Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[NH:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([NH2:29])=[O:28]>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:25]5[CH2:32][CH2:31][CH2:30][C@H:26]5[C:27]([NH2:29])=[O:28])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Reactant: NC(=O)[C@@H]1CCCN1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCC[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 67 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and L-prolinamide, were reacted and the crude product recrystallised from IMS to give 369 as a white solid (130 mg, 67%). LCMS: RT=2.48 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d6) δ: 9.06 (1H, s), 7.80 (1H, s), 7.35 (1H, br), 6.94 (1H, br), 5.96 (1H, s), 5.90-5.88 (1H, m), 4.50 (4H, d, J=17.28 Hz), 4.32 (1H, m), 3.61 (1H, m), 3.45 (1H, m)), 2.26 (2H, s), 2.24-2.15 (1H, m), 1.98-1.97 (3H, m), 1.47 (6H, dd, J=6.59, 3.27 Hz)
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=1.C([O-])(O)=O.[Na+].Cl[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([OH:37])=[O:36])=[CH:29][CH:28]=1)(=[O:26])=[O:25].Cl>O1CCOCC1.O>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([C:27]3[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 82.7 %

Procedure:
To a suspension of 1-(α,α,α-trifluoro-m-tolyl)piperazine hydrochloride (0.43 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (A) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL) and the pH of the medium was brought to ˜4 with 2 N HCl. The precipitated solid was filtered, washed with water, and dried in vacuum to give the title compound (0.59 g, 82%). 1H NMR (DMSO-dc, HMDSO), δ: 2.96-3.67 (SH, m, overlapped with a signal of water); 6.74 (1H, d, J=16.3 Hz); 7.01-7.57 (4H, m); 7.67 (1H, d, J=16.3 Hz); 7.82 (2H, d, J=8.4 Hz); 8.00 (2H, d, J=8.4 Hz); 12.71 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:47][N:48]([CH3:55])[CH2:49][C:50]([CH3:54])([CH3:53])[CH2:51][NH2:52]>C(Cl)(Cl)Cl.CS(C)=O.C(Cl)Cl>[CH3:47][N:48]([CH3:55])[CH2:49][C:50]([CH3:54])([CH3:53])[CH2:51][NH:52][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:29]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CN(C)CC(C)(C)CN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C)CC(C)(C)CNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Temperature: 85 °C
Yield: 11.5 %

Procedure:
3-Fluoro-N-[4-(2-methylsulfanyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-morpholin-4-yl-benzamide (457 mg, 0.908 mmol) and MCPBA (447 mg, 1.998 mmol) in CHCl3 (5 ml) is stirred at room temperature for 1 h. The mixture is diluted with CHCl3 (5 ml) washed with sat'd NaHCO3 solution (5 ml), water (5 ml), dried over Na2SO4 and concentrated to give a yellow solid. The yellow solid is mixed with N,N,2,2-tetramethyl-1,3-propanediamine (1.18 g, 9.08 mmol) and DIPA (1.58 ml, 9.08 mmol) in DMSO (2 ml), and heated to 85° C. for 4 h. The resulting mixture is diluted with CH2Cl2 (2 ml), washed with 0.01 N NaOH, dried over Na2SO4, concentrated. The residue is purified by column chromatography on silica gel (EtOAc) to give N-{4-[2-(3-dimethylamino-2,2-dimethyl-propylamino)-pyrimidin-4-yloxy]-naphthalen-1-yl}-3-fluoro-5-morpholin-4-yl-benzamide as a white solid (60 mg). 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 8.08 (s, 1H), 8.01 (d, 1H), 7.92 (m, 2H), 7.57 (t, H), 7.51 (t, 1H), 7.30 (d, 2H), 7.21 (d, 1H), 6.82 (dt, 1H), 5.87 (s, 1H), 4.33 (m, 1H), 3.23 (s, 1H), 2.27 (s, 6H), 2.21 (m, 2H), 2.02 (m, 2H), 1.82 (m, 2H), 1.57 (m, 3H), 1.39 (m, 3H), 0.98 (s, 6H); MS 586.37 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:9]=[CH:8][C:6]=2[CH:7]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CC#N>[N:31]1([CH2:2][C:3]2[O:4][C:5]3[CH:11]=[C:10]([O:12][C:13]4[S:14][C:15]5[C:16]([N:21]=4)=[N:17][CH:18]=[CH:19][CH:20]=5)[CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: ClCc1cc2ccc(Oc3nc4ncccc4s3)cc2o1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1cnc2nc(Oc3ccc4cc(CN5CCOCC5)oc4c3)sc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
To a solution 2-(2-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (110 mg, 0.3 mmol) in MeCN (3 mL) was added DIEA (209 μL, 0.155 mg, 0.8 mmol) followed by morpholine (27 μL, 27 mg, 0.3 mmol) and stirred (rt, 12 h). The reaction mixture was partitioned between DCM (15 mL) and saturated NaHCO3 (5 mL). The organic layer was washed with saturated NH4Cl (10 mL), dried, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography to provide the title compound as colorless crystals (41 mg, 37%). MS (ESI): mass calcd. for C19H17N3O3S, 367.1; m/z found, 368.1.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.01 (dd, J=7.9, 1.7, 1H), 7.59-7.51 (m, 2H), 7.28-7.25 (m, 1H), 7.20 (dd, J=8.0, 4.8, 1H), 6.65 (s, 1H), 3.75 (dd, J=15.5, 10.8, 4H), 3.70 (s, 2H), 2.62-2.49 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][C:32]=2[CH3:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45]([NH2:47])=[O:46].O.[C:52]([OH:56])(=[O:55])[CH:53]=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:19]1[CH:20]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH:53]([NH:41][C:42]3[CH:50]=[CH:49][CH:48]=[C:44]([C:45](=[O:46])[NH2:47])[CH:43]=3)[C:52]([OH:56])=[O:55])=[CH:33][C:32]=2[CH3:40])=[O:27])[CH:22]=[CH:23][CH:24]=1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(B(O)O)cc2C)c1
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=CC(=O)O
Solvent: O
Product: CCOC(=O)C[C@@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(C(Nc3cccc(C(N)=O)c3)C(=O)O)cc2C)c1
Yield: 44 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 39E (200 mg, 0.36 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 41A (232 mg, 44%) as a brown oil. MS (ESI) m/z 697.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[CH:9][NH:10]2)=[CH:6][C:5]=1[F:14].[CH3:15][C@@H:16]1[CH2:18][O:17]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:13])=[CH:9][N:10]2[CH2:15][C@H:16]([OH:17])[CH3:18])=[CH:6][C:5]=1[F:14]
Reactant: C[C@@H]1CO1
Reactant: Cc1c[nH]c2cc(Cl)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1cn(C[C@@H](C)O)c2cc(Cl)c(F)cc12
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 0.07 g of sodium hydride dispersion in 10 ml of tetrahydrofuran was treated with 0.33 g of 6-chloro-5-fluoro-3-methylindole at 0° and stirred as this temperature for 1 hour. After the addition of 0.19 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 17 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 20 g of silica gel with toluene-ethyl acetate (9:1). 0.22 g (50%) of (R)-1-(6-chloro-5-fluoro-3-methylindol-1-yl)-propan-2-ol was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Yield: 36 %

Procedure:
A solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.75 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 90 mg (36%) of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a tan solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 2.5 (s, 3H). IR (KBr, cm−1) 3451, 3191, 1627, 1600, 1584, 1562, 1435, 1329, 1322, 1263, and 774. MS (ES) m/e 329, 331.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.O>CN1CCCC1=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
Piperazine (12.9 g) was suspended in N-methyl-2-pyrrolidone (130 mL), and a solution of 2-chloro-5-trifluoromethylpyridine (9.08 g) in N-methyl-2-pyrrolidone (30 mL) was added dropwise. The mixture was stirred at room temperature for 18 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure to give 1-(5-trifluoromethyl-2-pyridyl)piperazine (11.5 g) as a white solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].[N:6]1[CH:11]=[CH:10][C:9]([SH:12])=[N:8][C:7]=1[SH:13].Cl.[CH2:15]([S:23]SC(=N)N)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O.CO>[CH2:15]([S:23][S:13][C:7]1[N:8]=[C:9]([S:12][S:23][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]=[CH:11][N:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Sc1ccnc(S)n1
Reactant: CCCCCCCCSSC(=N)N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCSSc1ccnc(SSCCCCCCCC)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of sodium bicarbonate (4.30 g; 0.05 mole) in water (60 ml) was added dropwise to a stirred suspension of pyrimidine-2,4-dithiol prepared as above (2.16 g, 0.015 mole) and S-n-octylthioisothiourea hydrochloride obtained in step (A) (7.695 g, 0.03 mole) in methanol (70 ml) at 60°-65° C. over 30 minutes. The mixture was stirred at room temperature for a further hour and then extracted into naphtha (3×50 ml). The organic extracts were washed with water, dried using anhydrous MgSO4 and evaporated yielding the product as an orange oil (5.54 g: 85%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:15])[CH:5]=1.[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([Cl:14])[C:4]([NH2:3])=[CH:5][C:6]=1[O:15][CH2:19][CH2:18][O:17][CH3:16]
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(N)c(Cl)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (1.00 g, 0.025 mole) in anhydrous dimethylformamide (40 ml) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid, methyl ester (4.03 g, 0.020 mole), stirred for 30 minutes, then treated with 2-bromoethyl methyl ether (3.48 g, 0.025 mole). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (250 ml). The aqueous suspension was filtered, and the solid was washed with water, air dried, collected, and recrystallized from ether/hexane to afford 2.75 g (53%) of 4-amino-5-chloro-2-(2-methoxyethoxy)benzoic acid methyl ester; mp 121.0°-122.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH2:22])[CH3:21])=[CH:7]2.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([C@@H:20]([NH:22][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)[CH3:21])=[CH:7]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(2-chloro-5-fluoro-phenyl)quinolin-3-yl)ethanamine (0.072 g, 0.215 mmol), 6-chloropurine (0.040 g, 0.26 mmol, 1.2 eq) and DIEA (0.42 mmol, 2.0 eq) in n-butanol (3 mL). N—((S)-1-(8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.68 (s, 1H), 8.60 (s, 1H), 8.02-8.10 (m, 2H), 7.92-7.99 (m, 1H), 7.85-7.93 (m, 1H), 7.54-7.63 (m, 1H), 7.50 (dd, J=8.80, 4.89 Hz, 1H), 7.07 (td, J=8.61, 3.13 Hz, 1H), 5.48-5.65 (m, 1H), 1.71 (d, J=7.04 Hz, 3H), Mass Spectrum (ESI) m/e=454 (M+1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22]>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:15]3/[C:14](=[O:22])[NH:13][C:21]4[C:16]/3=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(I)n[nH]c2c1

Procedure:
The title compound was synthesized from 3-iodo-1H-indazole-6-carbaldehyde (15 mg, 0.0551 mmol) and oxindole (8 mg, 0.0616 mmol) according to the method described for Example A11B and purified by column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 96:4) to obtain 6.9 mg, 33% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.89-7.82 (m, 2H), 7.63-7.49 (m, 3H), 7.23 (t, J=8.21 Hz, 1H), 6.91 (d, J=7.07 Hz, 1H), 6.89-6.83 (m, 1H); MS ESI 388.0 [M+H]+, calcd for [C16H10IN3O+H]+ 387.99.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].[OH:8]N1C(=O)CCC1=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[CH3:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[OH:8][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])=[CH:18][CH:19]=1
Reactant: C#CCCC(=O)O
Reactant: CC(O)c1ccc(N)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCC(=O)Nc1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-hydroxysuccinimide-(4-pentynoate) (Ref: Malkoch, M.; Schleicher, K.; Drockenmuller, E.; Hawker, C. J.; Russell, T. P.; Wu, P.; Fokin, V. V., Structurally Diverse Dendritic Libraries: A Highly Efficient Functionalization Approach Using Click Chemistry. Macromolecules 2005, 38, (9), 3663-3678.) (200 mg, 1.0 mmol) and p-aminophenylethanol (125 mg, 0.9 mmol) were dissolved in 2 mL of dichloromethane together with triethyl amine (140 μL, 1.0 mmol), and 5 drops of dimethyl formamide. The reaction mixture was stirred at room temperature for 2 hours. The crude reaction product was concentrated, dissolved in 10 mL of ethyl acetate and washed with 5 mL of water followed by, 5 mL of 0.5 M HCl (aq.), 5 mL of 10 NaHCO3 (aq.) and finally 5 mL of water. The organic phase was dried with MgSO4, filtered, and the solvent was evaporated. The product was further purified by column chromatography on silica gel eluting with a gradient of toluene (T) and ethyl acetate (E) from 4:1 to 1:2 (T:E). The product N-(4-(2-(hydroxy)ethyl)phenyl)pent-4-ynamide was characterized by NMR and MALDI-TOF.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=O)[NH:30][CH:31]=2)=[O:26])[CH2:19]1>C(O)C.N1CCCCC1>[CH3:24][C@H:22]1[NH:23][C@@H:18]([CH3:17])[CH2:19][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=[C:9]3[C:8]4[C:12](=[CH:13][CH:14]=[CH:15][C:7]=4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:11][C:10]3=[O:16])[NH:30][CH:31]=2)=[O:26])[CH2:21]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.5 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-4-phenyl-1,3-dihydro-indol-2-one as a yellow solid (21.5 mg, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][OH:37]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][CH2:35][CH2:36][OH:37])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCCCO)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (0.6 g) obtained in Example 2 was suspended in dimethyl sulfoxide (40 ml), and to the suspension was added potassium carbonate (0.8 g), and the mixture was stirred at room temperature for 30 minutes. 3-bromo-1-propanol (0.3 ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, washed with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (0.25 g, 37%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[Cl:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(OCCCl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-hydroxybenzoate (10.0 g, 65.7 mmol) in DMF (100 mL) was added potassium carbonate (18.17 g, 131.4 mmol) and 2-chloroethyl-p-toluenesulfonate (15.7 g, 67.0 mmol). After stirring at 60° C. overnight the reaction mixture was poured into H2O, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (10% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]([C:22]1[N:23]([CH3:45])[C:24](=[O:44])[C:25]2[C:30]([C:31]=1[C:32]1[C:33]([CH3:43])=[C:34]3[C:39](=[C:40]([F:42])[CH:41]=1)[O:38][CH2:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:50]([CH3:53])([CH3:52])[CH3:51])(=O)C.C([O-])(O)=O.[Na+]>Cl(O)(=O)(=O)=O>[C:50]([O:21][C@@H:20]([C:22]1[N:23]([CH3:45])[C:24](=[O:44])[C:25]2[C:30]([C:31]=1[C:32]1[C:33]([CH3:43])=[C:34]3[C:39](=[C:40]([F:42])[CH:41]=1)[O:38][CH2:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1c(-c2c([C@H](O)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C)c(=O)c3ccccc23)cc(F)c2c1CCCO2
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1c(-c2c([C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OC(C)(C)C)n(C)c(=O)c3ccccc23)cc(F)c2c1CCCO2
Reaction time: 18 h
Yield: 48.6 %

Procedure:
A solution of (S)-3-(2-((tert-butyldiphenylsilyl)oxy)-1-hydroxyethyl)-4-(8-fluoro-5-methylchroman-6-yl)-2-methylisoquinolin-1(2H)-one (92 mg, 0.148 mmol) in tert-butyl acetate (1994 μl, 14.80 mmol) was treated with 2 drops of 70% perchloric acid. After 18 h, the reaction mixture was poured into sat. aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by ISCO (0-30% EtOAc-hexanes) to afford (S)-3-(1-(tert-butoxy)-2-((tert-butyldiphenylsilyl)oxy)ethyl)-4-(8-fluoro-5-methylchroman-6-yl)-2-methylisoquinolin-1(2H)-one (49 mg, 0.072 mmol, 48.9% yield) as a white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.45 (dd, J=1.5, 7.7 Hz, 1 H), 7.70-7.63 (m, 2 H), 7.63-7.56 (m, 2 H), 7.41 (none, 8 H), 6.89 (d, J=11.3 Hz, 1 H), 6.85-6.78 (m, 1 H), 4.83 (dd, J=2.0, 7.4 Hz, 1 H), 4.30 (t, J=5.2 Hz, 2 H), 3.88 (dd, J=7.5, 10.6 Hz, 1 H), 3.82 (s, 3 H), 3.58 (dd, J=2.0, 10.7 Hz, 1 H), 2.73-2.52 (m, 2 H), 2.20-2.07 (m, 2 H), 1.64 (s, 3 H), 1.16 (s, 9 H), 0.98 (s, 9 H); LC/MS (m/z) ES+=678 (M+1).