Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:26][C:27]1[CH:32]=[C:31]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:15]([NH:14][C@H:5]2[CH2:4][O:3][C:2]([CH3:25])([CH3:1])[O:7][C@H:6]2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[CH:30]=[CH:29][CH:28]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2cccc(Cl)c2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 59.1 %

Procedure:
To a reaction flask charged with 16.2 mg (0.014 mmol) of Tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (2.0 mL) under nitrogen was added 142 mg (0.31 mmol) of the product from Example 6 and ethylene glycol dimethyl ether (0.8 mL). The resulting yellow solution was stirred for 10 min before the addition of 57.8 mg (0.37 mmol) of 3-chlorophenylboronic acid dissolved in ethylene glycol dimethyl ether (0.6 mL) and the subsequent addition of 0.32 mL (0.65 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for ˜24 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the residue was purified by column chromatography (hexane/ethyl acetate) to yield 80 mg (59%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:27]3[C:22](=[CH:23][N:24]=[CH:25][CH:26]=3)[C:18]3([CH2:21][O:20][CH2:19]3)[O:17][C:15]=2[CH:16]=1)(C)(C)C.[ClH:33].C(OCC)C>ClCCl>[NH2:7][C@@H:8]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]2[C:27]3[C:22](=[CH:23][N:24]=[CH:25][CH:26]=3)[C:18]([CH2:21][OH:20])([CH2:19][Cl:33])[O:17][C:15]=2[CH:16]=1
Reactant: Cl
Reactant: CC(C)C[C@@H](COc1ccc2c(c1)OC1(COC1)c1cnccc1-2)NC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C[C@H](N)COc1ccc2c(c1)OC(CO)(CCl)c1cnccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of ((S)-tert-butyl(4-methyl-1-(spiro[chromeno[3,4-c]pyridine-5,3′-oxetan]-8-yloxy)pentan-2-yl)carbamate (10 mg, 0.023 mmol) (prepared as described in Example 19, Part D) in dichloromethane (1 mL) cooled to 0° C. was added 1M HCl in diethyl ether (23 μL, 0.023 mmol) dropwise and the solution stirred for 30 min. The reaction was then warmed to room temperature and stirred for 2 h. After completion of reaction, the volatiles were removed under reduced and purified by preparative HPLC to afford product (8-(((S)-2-amino-4-methylpentyl)oxy)-5-(chloromethyl)-5H-chromeno[3,4-c]pyridin-5-yl)methanol (2.08 mg, 5.52 μmol, 24% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ 8.82 (m, 1H), 8.69 (m, 1H), 8.35 (m, 1H), 8.09 (m, 1H), 6.94 (m, 1H), 6.82 (s, 1H), 4.36-4.20 (m, 6H), 3.73 (m, 1H), 1.82-1.68 (m, 3H), 1.04 (m, 6H); LCMS (ESI) m/e 377.2 [(M+H)+, calcd for C20H26ClN2O3 377.2]; LC/MS retention time (Method E): tR=1.71 min; HPLC retention time (method A): tR=8.12 min; HPLC retention time (method B): tR=9.87 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH3:21])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([CH3:19])=[C:7]([CH3:20])[CH:6]=2.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C:2]2[C:3](=[O:22])[N:4]([CH3:21])[C:5]3[C:10]([C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][C:8]([CH3:19])=[C:7]([CH3:20])[CH:6]=3)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc2c(-c3ccccc3Cl)c(N)c(=O)n(C)c2cc1C
Solvent: c1ccccc1
Product: Cc1cc2c(-c3ccccc3Cl)c(NC(=O)Nc3ccc(Cl)cc3)c(=O)n(C)c2cc1C
Yield: 80.8 %

Procedure:
A mixture of 3-amino-4-(2-chlorophenyl)-1,6,7-tri-methyl-2(1H)-quinolone (156 mg), 4-chlorophenyl isocyanate (115 mg) and benzene (4 ml) was refluxed for 1.5 hours and then distilled to remove the solvent. The remaining crystals as collected by filtration were washed with isopropyl ether to obtain N-(4-chlorophenyl)-N'-[4-(2-chlorophenyl) -1,2-dihydro-1,6,7-trimethyl-2-oxo-3-quinolyl]urea (188 mg, 80.7%). Recrystallization from acetone - hexane gave colorless needles. mp 207°-209° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-])=O.O.O.Cl[Sn]Cl>CCO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH2:18]
Reactant: COC(=O)c1ccccc1Sc1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccccc1Sc1ccc(Cl)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a mixture of 2-(4-chloro-2-nitro-phenylsulfanyl)-benzoic acid methyl ester (189JO09) (232 mg, 0.72 mmol) in EtOH (5 mL) was added SnCl2.2H2O (812 mg, 3.6 mmol) and the resulting mixture was stirred at 80° C. for 2 h and then concentrated. The residue was treated with ice, and then Na2CO3 was added until a pH of 10 was reached. EtOAc was added and the slurry was filtered through celite. The EtOAc-phase was washed with water and brine, dried (Na2SO4) and concentrated to give 149 mg (70%) of the title compound (189JO11). 1H NMR (CDCl3) δ 8.02 (dd, 1 H, J=1.6, 7.8 Hz), 7.39 (d, 1 H, J=8:2 Hz), 7.29 (m, 1 H), 7.15 (dt, 1 H, J=1.2, 7.8 Hz), 6.87 (d, 1 H, J=2.2 Hz), 6.80 (dd, 1 H, J=2.2, 8.2 Hz), 6.76 (dd, 1 H, J=1.2, 8.0 Hz), 3.96 (s, 3 H).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=2)[CH2:28][N:29]([CH3:41])[C:30](=[O:40])[CH2:31][NH:32]C(=O)OC(C)(C)C)=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:2].[ClH:18].[Cl:1][C:11]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:12]1[CH2:17][CH2:16][N:15]([C:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:44]=[CH:43][CH:42]=[C:27]([CH2:28][N:29]([C:30](=[O:40])[CH2:31][NH2:32])[CH3:41])[CH:26]=3)=[CH:23][N:24]=2)[CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: CN(Cc1cccc(-c2cnc(Cl)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc(-c2cnc(N3CCN(c4ccc(C(=O)O)cc4Cl)CC3)nc2)c1)C(=O)CN
Temperature: 130 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
3 chloro-4-(piperazin-1-yl)benzoic acid hydrochloride (142 mg) was suspended in DMF (3 ml), and tert-butyl (2-{[3-(2-chloropyrimidin-5-yl)benzyl](methyl)amino}-2-oxoethyl)carbamate (190 mg) and DIPEA (371 mg) were added thereto, followed by stirring at 130° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane, and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino)methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid dihydrochloride (72 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1)=[O:7].[H-].[Na+].I[CH3:38]>CN(C=O)C>[CH3:38][N:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[S:11][CH:12]=[C:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=3)[N:9]=2)=[CH:27][CH:26]=1)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1cc(C(=O)c2csc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)c2csc(-c3ccc(CN(C)C(=O)OC(C)(C)C)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
At 0° C., to a solution of compound 68a (100 mg, 0.2 mmol) in 5 mL DMF was added sodium hydride (10 mg, 0.2 mmol), then iodomethane (77 mg, 0.4 mmol) was added to the reaction mixture and stirred at RT overnight. The mixture was quenched with a sat. NaHCO3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 71a. Yield: 61.3%. 1H NMR (500 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.02 (d, 2H, J=8.0 Hz), 7.82 (s, 2H), 7.36 (br, 2H), 4.50 (s, 2H), 4.00 (s, 3H), 3.98 (s, 6H), 2.90 (d, br, 3H), 1.50 (s, 9H). MS (ESI) m/z 521.2 (M+Na)+, 496.9 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.[C:52]1([CH2:58][C:59](Cl)=[O:60])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:51]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][CH:45]1[CH2:46][CH2:47][N:48]([C:59](=[O:60])[CH2:58][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:49][CH2:50]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Clc1cnc2nc1Nc1ccc(NC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N1CCC(Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 29 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-piperidin-4-yl-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and benzeneacetyl chloride as the starting materials in 29% yield. LCMS for C30H31ClN7O (M+H)+: m/z=540.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[N:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:25]=[CH:26][C:27]=1[C:2]1[S:6][C:5]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2nnc(Br)s2)CC1
Reactant: COc1cc(-n2cccn2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-n2cccn2)ccc1-c1nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
To a 5 mL microwave vial was added tert-butyl 4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.29 mmol), 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole (173 mg, 0.58 mmol), K3PO4 (153 mg, 0.72 mmol), and Pd(PPh3)4 (17 mg, 0.015 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture was purged with N2 for 10 min and heated to 100° C. in the microwave for 1 hour. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/Heptane) to give 87 mg (68.5%) of tert-butyl 4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate: MS (M+1)=440.4; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.57 (d, J=8.59 Hz, 1H), 8.03 (d, J=2.53 Hz, 1H), 7.78 (d, J=1.52 Hz, 1H), 7.62 (d, J=2.02 Hz, 1H), 7.32 (dd, J=2.02, 8.59 Hz, 1H), 6.59 (m, 1H), 6.51-6.55 (m, 1H), 4.15-4.22 (m, 2H), 4.11 (s, 3H), 3.69 (t, J=5.56 Hz, 2H), 2.78-2.90 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:23]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 53.4 %

Procedure:
0.248 g (0.00121 mol) of 1-benzyl-4-hydroxymethyl-piperidine was dissolved in 5 ml of toluene and treated with 0.2 ml (0.00145 mol) of triethylamine and 0.155 ml (0.00133 mol) of benzoyl chloride. The mixture was boiled at reflux for 18 hrs., the solvent was distilled off and the residue was taken up in ether. The organic phase was washed with water and saturated sodium chloride solution and dried over magnesium sulfate. It was concentrated and the residue was chromato-graphed on silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.2 g (53%) of 1-benzylpiperidin-4-ylmethyl benzoate was obtained as a yellow oil. MS: me/e (% basic peak)=309 (C20H23NO2+, 18), 308 (17), 232 (14), 204 (41), 159 (18.6), 105 (25.5), 91 (100).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].[OH-].[Na+].[BrH:18]>O>[Br:18][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Br
Reactant: Nc1cccc2ncccc12
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cccc2ncccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. mixture of 1.0022 g (6.94 mmol) 5-aminoquinoline (9) and 6 mL 24% aqueous hydrobromic acid was added a solution of 0.5 g (7 mmol) sodium nitrite in 3 mL H2O. After 5 min at 0° C., the mixture was added over 5 min to 1.2026 g (8.38 mmol) cuprous bromide in 10 mL 47% aqueous hydrobromic acid. After stirring at room temperature for 7.5 h, the reaction mixture was basified with ice and 50% aqueous NaOH and filtered. The filtrate was extracted three times with 50 mL ethyl ether, and the combined ether layers were concentrated in vacuo. The resulting residue was combined with precipitate from the above filtration, dissolved in 50% MeOH:CH2Cl2 and filtered. The filtrate was concentrated in vacuo, dissolved in 10% (10% NH4OH:MeOH):CH2Cl2 and filtered over silica. The filtrate was concentrated in vacuo to yield 10. 1H NMR (DMSO, 400 MHz) δ 8.997 (d, 1H, J=2.83 Hz, ArH); 8.525 (d, 1H, J=8.59 Hz, ArH); 8.089 (d, 1H, J=8.50 Hz, ArH); 8.000 (d, 1H, J=7.49 Hz, ArH); 7.741-7.701 Hz (m, 2H, ArH); MS (Electrospray): m/z 207.9, 209.9 (M+H, 79Br, 81Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6]2.F[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6]2
Reactant: CCCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 80 %

Procedure:
6-(Methyloxy)-3-pentyl-2-phenyl-1-naphthalenol (113) (0.41 g, 1.28 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMF at 100° C. to give 0.44 g (80%) of the title compound (114) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=6.8 Hz, 3H), 1.10-1.25 (m, 4H), 1.40-1.55 (m, 2H), 2.47 (t, J=7.9 Hz, 2H), 3.94 (s, 3H), 6.68 (d, J=8.6 Hz, 2H), 7.05 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.14 (m, 2H), 7.18 (d, J=2.4 Hz, 1H), 7.19-7.25 (m, 3H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 425 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[N:10]([S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:11]=[CH:12][C:3]=12
Reactant: N#Cc1cnc2[nH]ccc2c1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 10 h

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (2.6 g, 14.64 mmol) and triethylamine (3.06 mL, 21.96 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C. and benzenesulfonyl chloride (2.253 mL, 17.57 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour and at room temperature for 10 hours and the mixture was concentrated. Water was added and the mixture was extracted with dichloromethane (three times). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether to afford the title compound. MS (ESI(+)) m/e 318 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:3]([NH:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[Cl:29][C:30]1[CH:40]=[CH:39][C:33]([CH:34]=[CH:35][C:36](O)=[O:37])=[CH:32][CH:31]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33](/[CH:34]=[CH:35]/[C:36]([NH:1][C@@H:2]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:3]([NH:5][CH2:6][C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[O:8])=[O:4])=[O:37])=[CH:39][CH:40]=1
Reactant: N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(Cl)cc1)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
To a suspension of (2S)-2-amino-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]-3-(2-pyridyl)propanamide (29 g) and 4-chlorocinnamic acid (13.1 g) in N,N-dimethylformamide (230 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15.2 g) and N-hydroxybenzotriazole (10.7 g) at 0° C. The mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into ice-cold saturated aqueous sodium hydrogencarbonate solution and the resulting solid was collected by filtration. The solid was washed successively with saturated aqueous sodium hydrogencarbonate solution and water. The solid was crystallized from water:ethanol (1:9 (v/v)) to give the title compound (34 g) as crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:21])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]2[O:11][C:10]([CH3:22])([CH3:23])[CH:9]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[CH3:24])=[CH:4][CH:5]=3)[C:13]=2[C:14]=1[CH3:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N(C)C)cc1)C(C)(C)O2
Reactant: BrCc1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(c1ccc(N(C)C)cc1)C(C)(C)O2
Yield: 40 %

Procedure:
Using 3-[(4-(dimethylamino)phenyl]-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[CH3:33][N:34](C(OC(C)(C)C)=O)[C@H:35]([C:40](O)=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38]>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[NH:2][C:40](=[O:41])[C@@H:35]([NH:34][CH3:33])[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CN[C@@H](CC(C)C)C(=O)Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and N-methyl-tert-butoxycarbonyl-L-leucine by using the same method as in Example 96.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.[OH:27][NH:28]/[C:29](=[N:38]\[H])/[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.[O-]CC.[Na+]>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:27][N:28]=[C:29]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)[N:38]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1ccc(O)cc1)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(O)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h
Yield: 17.6 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (29 mg, 0.078 mmol) and (1Z)—N-hydroxy-2-(4-hydroxyphenyl)ethanimidamide (14 mg, 0.084 mmol) were heated in EtOH (1 ml) with 21% ethanolic sodium ethoxide (0.043 ml, 0.117 mmol) under microwave irradiation at 140° C. for 10 min. The mixture was partitioned between EtOAc and 2M HCl and the organic phase evaporated. This material was stirred with EtOH (1 ml) and 2M NaOH (0.5 ml) for 18 h, before being worked up again by partition between EtOAc and 2M HCl. Purification by MDAP afforded the title compound (6.5 mg).