Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:29][CH:28]=[CH2:27])=[CH:8][CH:7]=1
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(OCC=C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 9 h
Yield: 92.1 %

Procedure:
To a solution of 18 (30 g, 107.4 mmol, 1.0 equiv) in DMF (170 mL) at room temperature was added solid K2CO3 (29.6 g, 214.2 mmol, 2.0 equiv) then allylbromide (10.2 mL, 116.3 mmol, 1.1 equiv) dropwise. The suspension was stirred at room temperature for 9 hours, after which time water (500 mL) was added and extracted with ether (4×250 mL). The organics were combined, washed with brine, dried over MgSO4, and concentrated. Purification by flash chromatography (20→60% EtOAc/hexane) afforded 19 (31.6 g, 92%) as a clear oil. Rf=0.27 (25% EtOAc/hexane); FTIR (neat, cm−1) 3343, 2919, 1721, 1510, 1239, 1215, 1176, 1052, 1017; 1H NMR (400 MHz, CDCl3) δ7.00 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.99 (m, 1H), 5.85 (m, 1H), 5.44 (d, J=8.0 Hz, 1H), 5.36 (dd, J=17.4, 1.2 Hz, 1H), 5.25 (s, 1H), 5.22 (dd, J=10.2, 1.6 Hz, 1H), 5.15 (dd, J=10.4, 1.2 Hz, 1H), 4.56 (dd, J=14.2, 6.0 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.45 (d, J=5.2 Hz, 2H), 3.66 (s, 3H), 3.03 (dd, J=14.4, 5.2 Hz, 1H), 2.96 (dd, J=14.0, 6.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ172.0, 157.5, 155.4, 133.1, 132.5, 130.0, 127.8, 117.4, 117.3, 114.5, 68.4, 65.5, 54.7, 52.0, 37.0; MS (ES+) calculated for C17H21NO5 (M+H)+: 320.1420, found: 320.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.N#N.C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>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>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:17]=[N:18][C:19]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:11][C:8]2[N:6]4[CH:7]=[C:2]([C:36](=[O:38])[CH3:37])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=2)=[CH:21][CH:20]=3)[CH2:23][CH2:24]1
Reactant: CN1CCN(c2cnc3ccc(Sc4nnc5ccc(Br)cn45)cc3c2)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: C1COCCO1
Product: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCN(C)CC5)cc4c3)n2c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of (86.1) (80 mg, 0.176 mmol) and PdCl2(PPh3)2 (12.3 mg, 0.018 mmol) in dioxane (6 ml) was bubbled by N2 for 10 min, then tributyl(1-ethoxyvinyl)stannane (127 mg, 0.351 mmol) was added and the solution was heated at 110° C. under N2 for 3 hours in oil bath. The reaction mixture was quenched with KF solution and extracted with EtOAc for three times. The combined extract was washed with brine and dried over anhydrous Na2SO4. Solvent was evaporated and the crude was dissolved in MeOH (10 ml). Drops of 3N HCl solution were added and the solution was then stirred at rt for 4 hours. Solvent was evaporated and the residue was purified on flash chromatography (gradient eluent: MeOH/DCM from 0-10%) to afford the title compound as yellow solid (0.16 g, >100%, contains some impurities). LCMS (method A): [M+H]+=419.2, tR=1.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10])=[O:5].[CH3:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][O:36][NH2:37])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([NH:37][O:36][CH2:35][C:34]1[CH:38]=[CH:39][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[O:10])=[O:5]
Reactant: COc1ccc(CON)cc1
Reactant: Cc1ccc(C(=O)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: COc1ccc(CONC(=O)c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)cc1

Procedure:
Compound 424 (100 mg, 0.25 mmol) and O-(4-methoxy-benzyl)-hydroxylamine (65 mg, 0.34 mmol) were treated as described for compound 337. Flash chromatography (ethyl acetate/petroleum ether: graduated from 80/20 to 60/40) provided the title compound. 13C NMR (CDCl3) δ 195.3, 165.6, 160.1, 159.3 (dd), 155.7 (dd), 148.2, 142.1, 139.7, 135.3, 133.8, 131.7, 131.1, 129.4, 129.1, 128.6, 127.8, 127.2, 124.6 (dd), 124.2 (dd), 116.2, 114.1, 112.8, 111.6 (dd), 105.0 (dd), 78.0, 55.3, 20.4
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cc[nH]c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=[N+]([O-])c1ccn(-c2ccc(F)cc2)c1
Yield: 35.7 %

Procedure:
To a dichloromethane solution (4.0 mL) of 3-nitropyrrole (200 mg, 1.78 mmol), 4-fluorophenylboronic acid (499 mg, 3.57 mmol), and copper acetate (II) (486 mg, 2.68 mmol), N,N-diisopropylethylamine (606 μL, 3.57 mmol) was added and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered with Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (131 mg, yield 36%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:18][CH:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH3:17])=[O:5])C.[OH-].[Na+]>C1COCC1>[C:30]([CH:19]([NH:18][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[C:12]([Cl:16])[CH:13]=2)[N:8]=1)[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)([OH:32])=[O:31]
Reactant: CCOC(=O)c1cc2cc(Cl)cc(C)c2nc1NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc2cc(C(=O)O)c(NC(Cc3c[nH]c4ccccc34)C(=O)O)nc12
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloro-8-methyl-quinoline-3-carboxylic acid ethyl ester is reacted with DL-tryptophan to provide 2-[1-carboxy-2-(1H-indol-3-yl)-ethylamino]-6-chloro-8-methyl-quinoline-3-carboxylic acid ethyl ester. The ester (107 mg, 0.24 mmol) is dissolved in THF (2 mL), then 0.7M aqueous NaOH (1 mL) is added and the mixture is stirred at rt for 23 h. The mixture is concentrated under reduced pressure treated with water and filtered. The filtrate is acidified by addition of 3N HCl till pH 2-3, and stirred for 40 min. Precipitate is filtered off and washed with cold water to provide after drying the title compound (55 mg, 61%) as pale green powder.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][OH:11].Cl.[OH-].[K+].O>CO.C1COCC1>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][OH:11]
Reactant: NO
Reactant: O=Cc1ccccc1I
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: ONCc1ccccc1I

Procedure:
2-Iodobenzaldehyde prepared above (10.3 g, 44.4 mmol) was dissolved in 50 mL MeOH and 10 mL THF. After addition of H2NOH.HCl (10 mL H2O) and 6N KOH, an additional 50 mL THF, 30 mL H2O, and 30 mL MeOH were added. The product was recovered as a cloudy orange oil (9.46 g, 85.6%, 90% desired product). IR (film): 3256, 3057, 2872, 1564, 1466, 1435, 1013, 748. 1H-NMR (400 MHz, CDCl3): δ 7.92 (dd, 1H, J=7.8, 1.2, C4-H), 7.58 (dd, 1H, J=7.4, 1.8, C7-H), 7.34 (td, 1H, J=7.4, 1.2, C6-H), 7.00 (td, 1H, J=7.6, 1.8, C5-H), 5.5 (br s, 1H, C1-NHOH), 5.0 (br s, 1H, C1-NHOH), 4.13 (s, 2H, C1-H2). 13C-NMR (100 MHz, CDCl3): δ 139.5, 139.1, 131.0, 129.4, 128.3, 100.1, 62.0. EI-MS m/z (rel int): 249 (M+, 36), 217 ([M−NHOH]+, 100), 122 ([M−I]+, 30). CI-MS (NH3) m/z (rel int): 284 ([M+2NH3+H]+, 30), 267 ([M+NH4]+, 100), 250 ([M+H]+, 27).
Reaction SMILES: Cl.[CH:2]([NH:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:10][C:9]=1[NH:19]C(=O)OC(C)(C)C)([CH3:4])[CH3:3]>O1CCOCC1.CO>[NH2:19][C:9]1[CH:10]=[CH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:13][C:8]=1[NH:7][C:6]([NH:5][CH:2]([CH3:4])[CH3:3])=[O:27]
Reactant: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A 4M solution of HCl in dioxane (2 mL) was added to a stirred solution of tert-butyl (2-(3-isopropylureido)-4-(thiophen-2-yl)phenyl)carbamate (0.15 g, 0.40 mmol, 1 equiv.) in methanol (4 mL) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added. The obtained solid was filtered, washed with water and dried to yield 1-(2-amino-5-(thiophen-2-yl)phenyl)-3-isopropylurea (0.10 g, 91% yield). ESI+ MS: m/z 276 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 7.67 (d, J=2.0 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.09 (dd, J=1.5, 8.0 Hz, 1H), 7.05-7.01 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.08 (d, J=8.0 Hz, 1H), 4.87 (s, 2H), 3.76 (sept, J=7.0 Hz, 1H), 1.10 (d, J=7.0 Hz, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH3:19])=[C:13]([CH3:21])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br-:22].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=[O:20])[CH2:19][Br:22])=[C:13]([CH3:21])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)c1c(C)cc(Oc2ccc3c(c2)OCO3)cc1C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
To a solution of 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)ethanone (4.80 g, 16.9 mmol) in acetonitrile (33.8 mL) was added tetrabutylammoniumtribromide (TBABr3, 8.14 g, 16.9 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)-2-bromoethanone (6.70 g), which was used directly for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:19]=[C:20]1[NH:24][C:23](=[O:25])[CH:22]([CH2:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)[S:21]1.C(P(=O)(OCC)OCC)#N>C(N(CC)CC)C.O1CCCC1>[C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[C:13]([S:15][CH3:16])[CH:12]=[CH:11][C:10]=1[NH:17][C:33](=[O:34])[CH2:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:22]2[S:21][C:20](=[O:19])[NH:24][C:23]2=[O:25])=[CH:37][CH:36]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CSc1ccc(N)c(N(C)C(=O)OC(C)(C)C)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ccc(NC(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To a mixture of N-(2-amino-5-methylthiophenyl)-N-methylcarbamic acid t-butyl ester (2.0 g) (obtained in Reference Example 4), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (2.31 g) (obtained in Reference Example 6), triethylamine (1.14 ml) and anhydrous tetrahydrofuran (40 ml) was added diethyl cyanophosphonate (1.34 g) and the resulting mixture was stirred at room temperature for 4 hours and allowed to stand overnight. To the reaction mixture were further added 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.84 g), triethylamine (0.3 g) and diethyl cyanophosphate (0.49 g) and the resulting solution was stirred at room temperature for 1.5 hours. At the end of this time the reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was chromatographed on a silica gel column using n-hexane/ethyl acetate (2/1) as the eluant to give the desired product (3.54 g).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]#[N:13])[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:22])[CH:21]=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:14][C:9]1[C:10]([C:12]#[N:13])=[N:11][C:2]([C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COC(=O)c1cc(Cl)c(C#N)nc1Cl
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)c(C#N)nc1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
A solution of methyl 2,5-dichloro-6-cyanonicotinate (2.0 g, 8.6 mmol), (3,5-difluorophenyl)boronic acid (1.5 g, 9.5 mmol) and potassium carbonate (2.6 g, 19 mmol) in water (16 mL) and 1,4-dioxane (41 mL) were bubbled with nitrogen gas (10 minutes). Bis(triphenylphosphine)palladium(II) chloride (0.67 g, 0.95 mmol) was added and the mixture was bubbled with nitrogen gas (10 minutes). The mixture was heated at 80° C. for 1 hour and diluted with ethyl acetate and water. The aqueous layer was separated and extracted again with ethyl acetate. The combined extracts were washed with water, washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-50%) gave the desired compound (2.5 g, 94%). LCMS calculated for C14H8ClF2N2O2 (M+H)+: m/z=309.0. found: 308.9.
Reaction SMILES: ClCCC(C1C=CC2[NH:10]COC=2C=1)=O.F[C:16]1[CH:42]=[CH:41][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([C:31]3[CH:40]=[CH:39][C:34]4[NH:35][C:36](=O)[O:37][C:33]=4[CH:32]=3)=[O:30])[CH2:23][CH2:22]2)=[CH:18][CH:17]=1.FC1C=CC(CC2CCNCC2)=CC=1>>[CH2:20]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]([C:31]2[CH:40]=[CH:39][C:34]3[NH:35][C:36](=[O:37])[NH:10][C:33]=3[CH:32]=2)=[O:30])[CH2:23][CH2:22]1)[C:19]1[CH:41]=[CH:42][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(CCN1CCC(Cc2ccc(F)cc2)CC1)c1ccc2[nH]c(=O)oc2c1
Reactant: O=C(CCCl)c1ccc2c(c1)OCN2
Agent: Fc1ccc(CC2CCNCC2)cc1
Product: O=C(CCN1CCC(Cc2ccccc2)CC1)c1ccc2[nH]c(=O)[nH]c2c1

Procedure:
from 6-(3-chloro-1-oxopropyl)-2,3-dihydrobenzoxazole and 4-(4-fluorobenzyl)piperidine 6-{3-[4-(4-fluorobenzyl)-1-piperidyl]-1-oxopropyl}-2,3-dihydrobenzoxazol-2-one, m.p. 168°-173° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.CN(C)[CH:17]=[O:18]>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:17]=[O:18]
Reactant: c1ccc2scnc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A solution of freshly distilled (b.p. 82° C., 2 torr) benzothiazole (10 g, 0.074 mole) in 250 ml tetrahydrofuran was cooled under nitrogen to -78° C. and stirred at this temperature for 15 minutes. To this was added dropwise over 15 minutes 29.6 ml (0.074 mole) 2.5M n-butyllithium, stirring continued for 25 minutes, and 8.6 ml (0.111 mole) dimethylformamide was added and the reaction mixture stirred for an hour. The mixture was allowed to warm to room temperature, 200 g ice was added and the solvent evaporated in vacuo. The aqueous residue was extracted with 5×100 ml ethyl acetate, the extracts dried (MgSO4), concentrated to a small volume and chromatographed on a silica gel column, eluting with 96:4 chloroform/ethyl acetate to yield 8.4 g of the desired aldehyde, m.p. 74.5°-75° C. 1H--NMR(CDCl3)ppm (delta): 7.54 (m, 2H), 7.97 (m, 1H), 8.21 (m, 1H), 10.1 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](Cl)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C([N+:25]([O-])=O)=CC=C(O)C=1.N1C=CC=CC=1>C(Cl)Cl>[NH2:25][C:13]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9](=[O:18])(=[O:17])[N:10]=[C:11]([O:15][CH3:16])[N:12]=1
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(N)=N1

Procedure:
A solution of 2-benzyl-3-chloro-5-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide (3.8 g) in methylene chloride (10 ml) is added dropwise to a stirred mixture of p-nitrophenol (1.7 g) and pyridine (2.4 g) in methylene chloride (20 ml). The reaction mixture is heated to reflux for 3 hours, cooled, washed with 3N aqueous HCl and saturated aqueous Na2CO3. The methylene chloride layer is dried over MgSO4, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[N:10][C:11](S(C)(=O)=O)=[N:12][C:13]=3[NH:15][CH2:16][C@H:17]([OH:19])[CH3:18])[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32].[OH-].[K+]>>[CH:1]1([C:6]2[C:14]3[C:9](=[N:10][C:11]([O:32][C:26]4[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=4[F:24])=[N:12][C:13]=3[NH:15][CH2:16][C@H:17]([OH:19])[CH3:18])[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(F)cc1F
Reactant: C[C@@H](O)CNc1nc(S(C)(=O)=O)nc2[nH]nc(C3CCCC3)c12
Agent: [K+]
Agent: [OH-]
Product: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2[nH]nc(C3CCCC3)c12

Procedure:
(R)-1-(3-Cyclopentyl-6-methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-propan-2-ol was treated with 2,4-difluorophenol in the presence of KOH using the procedure of step 6 of Example 4 to afford 0.56 mg of (R)-1-[3-Cyclopentyl-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=390.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>CN(C=O)C>[Br:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Br)cc1)c1ccccc1

Procedure:
Prepared by reacting 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 1.5 equivalents of 4-bromo-aniline in DMF (110° C., for 2 hours), subsequent treatment with piperidine (20° C., 0.5 hours) and precipitation with water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(COc2ccc(Cl)c([N+](=O)[O-])c2)c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-3-methyl-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(3-methyl-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: C[O:2][C:3]1[CH:35]=[CH:34][CH:33]=[CH:32][C:4]=1[CH2:5][N:6]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.B(Br)(Br)Br>C(Cl)Cl>[C:19]1([CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]3[CH:32]=[CH:33][CH:34]=[CH:35][C:3]=3[OH:2])[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH2:18][CH2:17]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccccc1CN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1CN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccn1
Temperature: -78 °C
Reaction time: 8 h
Yield: 68.31 %

Procedure:
Compound 3 (0.23 g, 0.4 mmol) was dissolved in 25 mL of CH2Cl2. The solution was cooled at −78° C. in a dry ice CH2Cl2 bath under argon atmosphere for 1 h. After the solution cooled, 1.0 M boron tribromide (3.28 g, 0.013 mol) dissolved in 25 mL of CH2Cl2 was added dropwise. The reaction mixture was allowed to reach room temperature and was stirred overnight. The solvent was removed and quenched with methanol (30 mL×3). After the methanol was removed, hydrochloric saturated methanol (5 mL) was stirred for 1 h at room temperature. The solution was rotovaped and washed with methanol (30 mL×3) before being extracted in CH2Cl2 with water (50 mL×3). The combined organic layers were evaporated and a dissolved in a minimum volume and purified by silica gel TLC plate that was developed in 3% methanolic NH3 (7 M NH3 in methanol)/97% CH2Cl2. The product was obtained as pale yellow oil (68.31%). 1H NMR (CDCl3) δ 8.562 (d, 1H, Ar), 7.652 (ddd, 1H, Ar), 7.280 (m, 3H, Ar), 7.220 (d, 2H, Ar), 7.161 (m, 3H, Ar), 6.980 (d, 1H, Ar), 6.823 (d, 1H, Ar), 6.755 (ddd, 1H, Ar), 3.790 (s, 2H, —CH2—), 3.757 (s, 2H, —CH2—), 3.168 (d, 2H, —CH2—), 2.544 (m, 3H, —CH—CH2—), 2.458 (t, 2H, —CH2—), 2.225 (t, 2H, —CH2—), 2.016 (m, 2H, —CH2—), 1.858 (d, 2H, —CH2—), 1.569 (m, 4H, —CH2—CH2—), 1.236 (m, 4H, —CH2—CH2—). Mass Spec.=458.32 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:26])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:25]=1.[Se](=O)=[O:28]>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:26])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:28])=[C:17]([CH3:24])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:25]=1
Reactant: O=[Se]=O
Reactant: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Solvent: C1COCCO1
Product: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a 200 mL round bottom flask equipped with a stir bar was added 2-(2,6-dichloro-phenylamino)-1,6,7-trimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (2.4 g, 6.2 mmol), selenium dioxide (2.0 g, 18 mmol) and dioxane (150 mL). The flask was fitted with a condenser and heated to reflux for 4.5 h. The reaction was then removed from heat and allowed to cool to room temperature. The slightly opaque solution was filtered through celite and washed with dichloromethane:methanol (9:1). The solution was concentrated and the resulting residue triturated with dichloromethane to produce 2-(2,6-dichloro-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (1.8 g, 72%) as a brownish yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.65 (s, 1H), 10.24 (s, 1H), 7.96 (d, 1H, J=8.6 Hz), 7.78 (d, 1H, J=8.6 Hz), 7.70 (d, 2H, J=7.8 Hz), 7.49 (d, 2H, J=7.8 Hz), 4.15 (s, 3H), 2.70 (s, 3H); ESMS (m/z): found, 401.