Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(=O)C(F)(F)F)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Li+]>CN(C=O)C>[N:18]([CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@@H]1CCCN1C(=O)C(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a flask protected by a safety screen, a solution of the product of step B (12.27 g, 0.042 mmol) and lithium azide (2.47 g, 0.051 mmol) in DMF (30 ml) was stirred at 45° C. for 18 hr. The solvent was evaporated in vacuo and the residue triturated with EtOAc (100 ml) and filtered. The filtrate was evaporated in vacuo and the residue dissolved in MeOH (255 ml) which was saturated with gaseous ammonia at 0° C. and then stirred at room temperature for 72 hr. The solvent was removed by distillation in vacuo to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:19][C:18]=1[F:26]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Product: CCC(=O)NC1CCc2c(-c3ccc(Cl)c(F)c3)cncc21
Yield: 87 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-chloro-3-fluorophenylboronic acid to give the title compound as grey solid in 87% yield. MS: 319.1 (M+H+, 1Cl).
Reaction SMILES: [CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].[C:32](Cl)(=[O:37])[CH2:33][C:34](Cl)=[O:35]>C1COCC1>[O:35]=[C:34]1[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:32](=[O:37])[CH2:33]1
Reactant: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.2 %

Procedure:
To 60 mL of THF at 0° C. is added dropwise over 20 min simultaneously a solution of 2.0 g (4.68 mmol) of N-Isopropyl-2-(2-phenylamino-phenylamino)-N-(4-trifluoromethyl-phenyl) acetamide, prepared as in Part A, in 30 mL of THF and 590 μL (6.08 mmol, 1.3 equiv) of malonyl dichloride in 30 mL of THF. The resulting solution is stirred at RT for 20 h and the solvent removed in vacuo. Purification of the resulting brown oil by silica gel flash column chromatography using hexane/EtOAc 3/2 as eluent afforded 1.35 g of the title compound as a light tan solid: mp 186°-188° C.; 1H NMR (CDCl3, 400 MHz) δ7.74 (d, 2H, J=8.1), 7.42 (d, 2H, J=8.1), 7.36 (m, 3H), 7.25 (m, 4H), 7.08 (ddd, 1H, J=1.4, 8.4, 8.4), 6.90 (dd, 1H, J=1.2, 8.2), 5.06 (m, 1H), 4.12 (dd, 2H, J=14.4, 95.5), 3.52 (dd, 2H, J=12.0, 34.5), 1.11 (d, 6H, J=6.6); low resolution MS (FAB)m/e 496 (MH+), 293, 265; Anal. (C27H24F3N3O3) Calcd. C, 65.45; H, 4.88; N, 8.48; Found C, 65.16; H, 4.95; N, 8.33.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:11]=[CH:10]2>CO>[Br:1][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[N:13]2
Reactant: BrBr
Reactant: COc1cccc2ccc(-c3cccnc3)nc12
Solvent: CO
Product: COc1ccc(Br)c2ccc(-c3cccnc3)nc12

Procedure:
Bromine (200 μl) was added in a dropwise manner to a stirred and cooled (0°-5° C.) solution of 8-methoxy-2-(3-pyridyl)quinoline (780 mg) in methanol (30 ml) under a nitrogen atmosphere. The reaction mixture was stirred for 15 minutes then quenched by the addition of 5% aqueous sodium metabisulfite solution (7ml). The reaction mixture was evaporated in vacuo and the residue partitioned between 0.5N sodium hydroxide solution (65 ml) and dichloromethane (75 ml). The aqueous phase was reextracted with dichloromethane (2×75 ml) and the combined organic phases were dried (magnesium sulfate), filtered and evaporated in vacuo. Trituration with diethyl ether afforded the title compound (570 mg) as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38].C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[CH3:46][S:47]([O:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38])(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 90.7 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-methyl-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (178 mg, 0.280 mmol) was dissolved in dichloromethane (6 mL), and the solution was treated with triethylamine (0.156 mL, 1.12 mmol) and methanesulfonyl chloride (0.043 mL, 0.56 mmol), followed by purification by slurry using hexane to obtain 4-methanesulfonyloxy-5-methyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (152 mg, yield 76%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[H][H]>CO.Cl.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][C:13]2([OH:18])[CH2:14][CH2:15][CH2:16][CH2:17]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19]
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(CCC3(O)CCCC3)nc21

Procedure:
To a solution of 300 mg of 1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl]-1-cyclopentanol in 20 ml of methanol were added six drops of 5N hydrochloric acid and 63 mg of 10% palladium/carbon and the mixture was stirred in a hydrogen atmosphere at room temperature for 17 hours. The palladium/carbon was filtered off, the filtrate was concentrated and the residue was dissolved in ethyl acetate and saturated sodium hydrogen carbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was subjected to a silica gel column chromatography (15 g of silica gel; dichloromethane, dichloromethane/methanol (40:1, 20:1 and 10:1) to give 1-[2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethyl]-1-cyclopentanol. This was dissolved in methanol and then five drops of 5N hydrochloric acid were added thereto followed by concentrating. Ether was added to the residue and the crystals were collected by filtration and washed with ether to give 6209 mg of the product. The yield was 69%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][CH:10]([CH2:12][CH2:13]O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:21])CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:11][CH:10]([CH2:12][CH2:13][F:21])[CH2:9]2)[CH:3]=1
Reactant: OCCC1CC(c2cccc(Br)c2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FCCC1CC(c2cccc(Br)c2)C1
Temperature: -78 °C
Yield: 41.4 %

Procedure:
2-[3-(3-Bromo-phenyl)-cyclobutyl]-ethanol (0.600 gm, 2.35 mmol) was dissolved in dichloromethane (10 mL) and chilled to −78° C. The solution was treated with (diethylamino)sulfur trifluoride (468 mg, 2.88 mmol) and monitored by TLC. The crude reaction was poured onto silica and purified by column chromatography (10% EtOAc in hexanes) to afford 250 mg of an oil (41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.79 (m, 2H) 1.83-2.09 (m, 2H) 2.14-2.34 (m, 2H) 2.37-2.44 (m, 1H) 3.27-3.63 (m, 1H) 4.27-4.52 (m, 2H) 7.16-7.24 (m, 2H) 7.29-7.40 (m, 2H); MS (EI) m/z 256 [M+·].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccnc1
Product: CN(C)C=CC(=O)c1cccnc1

Procedure:
Reactant 3 can be obtained by the following procedures. A mixture of 3-acetylpyridine (2.47 mol) and N,N-dimethylformamide dimethylacetal (240 mL) is heated at reflux for 16 h. The solvent is removed in vacuo and hexanes (100 mL) is added to the residue to crystallize a solid. The solid is recrystallized from methylene chloride-hexanes to give 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one. 1H NMR (400 MHz, d-chloroform) δ 9.08 (d, J=2.4 Hz, 1H), 8.66 (m, 1H), 8.20 (m, 1H), 7.87 (m, 1H), 7.37 (m, 1H), 5.68 (d, J=16.4 Hz, 1H), 3.18 (s, 3H), 2.97 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[N:14][C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:28][N:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[ClH:42].[OH:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[N:14][C:15]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:28][N:29]1[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4nc(-c5ccccc5)ccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3nc(-c4ccccc4)ccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.019 g, 0.034 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(6-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.014 g, 74%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH2:27])=[O:26])[CH:20]=2)[CH:12]=1)(=O)C.Cl.CCOCC>O>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18][C:19]1[CH:20]=[C:21]([C:25]([NH2:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)Oc1cccc(COc2cccc(C(N)=O)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: NC(=O)c1cccc(OCc2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.7 %

Procedure:
A solution of K2CO3 (500 mg, 3.62 mmol, 5.75 equiv.) in water (5 ml) was added to a solution of 3-[3-(aminocarbonyl)phenoxy]methylphenyl acetate (180 mg, 0.63 mmol, 1 equiv.) and the mixture was stirred at r.t., under N2, for 3 h; The mixture was acidified with 10% HCl solution to pH 1, and was extracted with EtOAc (2×30 ml). The combined organic extracts were washed with water (30 ml), dried (Na2SO4) and evaporated to dryness under reduced pressure, to give a clear oil residue which, after trituration with Et2O, solidified to a white solid (70 mg, 46% yield). Mp 122-123° C., HPLC-MS (method 1): m/z 244 [M+H]+. Rt=2.92 min.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C1COCC1>[CH2:16]([C:5]1[N:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:10])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(=O)c1cccnc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1cccnc1Cc1ccccc1

Procedure:
NaH (300 mg; 60%) is added to the solution of methyl nicotinoylacetate (896 mg, 5 mmol) in THF (15 mL) at 0° C. under argon atmosphere. The reaction mixture is stirred for 15 minutes at the temperature and benzyl bromide (0.36 mL) is added. The reaction mixture is heated at reflux overnight. The reaction mixture is poured into iced 1N HCl and extracted with EtOAc three times. The combined organic extract is washed with brine and dried over MgSO4. Concentration under reduced pressure gives the residue which is purified over column chromatography to afford methyl 2-benzyl-nicotinoylacetate intermediate (389 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[N:3]([CH2:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[CH2:7][N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:9]3=[O:14])[CH3:2])[CH:27]=[CH:28][CH:29]=1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 3-chloro-phenyl-isocyanate (0.27 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 3-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.68 g, 82%): mp 193-195° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.29 (99%); 1H NMR (DMSO-d6): δ 2.00-2.04 (m, 1H), 2.32-2.38 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.92 (m, 1H), 2.98 (s, 3H), 4.38 (d, J=17.3 Hz, 1H), 4.45 (d, J=17.3 Hz, 1H), 4.65 (s, 2H), 5.10-5.18 (dd, J=4.5, 13.2 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.46-7.41 (In, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.64-7.67 (m, 2H), 8.65 (s, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 22.57, 31.19, 34.76, 46.27, 48.37, 51.60, 118.00, 119.08, 121.42, 121.77, 128.48, 129.85, 129.92, 131.93, 132.69, 133.62, 140.15, 142.04, 155.34, 168.00, 171.01, 172.84. Anal Calcd for C22H21ClN4O4: C, 59.93; H, 4.80; N, 12.71, Cl, 8.04. Found: C, 59.30; H, 4.66; N, 12.33, Cl, 8.36.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]>>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCC(CNc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1
Yield: 51.6 %

Procedure:
Following general procedure F, {6-bromo-4-[(1-methylpiperidin-4-yl)methylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.120 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.180 mmol) to afford the desired product (29 mg, 51%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ 9.13 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.02-7.83 (m, 2H), 7.56-7.37 (m, 2H), 3.84 (d, J=5.9 Hz, 2H), 2.89-2.74 (m, 3H), 2.71 (s, 3H), 2.05 (d, J=13.4 Hz, 3H), 1.65-1.47 (m, 2H), 1.28 (s, 3H), 1.24-1.16 (m, 2H), 1.16-1.02 (m, 2H), 0.88 (d, J=6.9 Hz, 1H); ESI MS m/z [C26H27ClFN3O2+H]+; HPLC>99% (AUC), tR=9.14 min.
Reaction SMILES: C([O:4][P:5](/[CH:11]=[CH:12]/[CH2:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:24])([O:7]C(C)C)=[O:6])(C)C.Br[Si](C)(C)C>ClCCl>[P:5](/[CH:11]=[CH:12]/[CH2:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][CH:18]=[N:19][C:20]=2[NH2:24])([OH:7])([OH:6])=[O:4]
Reactant: CC(C)OP(=O)(/C=C/CCn1cnc2c(N)ncnc21)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2CC/C=C/P(=O)(O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
To a solution of (E)-9-[4-(diisopropoxyphosphoryl)but-3-enyl]adenine (111 mg, 314 μmol) in dichloromethane (6 ml) was added bromotrimethylsilane (0.9 g, 6.28 mmol) and the mixture was stirred at room temperature under dry nitrogen for 18 hr. The solution was evaporated to dryness and the residue azeotroped with methanol (×3). The residue was purified by column chromatography on reverse phase silica gel eluting with water to give (E)-9-(4-phosphonobut-3-enyl)adenine as a white solid (69 mg, 81%), m.p. 263°-266° C.; λmax (MeOH) 261 (10,810)nm; υmax (KBr) 3360, 3095, 1685, 1605, 1520, 1415,and 1228 cm-1 ; δH (D2O +one drop of NH4OH solution) 2.63 (2H, m, CH2), 4.31 (2H, t, J 7 Hz, CH2N), 5.72 (1H, pseudo-t, J 17 Hz, PCH =CH), 6.14 (1H, pseudo-tt, J 7 Hz and 17 Hz, PCH=CH), 8.13 (1H, s, H-2/H-8), 8.19 (1H, s, H-2/H-8); FABMS (thioglycerol) 270 (MH+) (Found: C, 37.29; H, 4.38; N, 24.09%. C9H12N5O3P.0.25HBr requires C, 37.35; H, 4.27; N, 24.20%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].[Br:11]Br.[OH-].[Na+].O>C(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:6]([CH3:10])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1cccc(C)c1N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCc1cc(Br)cc(C)c1N
Temperature: 7.5 °C
Yield: 98.2 %

Procedure:
In a 2.5 L three-necked round-bottom flask 2-ethyl-6-methyl aniline (250 g, 1.85 mol) is dissolved in DCM (900 mL) and cooled to 5-10° C. Bromine (310.3 g, 1.94 mol) is added over a period of 105 min such as to keep the temperature at 5-15° C. An aq. 32% NaOH solution (275 mL) is added over a period of 10 min to the greenish-grey suspension while keeping the temperature of the reaction mixture below 25° C. DCM (70 mL) and water (100 mL) are added and the phases are separated. The aq. phase is extracted with DCM (250 mL). The combined org. phases are washed with water (300 mL) and concentrated at 50° C. to afford the 4-bromo-2-ethyl-6-methyl-aniline (389 g) as a brown oil; 1H NMR (CDCl3): δ 1.27 (t, J=7.3 Hz, 3H), 2.18 (s, 3H), 2.51 (q, J=7.3 Hz, 2H), 3.61 (s br, 1H), 7.09 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:20][CH3:21])[C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)c1c(Cl)[nH]c(=O)[nH]c1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cl)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 0.67 h

Procedure:
6-Chloro-5-isopropyl-1H-pyrimidine-2,4-dione (18.8 g, 100 mmol) was stirred with anhydrous powdered potassium carbonate (16.56 g, 120 mmol) in DMF (200 mL) at room temperature. After 40 min., iodoethane (8 mL, 100 mmol) was added and the mixture was stirred overnight. The mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (from 1:4 to 1:2)) to give 13.8 (63%) of 6-chloro-1-ethyl-5-isopropyl-1H-pyrimidine-2,4-dione as a white solid. m.p. 160-161° C.; 1H-NMR (200 MHz, CDCl3) δ 1.28-1.35 (9H, m), 3.22 (1H, m), 4.15 (2H, q, J=7.2 Hz); m/z (EI) 216 (M+).
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2Cl)=[N:14][C:13]([Cl:18])=[CH:12][CH:11]=3)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]2)=[N:24][CH:25]=1>>[C:35]([O:34][C:33](=[O:39])[NH:32][C@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[N:14]=4)[N:9]=[CH:8][C:7]=3[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])=[CH:25][N:24]=2)[CH2:27]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CCC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CCC4)cnc4ccc(Cl)nc34)cn2)C1
Yield: 91.8 %

Procedure:
Following general procedure I, cyclobutyl(4,6-dichloro-1,5-naphthyridin-3-yl)methanone (200 mg, 0.71 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (311 mg, 1.1 mmol) to afford the desired product (350 mg, 78%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 11.52 (s, 1H), 8.88 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.31 (dd, J=9.0, 2.7 Hz, 1H), 6.72 (d, J=9.0 Hz, 1H), 4.81 (br s, 1H), 4.15-3.97 (m, 1H), 3.91-3.60 (m, 3H), 3.58-3.31 (m, 2H), 2.54-2.21 (m, 4H), 2.20-2.00 (m, 1H), 2.00-1.85 (m, 2H), 1.82-1.63 (m, 2H), 1.51 (s, 9H); ESI MS m/z 537 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=O)[O:4][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]=1[Br:7].[NH2:15][NH2:16].O>CCO>[Br:7][C:6]1[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:16][NH:15][C:3](=[O:4])[CH:2]=1
Reactant: O=C1OC(c2ccccc2)C(Br)=C1Br
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1cc(Br)c(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-dibromo-5-phenylfuran-2(5H)-one (4.951 g, 15.57 mmol) in EtOH (5 mL) at 0° C. was added hydrazine, H2O (0.840 mL, 17.13 mmol). The reaction mixture was stirred at room temperature for 10 min before heating to reflux for 2 h. The reaction was cooled to room temperature. The precipitate formed was collected by filtration and washed with cold ethanol to yield the title compound as a pale yellow solid (2.530 g). LCMS m/z=351 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.47-7.49 (m, 3H), 7.51-7.54 (m, 3H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC1C=CC([N:48]([CH2:55][CH2:56][CH:57]([CH3:59])[CH3:58])C2CCNCC2)=CC=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:48][C@@H:55]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:25]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13]1)=[O:5]
Reactant: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](N)CC(C)C)CC1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
The preparation of (4-Benzyloxy-phenyl)-(3-methyl-butyl)-piperidin-4yl-amine 4-[(4-Benzyloxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (3.27 g, 7.22 mmol) was dissolved in CH2Cl2 (25 mL), treated with TFA (25 mL), and stirred for 30 minutes. The reaction was concentrated, diluted with EtOAc (300 mL), washed twice with saturated sodium bicarbonate solution and brine, dried over Na2SO4, and concentrated to give 2.62 g of the desired product.