Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]2)[CH2:28][O:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][C:26]1([CH3:38])[O:30][C@H:29]([CH2:31][N:32]2[CH:36]=[CH:35][C:34]([NH:37][C:11](=[O:12])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]=[CH2:24])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:33]2)[CH2:28][O:27]1
Reactant: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 65.2 %

Procedure:
To a solution of (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.215 g, 0.64 mmol) in N,N-dimethylformamide (5 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.153 g, 0.78 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.530 g, 1.20 mmol). The mixture was stirred at 0° C. and triethylamine (0.122 g, 1.21 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.214 g, 65%) as a white solid: HR-ES-MS m/z calculated for C27H33FN4O5 [M+H]+ 513.2508, observed 513.2505, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.45 (br. s., 1H), 1.49-1.67 (m, 1H), 1.67-1.84 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.04-4.18 (m, 2H), 4.23 (d, J=18.4 Hz, 1H), 4.35 (dq, J=6.0, 5.7 Hz, 1H), 4.60 (d, J=18.4 Hz, 1H), 4.81-4.93 (m, 1H), 4.91 (s, 1H), 5.52 (d, J=11.4 Hz, 1H), 6.00 (d, J=17.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 6.86 (dd, J=17.8, 11.4 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.42 (td, J=7.8, 1.2 Hz, 1H), 7.57-7.64 (m, 2H), 10.81 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH2:8][CH2:7]2)([O-:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cc([N+](=O)[O-])ccc32)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc3cc([N+](=O)[O-])ccc32)CC1
Reaction time: 1 h
Yield: 93 %

Procedure:
tert-Butyl 4-(5-nitroindolin-1-yl)piperidine-1-carboxylate (9.72 mmol, 3.377 g) was stirred at 0° C. in tetrahydrofuran (25 mL). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (10.69 mmol, 2.427 g) in tetrahydrofuran was added dropwise. The reaction was stirred at <10° C. for 1 hour. The reaction was stirred for 2 hours at room temperature. Ethyl acetate was added and the reaction washed with saturated sodium bicarbonate solution. The mixture was passed through a celite plug before being separated. The organic phase was concentrated at reduced pressure to afford the title compound (3.123 g). MS (ESI) m/z 290.3 [M-Boc+H]+
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23](O)=O.[F:26][C:27]1[CH:28]=[C:29]([NH2:34])[C:30]([NH2:33])=[CH:31][CH:32]=1>C1(C)C=CC=CC=1.O>[F:26][C:27]1[CH:32]=[CH:31][C:30]2[NH:33][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([C:14]5=[CH:15][C:16]6[O:20][CH2:19][O:18][C:17]=6[CH:21]=[C:13]5[O:12][CH2:11]4)[C:2]3=[O:1])=[N:34][C:29]=2[CH:28]=1
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Reactant: Nc1ccc(F)cc1N
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N(Cc2nc3cc(F)ccc3[nH]2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 25.7 %

Procedure:
A mixture of (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetic acid (0.50 g, 1.47 mmol) and 4-fluorobenzene-1,2-diamine (0.15 g, 1.18 mmol) in anhydrous toluene (20.0 mL) was refluxed overnight under N2. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/1) to give the title compound (0.13 g, 22%): mp 138-142° C.; 1H NMR (300 MHz, CDCl3) δ 7.47-7.39 (m, 1H), 7.32-7.22 (m, 2H), 7.16-6.93 (m, 3H), 6.18 (s, 1H), 6.07 (s, 1H), 5.84-5.78 (m, 2H), 5.20-5.14 (m, 2H), 4.98 (d, 1H), 4.60 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 179.2, 161.3, 158.1, 156.2, 149.2, 149.1, 142.5, 141.2, 131.5, 129.5, 124.4, 124.0, 118.0, 111.6, 111.2, 109.9, 103.1, 101.7, 93.5, 80.5, 58.5, 38.9; MS (ES+) m/z 430.2 (M+1).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@@H:8]1[O:12]C(C)(C)[O:10][C@@H:9]1[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[C:32](=[O:33])[C:31]3[C:30]4[N:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:24][C:23]=3[C:22]([CH3:35])([CH3:34])[C:21]=2[CH:36]=1)(C)(C)C.CO.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:34][C:22]1([CH3:35])[C:23]2[O:24][C:25]3[CH:26]=[CH:27][CH:28]=[N:29][C:30]=3[C:31]=2[C:32](=[O:33])[C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:9]([OH:10])[C@H:8]([OH:12])[CH2:7][OH:6])=[CH:36][C:21]1=2
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(C)(C)c2oc4cccnc4c2C3=O)O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)c2cc(OC[C@@H](O)[C@H](O)CO)ccc2C(=O)c2c1oc1cccnc21
Temperature: 57.5 °C
Yield: 28.1 %

Procedure:
To the mixture of 8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-10,10-dimethyl-10H-11-oxa-4-aza-benzo[b] fluoren-5-one (Compound GT15-6, 27 mg), MeOH (0.1 ml) and THF (0.3 ml), 0.5 N sulfuric acid (0.1 ml) was added, and the mixture was stirred and heated at 55 to 60° C. for 4 hrs. The reaction mixture was neutralized with saturated aqueous solution of sodium bicarbonate. The resulting solid was filtered and washed with diethyl ether. The filtrate was extracted with the mixture solution of DCM and MeOH (DCM:MeOH=10:1). The organic layer was washed with saturated brine, and dried over magnesium sulfate. The filtered solid and the residues obtained after concentration under reduced pressure were combined and purified by silica gel column (DCM/MeOH) to obtain the title compound (5.4 mg, 28%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:19]([Si:16]([CH3:18])([CH3:17])[O:15][CH2:14][CH2:13][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.426 g, 10.7 mmol) in DMF (30 mL) at room temperature was added 3-hydroxybenzaldehyde (1.00 g, 8.20 mmol). The resulting suspension was stirred at room temperature for 1 hour and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (4.4 mL, 20.5 mmol), was then added. The resulting mixture was stirred at 60° C. under nitrogen for 14 hours, cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (250 mL), and concentrated. The crude product was purified by column chromatography (SiO2, hexane/ethyl acetate=4:1) to afford 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde. It was re-dissolved in THF (50 mL), mixed with 1 N tetra-n-butylammonium fluoride in THF (15 mL), and stirred at room temperature for 8 h. The reaction mixture was then concentrated and the residue was purified by column chromatography (SiO2, hexane/ethyl acetate=4:1) to afford 3-(2-hydroxy-ethoxy)-benzaldehyde as a colorless oil. Yield: 0.68 g (50% for two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9]1)(=[O:29])=[O:28]
Reactant: Clc1cccc(C2CNc3ccccc32)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(c2cccc(Cl)c2)c2ccccc21
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3-chlorophenyl)indoline (3.88 g, 16.9 mmol) and DIEA (2.40 g, 18.6 mmol) in DCM (40 mL) was added dropwise methanesulfonyl chloride (2.13 g, 18.6 mmol) at about 0° C. The mixture was stirred for about 1.5 hours. The solution was diluted with DCM and washed with saturated NaHCO3 solution (2 times), 1N HCl aqueous solution (2 times) and brine (2 times) and dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:4. The title compound was obtained as an oil Yield: 4.40 9, 85%. Rf=0.41, silica, EtOAc/hexane 1:2. 1H NMR (300 MHz, CDCl3) δ:7.52 (d, 1H), 7.24-7.34 (m, 3H), 7.20 (s, 1H), 7.02-7.14 (m, 3H), 4.59 (t, 1H), 4.38 (t, 1H), 3.87 (dd, 1H), 2.92 (s, 3H).
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23].O>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].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>[C:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:16]([F:15])[CH:17]=2)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1F
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: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)cc1F
Temperature: 100 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.6 mmol) and [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (0.85 g, 4.3 mmol) in 1,4-dioxane (12 mL) and 10% sodium carbonate in water (5.73 mL, 5.40 mmol) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (166 mg, 0.144 mmol) was added, the mixture was bubbled with N2 for 5 min. more and heated at 100° C. overnight. The mixture was cooled to room temperature and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude product.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][NH:10]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: CCC(=O)O
Product: c1ccc2c(c1)CNC2
Temperature: 25 °C
Yield: 62.6 %

Procedure:
A solution of 12.0 g (0.044 mol) of 2-(p-tolylsulfonyl) isoindoline, 12.0 g (0.13 mol) of phenol, 90 ml of 48% HBr, and 15 ml (0.201 mol) of propionic acid was refluxed for two hours. The mixture was cooled to room temperature, triturated with diethyl ether, and then added to a solution of 75 gm of sodium hydroxide in 200 ml of cold water. This mixture was extracted with diethyl ether and the combined ether extracts were washed with water. The organic phase was dried over magnesium sulfate, concentrated in vacuo and kugelrohr distilled to give 3.28 g (61%) of a white solid, m.p. 118°-127° C. NMR: (CDCl3) δ 2.2 (1H,s), 4.0 (4H, s), 6.95 (4H, s)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1.Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33].[H-].[Na+]>CN(C=O)C>[CH3:33][N:32]([CH3:34])[CH2:31][CH2:30][CH2:29][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1
Reactant: CN1C(=O)C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C1=O
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)N(C)C2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
Sodium hydride (60 to 72%, oily, 50 mg) was washed with pentane and then suspended into DMF (0.3 mL). A DMF solution (1.2 mL) of 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (150 mg, 0.44 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 1887, 1988) was added thereto, and the whole was stirred at room temperature for 45 minutes. On the other hand, DMF (1.2 mL) was added at 0° C. to a mixture of (3-chloropropyl)dimethylamine hydrochloride (70 mg, 0.44 mmol) and sodium hydride (60 to 75%, oily, 18 mg) washed with pentane, and the whole was stirred for 5 minutes and then warmed to room temperature with standing. The supernatant was added to the solution of sodium salt of 2,3-bis(1H-indol-3-yl)-N-methylmaleimide. The resulting mixture was stirred at 40° C. for 1.5 hours, and then DMF was removed under reduced pressure. To the residue were added dichloromethane and saturated aqueous sodium chloride solution, and the organic layer was separated. The water layer was further extracted with dichloromethane. The resulting organic layers were combined and dried over sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by column chromatography over silica gel (chloroform saturated with ammonia:methanol=10:1) to obtain 2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-N-methylmaleimide (77 mg, 41%) as dark red solids.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:15]=[N+]=[N-].[Na+]>CN(C)C=O.ClCCl>[NH2:15][CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1ccc(CBr)cc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-bromomethylsalicylate (4.8 g, 18.6 mmoles) was dissolved in dry N,N-dimethylformamide (50 mL) and sodium azide (1.2 g, 18.9 mmoles) was added. The suspension was stirred at room temperature for 2 hours. The reaction mixture was then diluted with dichloromethane (150 mL) and extracted with 1N aqueous hydrochloric acid (100 mL), water (100 mL), and saturated aqueous sodium chloride(50 mL). Finally, the solution was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give ethyl 4-aminomethylsalicylate as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[N:17][OH:18])[CH:11]=1)[CH3:9])(C)(C)C.[CH3:20][N:21]([CH3:25])[CH2:22][C:23]#[CH:24]>ClCCl>[CH3:20][N:21]([CH2:22][C:23]1[O:18][N:17]=[C:16]([C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH:24]=1)[CH3:25]
Reactant: C#CCN(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(C=NO)c1
Solvent: ClCCl
Product: C[C@H](N)c1cccc(-c2cc(CN(C)C)on2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a solution of (S)-{1-[3-(hydroxyimino-methyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (260 mg, 1 mmol) in dichloromethane (5 mL) was added dimethylpropargylamine (323 μL, 3 mmol) followed by household bleach (5 mL). The reaction mixture was stirred vigorously at room temperature for 2 h, the two layers were separated, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo, the crude product was dissolved in CH2Cl2 (8 mL) and trifluoroacetic acid (2 mL), and the reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was purified by solid phase extraction (SCX cartridge, silica gel benzene sulfonic acid linked) to give the title product (200 mg, 82% yield) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[Cl:12]CCCl.[Cl-].[P+]=O>CN(C=O)C>[Cl:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1O
Reactant: ClCCCl
Agent: O=[P+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Cl
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A 350 ml three-necked round-bottomed flask equipped with a magnetic bar, a thermometer, a dropping funnel and a reflux condenser is charged with 3-methyl-5-nitro-pyridin-2-ol (23.1 g), and 1,2-dichloroethane (150 ml). Phosphorous oxide chloride (17 ml) is added dropwise. Into this mixture DMF (11.5 ml) is added dropwise at room temperature. The reaction mixture is heated at 70° C. under stirring for 0.5 hour. After cooling the mixture to ambient temperature, it is concentrated in vacuo at 50° C., to obtain a brown oily gum. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 7:3 (v:v) gives 23.34 g of the compound as a light yellow solid (MP: 40-42° C.).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]I>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(O)cc1
Reactant: Brc1csc2ccccc12
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(Oc2csc3ccccc23)cc1
Temperature: 140 °C

Procedure:
A mixture of 4.00 g (19.7 mmol) of 3-bromobenzo[b]thiophene, 4.96 g (40 mmol) of 4-methoxyphenol, 5.52 g (40 mmol) of K2CO3, and 0.20 g (1.0 mmol) of CuI was heated to 140° C. and sonicated at this temperature for 2 h. The reaction was allowed to cool, taken up in CH2Cl2, and the mixture was washed several times with 0.5 N NaOH. The organic layer was dried over Na2SO4 and concentrated in vacuo to an oil that was subjected to chromatography (SiO2; gradient of 0-5% EtOAc in hexanes). The fractions containing the desired product were combined, evaporated in vacuo, and the residue was recrystallized from hexanes to afford 500 mg (1.95 mmol; 10%) of the title compound as a white solid.
Reaction SMILES: COC1C=CC([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[F:31][C:32]([F:43])([F:42])[O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1C=O>>[F:31][C:32]([F:42])([F:43])[O:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccccc1OC(F)(F)F
Product: O=C(NCCNCc1ccccc1OC(F)(F)F)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 2-(trifluoromethoxy)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 476 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.28 (1H, s) 8.05 (1H, t, J=5.64 Hz) 8.01 (1H, d, J=5.42 Hz) 7.77 (1H, d, J=5.42 Hz) 7.58 (1H, dd, J=6.86, 2.17 Hz) 7.47 (1H, d, J=5.42 Hz) 7.25-7.39 (4H, m) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.49, 1.93 Hz) 3.76 (2H, s) 3.33-3.42 (2H, m) 2.65 (2H, t, J=6.49 Hz)
Reaction SMILES: C(OC(=O)[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])(C)(C)C.C([O:30][C:31](=[O:44])[C:32]#[C:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)C>>[CH3:8][NH:7][C:9]1[N:10]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH:33]([C:34]2[CH:35]=[N:36][C:37]4[C:42]([CH:43]=2)=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:32][C:31]([OH:44])=[O:30])[CH:22]=[CH:21]3)[CH:12]=[CH:13][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Reactant: CCOC(=O)C#Cc1cnc2ccccc2c1
Product: CNc1cccc(CCOc2ccc3c(ccn3C(CC(=O)O)c3cnc4ccccc4c3)c2)n1
Yield: 48 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and quinolin-3-yl-propynoic acid ethyl ester, using the procedure described in Example 16, step (d1), in 48% yield, as an E/Z isomeric mixture. H1 NMR (Cl3CD), δ: 8.91 (d, 0.3H, J=2.1 Hz), 8.88 (d, 0.3H, J=2.3 Hz), 8.17 (d, 0.7H, J=8.8 Hz), 8.14-8.11 (m, 1H), 7.97 (d, 0.3H, J=2.0 Hz), 7.82-7.74 (m, 2H), 7.60 (m, 1H), 7.53 (m, 1H), 7.49 (m, 1H), 7.17 (m, 1H), 7.11 (m, 1H), 6.92-6.97 (m, 2H), 6.78 (dd, 0.7H, J=2.5, 9.0 Hz), 6.70 (dd, 0.3H, J=2.5, 9.0 Hz), 6.64 (d, 0.3H, J=3.2 Hz), 6.55 (d, 0.7H, J=3.5 Hz), 6.39 (s, 0.3H), 6.32 (s, 0.7H), 4.39 (m, 2H), 4.10 (q, 1.4H, J=7.2 Hz), 4.04 (q, 0.6H, J=7.2 Hz), 1.39 (s, 0.9H), 1.38 (s, 2.1H), 3.21 (m, 2H), 1.51 (s, 9H), 1.14 (t, 2.1H, J=7.2 Hz), 1.05 (t, 0.9H, J=7.2 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(#N)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([S:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: Fc1ccc(S)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Oc1ccc(C(=O)Sc2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 4-acetoxybenzoyl chloride (7.74 g) in dry acetonitrile (10 ml) was added to a solution of 4-fluorothiophenol (5.00 g) in acetonitrile (40 ml). The mixture was cooled to 5° C. by immersion in an ice-water bath and pyridine (3.15 ml) added dropwise to the stirred solution. The mixture was stirred at 5° C. for 1 hour, allowed to reach room temperature and stirred for a further 2 hours, and then the solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the separated organic layer was washed successively with water, dilute hydrochloric acid, and water again. Evaporation of the solution, which had been dried over magnesium sulphate, afforded the desired thioester as a pale yellow solid (10.81 g).