned between chloroform and aqueous ammonium hydroxide. The organic layer is dried and concentrated in vacuo to give 5.81 g of crude product. The residue is purified by chromatography (silica gel: chloroform/methyl alcohol) to give 1.73 g of the desired product.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.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>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([F:13])[CH:19]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)cnc1-c1cccc(F)c1
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A solution of methyl 2,5-dichloronicotinate (8.2 g, 40 mmol), (3-fluorophenyl)boronic acid (6.1 g, 44 mmol), and potassium carbonate (12 g, 86 mmol) in water (71 mL) and 1,4-dioxane (190 mL) was degassed with nitrogen (10 minutes). The reaction mixture was treated with bis(triphenylphosphine)palladium(II) chloride (3.1 g, 4.4 mmol), degassed with nitrogen (10 minutes), and heated at 80° C. for 14.5 hours. The reaction mixture was diluted with ethyl acetate and water and filtered over celite. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0-80%) gave the desired product (8.7 g, 83%). LCMS calculated for C13H10ClFNO2 (M+H)+: m/z=266.0. found: 265.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C@H:13]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C@H:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH2:33][O:31][C:28]1[CH:27]=[CH:26][C:25]([C@H:13]2[C:12]3[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=3)[O:16][CH2:15][C@H:14]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: Oc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)COc1ccc([C@H]2c3ccc(OCc4ccccc4)cc3OC[C@H]2c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
(+,-) cis 4-(7-Benzyloxy-3-phenyl-chroman-4-yl)-phenol (0.5 g, 1.22 mmol), methyl bromoacetate (0.37 g, 2.44 mmol), 18-crown-6 (0.48 g, 1.83 mmol), and potassium carbonate 0.25 g, 1.83 mmol) was slurried in toluene (25 ml), and stirred at 100° C. for 75 min. After cooling the reaction mixture was filtered through a 1.6×6 cm silica column, eluted with 10% tetrahydrofuran in toluene and evaporated.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CN2CCC(=Nc3cccnc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(CN2CCC(Nc3cccnc3)CC2)cc1
Temperature: 50 °C

Procedure:
To a stirred solution of 27 parts of N-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine in 40 parts of ethanol are added portionwise 3.8 parts of sodium borohydride. After the addition is complete, the whole is heated to 50° C. The solvent is evaporated. The oily residue is dissolved in 150 parts of hydrochloric acid 1N and filtered. The filtrate is rendered alkaline with ammonium hydroxide and extracted with methylbenzene. The organic layer is dried over magnesium sulfate, filtered and evaporated. The solid residue is washed with 2,2'-oxybispropane and dried, yielding 14 parts of N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine; mp. 131°-133° C.; beige, amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9](N)[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4].[BrH:17].N([O-])=O.[Na+]>O.Br.O.[Cu]Br>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([Br:17])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:16])=[O:4]
Reactant: COC(=O)n1c(C)cc2c(N)c(Cl)ccc21
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)n1c(C)cc2c(Br)c(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Amino-5-chloro-2-methyl-indole-1-carboxylic acid methyl ester (2.04 g, 8.54 mmol) is suspended in a 4.8% solution of HBr in water (75 ml). After cooling to 0° C., a solution of sodium nitrite (1.23 g, 17.94 mmol) in water (30 ml) is slowly added during 20 minutes. After 30 minutes at 0° C., it is slowly added to a solution of copper(I) bromide (25.1 g, 175 mmol) in 48% HBr/H2O (75 ml), while the temperature is kept below 5° C. After the addition is complete, the suspension is stirred at RT for 2 hours and then at 85° C. for 5 minutes. After cooling to RT, the mixture is extracted with CH2Cl2/MeOH (95:5, 800 ml). The organic layer is washed with saturated aqueous NaCl solution, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 4:1) affords the title compound. 1H NMR (DMSO, 400 MHz) δ 2.61 (s, 3H), 4.03 (s, 3H), 6.56 (s, 3H), 7.46 (d, J=9 Hz, 1H), 8.05 (d, J=9 Hz, 1H); ES-MS: 303 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].CO.Cl.[H][H]>[Pd].CC(O)C>[ClH:1].[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]([CH3:15])[CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:16]
Reactant: [H][H]
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCCl)C(C)CCC2
Yield: 86 %

Procedure:
A mixture of 9.5 parts of 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]-pyrimidin-4-one, 160 parts of methanol and 40 parts of 2-propanol saturated with hydrogen chloride was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated, yielding 9.5 parts (86%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (intermediate 175).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([Cl:19])[C:16](Cl)=[C:15]([Cl:21])[CH:14]=1>O.CS(C)=O>[Cl:19][C:17]1[CH:18]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=1
Reactant: Nc1ccc(O)cc1
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1
Reaction time: 2 h

Procedure:
32.5 g of potassium hydroxide flakes in 30 ml of water were added to 54.5 g (0.5 mole) of 4-aminophenol dissolved in 350 ml of dimethylsulfoxide, and 150 ml of a water/dimethylsulfoxide mixture were distilled off in vacuo at 15-20 mm Hg. 125 g (0.5 mole) of 1-trifluoromethyl-3,4,5-trichlorobenzene [nD20 : 1.5008 67- 68% of theory, compare J. Am. Chem. Soc. 57, 2066-2068 (1935) and U.S. Pat. No. 2,654,789] were then added to the reaction mixture at about 70°-80° C and the mixture was stirred for a further 2 hours at 120°-130° C. The substance was precipitated with water, filtered off, washed with water and recrystallized moist from an ethanol/water mixture, thus giving 40-50% of theory of 4-(2,6-dichloro-4-trifluoromethylphenoxy)-aniline of melting point 128°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=1.Br[CH2:25][C:26]([CH3:28])=[CH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:27][C:26]([CH3:28])=[CH2:25])[CH:12]=2)[CH:7]=1
Reactant: C=C(C)CBr
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=C(C)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
N-(3-Methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (34 mg, 0.11 mmol), 3-bromo-2-methylprop-1-ene (11 μl, 0.11 mmol), cesium carbonate (69 mg, 0.21 mmol) and DMA (210 μL) were combined in a vial and stirred at 100° C. for 1.25 hours. The reaction mixture was diluted with EtOAc, washed with aqueous sodium bicarbonate, then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude N-(3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine as a yellow oil. MS ESI calcd. for C19H19F3N5 [M+H]+ 374. found 374.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][C:31]([N:28]6[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]6)=[CH:36][CH:35]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N5CCN(C)CC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 2-(4-methylpiperazine-1-yl)pyridine-5-boronic acid pinacol ester (Combi-Blocks, San Diego, USA, 40 mg, 0.132 mmol) to give the title compound as a white solid. (HPLC: tR 2.04 min (Method A); M+H=469 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.91 (s, 1H), 8.30-8.24 (m, 1H), 8.14-8.10 (m, 1H), 8.07-8.01 (m, 1H), 7.90-7.83 (m, 1H), 7.62-7.56 (m, 1H), 7.45-7.41 (m, 1H), 6.97-6.90 (m, 1H), 3.92 (s, 3H), 3.55 (s, 7H), 2.41-2.35 (m, 4H), 2.21 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16](Cl)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].O.CCOC(C)=O.[CH3:32][N:33](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([C:32]#[N:33])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C[C@@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C[C@@H](Nc1nc(C#N)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
In a microwave reaction vessel was dissolved (R)-3-(6-chloro-3-nitro-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (0.75 g, 2.14 mmol) in DMF (12 ml). Added the zinc cyanide (0.15 g, 1.29 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.21 mmol). Reaction mixture was degassed using a stream of nitrogen and capped. Reaction was heated in a microwave at 120° C. for 1 hour and then stirred at room temperature for 72 hours. After this time the reaction was poured into water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via silica gel flash column chromatography (12 g silica gel, 5-20% EtOAc/hexanes) to afford 0.70 g (96%) of the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[CH:12]=1>O>[NH2:10][C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:25])([F:27])[F:26])=[CH:19][C:18]=2[Cl:28])[C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c([N+](=O)[O-])c1N
Reaction time: 0.17 h

Procedure:
To 2.8 g of concentrated nitric acid was added dropwise 3.7 g of concentrated sulfuric acid at room temperature, followed by stirring for 10 minutes to obtain a mixed acid solution. A 0.5 g quantity of 5-amino-3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methylpyrazole (13) was added in small portions to the solution at 60° C., and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was added to water, the resulting mixture was extracted with ether, and the aqueous layer was made weakly alkaline with a saturated sodium carbonate aqueous solution and then extracted with ethyl acetate, followed by washing with brine and drying over anhydrous magnesium sulfate. Removal of the solvent gave 0.2 g of the desired compound in the form of orange crystals (yield 35.1%), m.p. 107°-108° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN1C(=O)CCC1>[O:21]1[CH2:22][CH2:23][N:18]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:7]=2)[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Nc1ccccc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1Nc1ccccc1
Yield: 82.5 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (0.50 g, 1.7 mmol) and morpholine (0.59 g, 6.8 mmol) in 15 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 5-Morpholino-2-nitro-N-phenylbenzenamine (0.42 g, 80%) was obtained by flash column chromatograph (30% acetyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.26 (t, J=5.2 Hz, 4H), 3.81 (t, J=5.2 Hz, 4H), 6.37 (d, J=2.7, 9.7 Hz, 1H), 6.45 (d, J=2.7 Hz, 1H), 7.25-7.47 (m, 5H), 8.18 (d, J=9.7 Hz, 1H), 9.87 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 47.5, 66.7, 96.6, 105.9, 125.0, 126.0, 129.4, 130.2, 139.4, 145.8, 156.0.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1
Reactant: O=C1CCC(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.05 g, 0.26 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.19 g, 0.78 mmol) and cesium carbonate (0.25 g, 0.78 mmol) were mixed in NMP (1 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (4×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]2[S:7][C:8]3[CH:14]=[C:13]([N:15]4[C:20](=[O:21])[CH:19]=[CH:18][CH:17]=[N:16]4)[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]2[S:7][C:8]3[CH:14]=[C:13]([N:15]4[C:20](=[O:21])[CH:19]=[CH:18][CH:17]=[N:16]4)[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1
Reactant: O=c1cccnn1-c1ccc2nc(C3CC(O)C3)sc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C1CC(c2nc3ccc(-n4ncccc4=O)cc3s2)C1
Reaction time: 3 h

Procedure:
The product of Example 48C (1.63 g, 5.45 mmole) was dissolved in 50 ml anhydrous dichloromethane. Dess-Martin periodinane (3.0 g, 7.07 mmole, [87413-09-0]) was added. After 3 hours at room temperature, the mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product which was purified by column chromatography (0.25% ammonium hydroxide and 2.5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.20 (d, J=2.03 Hz, 1H) 8.07 (d, J=8.82 Hz, 1H) 7.94 (dd, J=3.73, 1.70 Hz, 1H) 7.75 (dd, J=8.82, 2.37 Hz, 1H) 7.26-7.31 (m, 1H) 7.09 (dd, J=9.49, 1.70 Hz, 1H) 4.01-4.15 (m, 1H) 3.54-3.79 (m, 5H). MS: (M+H)+=298.