Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:29]1[C:30]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]([N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[O:43])=[CH:37][CH:36]=2)=[N:31][N:32]([CH3:34])[CH:33]=1>>[CH:15]([C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:29]4[C:30]([C:35]5[CH:36]=[CH:37][C:38]([NH:41][C:42]([N:44]6[CH2:45][CH2:46][CH2:47][CH2:48]6)=[O:43])=[CH:39][CH:40]=5)=[N:31][N:32]([CH3:34])[CH:33]=4)=[C:3]3[CH:10]=2)=[CH:18][CH:17]=1)=[O:16]
Reactant: Cn1cc(Br)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1
Reactant: O=Cc1ccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Product: Cn1cc(-c2ccnc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N3CCCC3)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 using 4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]benzaldehyde and then following the procedure described for Intermediate 100 with N-[4-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]-1-pyrrolidinecarboxamide provided the title compound. ESMS [M+H]+: 631.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5 mmol of 2-(4-((6-chloro-2-quinolinyl)oxy)phenoxy)propionyl chloride, prepared as in Step A of Example 1 employing the corresponding acid, in 10 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.09 g (5.5 mmol) of 4-aminobenzotrifluoride, hydrochloride, 1.21 g (12.0 mmol) of triethylamine and 50 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 hours and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was recrystallized from methylcyclohexane to give 1.79 g (74 percent of theoretical) of the desired product as colorless crystals melting at 142°-146° C. The structure of the compound was confirmed by its IR and NMR spectrum. (Compound 6). The carbon, hydrogen and nitrogen contents were determined to be as follows:
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[C:8]=1[CH:14]=O)[CH2:4][CH3:5])[CH3:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[K+]>CO.O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([F:13])[C:8]=1[CH:14]=[N:17][OH:18])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccnc(F)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCN(CC)Cc1ccnc(F)c1C=NO
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a solution of compound 88 (150 mg, 0.71 mmol) in methanol (2 mL) was added a solution of hydroxylamine hydrochloride (74 mg, 1.07 mmol) and potassium acetate (105 mg, 1.07 mmol) in water (7 mL). The mixture was stirred at room temperature for 4 h and the methanol was then evaporated under reduce pressure. A saturated aqueous sodium chloride solution (10 mL) was added and the mixture was extracted with dichloromethane (4×20 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (Al2O3, AcOEt→AcOEt/EtOH, 85/15, vi/v) to give compound 89 (131 mg, 0.58 mmol) as a white solid. Yield 81%; Rf (Al2O3, AcOEt/EtOH, 85/15, v/v) 0.89; mp 97-99° C.; IR (KBr) ν 1264, 1331, 1392, 1605, 2750-2980, 3100, 3191 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.05 (t, 6H, J=7.1 Hz), 2.57 (q, 4H, J=7.1 Hz), 3.83 (s, 2H), 7.56 (d, 1H, J=5.1 Hz), 8.13 (d, 1H, J=5.1 Hz), 8.43 (s, 1H); ESI-MS m/z 225.8 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[O:11]1[CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1ncccc1C1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a round bottomed flask was added 2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (3.4590 g, 19.09 mmol), 4-aminophenol (3.12 g, 28.6 mmol), and cesium carbonate (18.66 g, 57.3 mmol) in DMSO (63.6 mL) at 110° C. to stir overnight. Reaction was allowed to cool to room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed 50% sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline. MS (ESI, pos. ion) m/z: 271.1 (M+1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([OH:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.N1C=CN=C1.[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].ClCCl>CN(C)C=O>[CH:16]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[O:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)([CH3:18])[CH3:17]
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[Si](Oc1cnc2[nH]ccc2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of 1H-Pyrrolo[2,3-b]pyridin-5-ol (0.5 g, 0.004 mol) and 1H-imidazole (0.98 g, 0.014 mol) in N,N-dimethylformamide (5 mL) was added triisopropylsilyl chloride (1 mL, 0.005 mol). The reaction mixture was stirred at room temperature overnight. Dichloromethane (10 mL) was added and the solution was washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (83, 0.4 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:19])=[CH:13]2.IC.[C:31](=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:31][N:15]1[C:16]2[C:12](=[C:11]([N+:20]([O-:22])=[O:21])[C:10]([O:9][C:8]3[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][C:3]=3[O:2][CH3:1])=[CH:18][CH:17]=2)[CH:13]=[C:14]1[CH3:19]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(C)cc3c2[N+](=O)[O-])c(OC)c1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2[N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of 3.1 (38 mg, 0.099 mmol) and iodomethane (6.8 μL, 0.11 mmol) dissolved in N,N-dimethylformamide (1 mL) was added cesium carbonate (35 mg, 0.11 mmol). The resulting intense red solution was stirred at room temperature overnight. After 19 h, the color had dissipated to a faint pink and HPLC indicated no 3.1 remained. Several drops of aqueous 20% citric acid solution were added and the mixture partitioned between ethyl acetate and water. The separated aqueous layer was extracted again with ethyl acetate. The combined organic extracts were washed with water twice then brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a yellow solid. The product was used without further purification. 1H NMR (400 MHz) (CDCl3) δ 7.35 (d, J=8.8 Hz, 1H); 6.95 (s, 1H); 6.83-6.76 (m, 3H); 6.71 (s, 1H); 4.16 (q, J=9.6 Hz, 2H); 3.88 (s, 3H); 3.70 (s, 3H); 2.48 (s, 3H); 1.27 (t, J=9.6 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][N:2]1[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:29])([CH3:28])[CH2:3]1.Cl[C:31]([O:33][CH3:34])=[O:32].Cl>N1C=CC=CC=1>[CH3:28][C:4]1([CH3:29])[CH2:3][N:2]([NH:1][C:31]([O:33][CH3:34])=[O:32])[C:7]2[CH:8]=[C:9]([S:12]([C:15]([F:27])([F:26])[C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])(=[O:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: COC(=O)Cl
Reactant: CC1(C)CN(N)c2cc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2O1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)NN1CC(C)(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc21
Yield: 70 %

Procedure:
3,4-Dihydro-4-amino-2,2-dimethyl-6-(nonafluorobutyl)sulfonyl-2H-1,4-benzoxazine (0.46 g) was dissolved in 5 ml of pyridine, followed by the dropwise addition of 0.12 ml of methyl chloroformate under ice cooling and stirring. After the reaction mixture was stirred for 15 hours at room temperature, the reaction mixture was added with 10% hydrochloric acid and then extracted twice with chloroform. The combined chloroform layer was washed with water and with saturated brine and was then dried over magnesium sulfate. The solvent was distilled off and the residue was purified by chromatography on a silica gel column, whereby 0.77 g of Compound No. 53 was obtained (yield: 70 %).
Reaction SMILES: II.[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27]1[CH2:31]O[CH2:29][CH2:28]1>>[CH2:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:29][CH2:28][CH2:27][CH2:31][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCOCc2ccccc2)cc1
Reactant: C1CCOC1
Agent: II
Product: C=CCCCCCCCCCCCCCCOCc1ccccc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into a clean flame dried and Ar flushed 500 mL RBF was added 14.2 mL (65 mmol) of commercially available 24. To this mixture was added 100 mL of anhydrous THF, 1.9 g (78 mmol) of Mg turnings and a pellet of I2 to accelerate the reaction. The reaction mixture was refluxed for 2 h and then cooled to room temperature and further to −78° C. To this was added 7.0 g (20.0 mmol) of 21 in 20 mL of anhydrous THF followed by addition of 6.5 mL (0.65 mmol) of lithium cuprate. The resulting mixture was allowed to warm to room temperature while stirring overnight followed by quenching with saturated aq. NH4Cl and extracted with EtOAc (3×). The combined EtOAc layers were then successively washed with water, saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvents evaporated under reduced pressure. The residue was then purified by combiflash using hexane/EtOAc as eluent to furnish 6.3 g of the compound 27 as colorless oil in 95% yield.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][C:33]([CH3:38])([CH3:37])[CH2:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][O:34][C:33]([CH3:37])([CH3:38])[CH2:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: CC1(C)CC(CCCCBr)CCO1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCOC(C)(C)C1

Procedure:
Prepared similarly to Intermediate 223 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)-2,2-dimethyltetrahydro-2H-pyran but conducting the alkylation over 1.5 hours at 60° C.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C(=O)([O-])[O-].[K+].[K+].C1(S(O[CH2:32][C:33]([N:35]2[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]2[C:41]([NH2:43])=[O:42])=[O:34])(=O)=O)C=CC=CC=1>CN(C)C=O>[CH2:14]([O:13][C:11]([C:6]12[CH2:5][CH2:4][C:3]([NH:2][CH2:32][C:33]([N:35]3[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]3[C:41]([NH2:43])=[O:42])=[O:34])([CH2:10][CH2:9]1)[CH2:8][CH2:7]2)=[O:12])[CH3:15]
Reactant: CCOC(=O)C12CCC(N)(CC1)CC2
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Temperature: 45 °C
Reaction time: 3 h
Yield: 17.9 %

Procedure:
Ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (4.63 g), potassium carbonate (5.47 g) and N,N-dimethylformamide (40 mL) were mixed together. To this mixture, a solution of (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide (5.93 g) in N,N-dimethylformamide (10 mL) was added at 40° C. and the mixture was stirred at 45° C. for 3 hours. Subsequently, the reaction mixture was concentrated under reduced pressure. Water (50 mL) was then added to the residue and the resulting crystal was collected by filtration, washed with water (30 mL), and dried at 50° C. under reduced pressure. The crude crystal was recrystallized from ethyl acetate (40 mL), washed with ethyl acetate (20 mL), and dried at room temperature under reduced pressure. This gave (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carboxamide as a white solid in the form of colorless powder (1.81 g). The filtrate and the wash were combined and concentrated to 20 mL. The resulting crystal was collected by filtration, washed with a mixture of ethyl acetate and diisopropyl ether (1:1, 20 mL) to give additional 1.19 g of the product. The total amount of the product was 3.00 g (45% yield).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N+]([O-])(O)=O.[OH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N+:6]([CH:20]1[C:15](=[O:14])[CH:16]=[CH:17][N:18]=[CH:19]1)([O-:9])=[O:7]
Reactant: Oc1ccncc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1C=CN=CC1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a cold solution of 35 ml. of fuming sulfuric acid and 45 ml. of fuming nitric acid was added 35 grams of the 4-hydroxypyridine nitrate. After allowing the mixture to warm to room temperature over night it was heated on a steam bath for 21/4 hours. It was cooled and poured onto 500 grams of ice. The resulting precipitate was collected on a filter, washed with a minimum of water and recrystallized from water to give 3-nitro-4-pyridone, m.p. 282°-284° C.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([N:13]([CH3:15])[CH3:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]([N:13]([CH3:15])[CH3:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cnn(C(C)(C)C)c(=O)c1Cl
Agent: [Pd]
Solvent: CO
Product: CN(C)c1cnn(C(C)(C)C)c(=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In methanol (40 ml) was dissolved 2-t-butyl-4-chloro-5-dimethylamino-3(2H)-pyridazinone (4.3 g) followed by addition of 10% palladium-on-carbon (water content 50%) (430 mg), and the mixture was stirred under hydrogen at room temperature for 48 hours. The catalyst was then filtered off and the filtrate was concentrated. To the residue was added saturated aqueous NaHCO3 solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was washed with n-hexane and dried. White powder, 3.4 g. 1H-NMR (CDC13) 6: 1.63(9H,s), 2.98(6H,s), 5.65(1H,d,J=3.OHz), 7.55(1H,d,J=3.0Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:26]([O:28][C:29]([CH3:31])=[CH2:30])=[O:27].O>N1C=CC=CC=1>[C:19]([NH:18][C:16](=[O:17])[NH:15][C:12]1[N:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:27])[O:28][C:29]([CH3:31])=[CH2:30])[CH:7]=2)=[CH:10][CH:11]=1)(=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Reactant: C=C(C)OC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A 0° C. suspension of Example C1 (1.2 g, 3.64 mmol) in pyridine (20 mL) was treated with isopropenyl chloroformate (0.398 mL, 3.64 mmol), stirred for 30 min, then treated with water. The resulting solid was collected via filtration and purified via silica gel chromatography (EtOAc/Hex, MeOH/DCM) to afford prop-1-en-2-yl (4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (820 mg, 54%). MS (ESI) m/z: 414.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([F:9])[CH2:6][CH2:7]Br)[CH3:2].[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14]([Cl:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([F:9])[CH2:6][CH2:7][N:18]1[CH:17]=[N:16][C:15]2[C:19]1=[N:20][C:12]([NH2:11])=[N:13][C:14]=2[Cl:21])[CH3:2]
Reactant: CCOC(=O)C(F)CCBr
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)CCn1cnc2c(Cl)nc(N)nc21
Yield: 73.7 %

Procedure:
4-Bromo-2-fluorobutyric acid ethyl ester (0.23 g), 2-amino-6-chloropurine (0.19 g) and anhydrous potassium carbonate (0.15 g) were mixed and stirred in dimethylformamide (3.7 ml) at room temperature for two days. The solution was filtered and evaporated in vacuo. The residue was triturated with chloroform (4+2 ml) and the clear chloroform solution was evaporated to give the desired product (0.24 g, 72%). TLC (silica gel, i-propanol-water-conc. ammonia 8-1-1): Rf =0.76. NMR (CDCl3, Me4Si)δ: 1.26 (t, CH3); 2.4-2.5 (m, CH2); 4.2-4.3 (t and q, NCH2 and CO2CH2); 4.77 and 5.03 (CHF, J=51 Hz); 5.2 (NH2); 7.77 (8-CH).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:19][C@H:20]([C@H:22]([N:26]1[CH:30]=[C:29]([C:31]([NH2:33])=[O:32])[N:28]=[CH:27]1)[CH2:23][CH2:24]O)[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:12]([O:19][C@H:20]([C@H:22]([N:26]1[CH:30]=[C:29]([C:31]([NH2:33])=[O:32])[N:28]=[CH:27]1)[CH2:23][CH2:24][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCO)n1cnc(C(N)=O)c1
Reactant: Oc1cccc2ccccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](OCc1ccccc1)[C@@H](CCOc1cccc2ccccc12)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a stirred mixture of 1-naphthol (48.5 mg, 0.336 mmol), 1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (85 mg, 0.280 mmol), and triphenylphosphine (88.2 mg, 0.336 mmol) in tetrahydrofuran (5 ml) was added dropwise diethyl azodicarboxylate (58.6 mg, 0.336 mmol) at ice-bath temperature. After the mixture was stirred overnight at room temperature, the solvent was removed in vacuo. The residue was purified by silica gel (10 g) chromatography eluting with chloroform/methanol (40:1) to give a mixture (60.6 mg) of 1-[(2S,3R)-2-benzyloxy-5-(1-naphthyloxy)-3-pentyl]imidazole-4-carboxamide (13) and by-products. This material was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: Cc1cc(I)c(NCC(F)(F)F)cn1
Reactant: OB(O)c1ccccc1Cl
Product: Cc1cc(-c2ccccc2Cl)c(NCC(F)(F)F)cn1

Procedure:
The title compound was prepared in analogy to example 72, from 4-iodo-6-methyl-N-(2,2,2-trifluoroethyl)pyridin-3-amine and 2-chlorophenylboronic acid after a reaction time of 15.5 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (71%). MS (ESI): m/z=301.07 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=2[C:6]2[C:7](=[O:20])[NH:8][C:9]([NH:13]C(=O)C(C)(C)C)=[N:10][C:11]=2[CH:12]=1.[C:25](O)(=[O:27])C>C[O-].[Na+]>[NH2:13][C:9]1[NH:8][C:7](=[O:20])[C:6]2[C:5]3[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=3[C:3]([CH2:2][O:27][CH3:25])=[CH:12][C:11]=2[N:10]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)C(=O)Nc1nc2cc(CBr)c3ccccc3c2c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Product: COCc1cc2nc(N)[nH]c(=O)c2c2ccccc12
Temperature: 65 °C

Procedure:
A solution of N-(6-(bromomethyl)-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.28 g, 0.72 mmole) in 0.3 M sodium methoxide (25 ml) was stirred and heated at 65° C. under a nitrogen atmosphere for 4 hours. After cooling, the mixture was acidified to pH 6 with glacial acetic acid, and then all solvent was removed under reduced pressure. The residue was triturated with water (20 ml), then filtered, washed with water and acetone, and dried to give 3-amino-6-(methoxymethyl)benzo[f]quinazolin-1(2H)-one as an off-white solid. (0.12 g, 58%) 1H NMR(DMSO-d6, 200 MHz) d 3.39(s, 3H, OCH3); 4.85(s, 2H, CH2); 6.54(br s, 2H, NH2); 7.33(s, 1H, Ar); 7.44(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.59(dt, J=6.9, 1.4 Hz, 1H, Ar); 7.96(dd, J=8.2, 1.0 Hz, 1H, Ar); 9.69(d, J=8 Hz, 1H, Ar); 11.11(br s, 1H, NH); 11.91(br s, <1H, pyr-NH30 ). Anal. Calculated for C14H13N3O2.1/2HOAc.1/10H2O: C, 62.75; H, 5.34; N, 14.64. Found C, 62.74; H, 5.31; N, 14.64.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][C:2]2[C:3]([CH2:11][CH3:12])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: CCc1nc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 105 °C
Yield: 31.9 %

Procedure:
A mixture of 3-bromo-2-ethyl-6-nitropyridine (2.31 g, 10.0 mmol), 2-chloropyridin-4-ol (2.59 g, 20.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) in DMA (20 mL) was sparged with Ar and heated at 105° C. overnight. The mixture was cooled to RT, treated with EtOAc, washed successively with 10% K2CO3 (1×), 5% LiCl (1×) and brine (1×), dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (892 mg, 25%). MS (ESI) m/z: 280.1 (M+H+).