Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: COc1ccc(CCn2ccc(-c3nc(C)c(C(=O)NCc4cccnc4)s3)n2)cc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-(2-bromo-ethyl)-4-methoxy-benzene as described in Example 49 and isolated as a white solid (0.030 mg, 21% yield). 1H NMR (400 MHz, CDCl3) δ 8.55-8.63 (bm, 2H), 7.72 (d, J=8 Hz, 1H), 7.28-7.33 (m, 1H), 7.15 (d, J=2 Hz, 1H), 6.97 (d, J=8 Hz, 2H), 6.80 (d, J=8 Hz, 2H), 6.72 (d, J=2 Hz, 1H), 6.12-6.19 (m, 1H), 4.64 (d, J=8 Hz, 2H), 4.33 (t, J=8 Hz, 2H), 3.77 (s, 3H), 3.12 (t, J=8 Hz, 3H), 2.76 (s, 3H); MS (M+H)+=433.9; Rt=1.25 min; HRMS (M+H)+=434.16.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2)[CH3:2].CO.[OH-].[K+]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:23]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2)[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(CC)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of ethyl 7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (3.64 g), methanol (20 mL), and tetrahydrofuran (40 mL) was added an aqueous solution (10 mL) of potassium hydroxide (1.6 g), and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (3.4 g, yield 100%) as pale-yellow crystals.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH:14]([S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17])=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC([O-])=O.[Na+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:19]1([S:16]([CH:14]=[CH:15][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]3)=[CH:4][CH:3]=2)(=[O:18])=[O:17])[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: C=CS(=O)(=O)N1CCOCC1
Reactant: O=C1CC[C@@H](c2ccc(I)cc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: O=C1CC[C@@H](c2ccc(C=CS(=O)(=O)N3CCOCC3)cc2)C1

Procedure:
A mixture of (3R)-3-(4-iodo-phenyl)-cyclopentanone (286 mg, 1 mmol), 4-(vinylsulfonyl)morpholine (265 mg, 1.5 mmol), tri(o-tolyl)-phosphin (20 mg), Pd(OAc)2 (8 mg) and NaOAc (164 mg) in DMF (4 mL) was heated at 130 C for 1.5 h. After cooling, the mixture 1H NMR (300 MHz, DMSO) δ 7.73 (d, J=8.2 Hz, 2H), 7.45-7.36 (m, 3H), 7.26 (d, J=15.5 Hz, 1H), 3.71-3.61 (m, 4H), 3.52-3.37 (m, 1H), 3.10-3.02 (m, 4H), 2.61-2.49 (m, 1H), 2.41-2.21 (m, 4H), 2.01-1.84 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[C:15](OCC)=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=2[CH2:15][OH:16])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccccc1-c1cc(OC)c(OC)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2ccccc2CO)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenyl)benzoate (655 mg) was dissolved in THF (20 mL), and to the solution lithium aluminum hydride (80 mg) was added at 0° C. under an argon atmosphere. The mixture was stirred at 0° C. for 1 hour as it is. A small amount of water and then sodium sulfate were added to the reaction mixture, and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resultant crude crystals were recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:23][OH:24].[OH-].[K+]>O.O1CCCC1>[OH:24][CH2:23][C:10]1[C:9](=[O:8])[C:18]2[C:13](=[CH:14][C:15]([C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=2)[N:12]([CH3:5])[CH:11]=1
Reactant: COS(=O)(=O)OC
Reactant: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(CO)c(=O)c2ccc(C(F)(F)F)cc21
Reaction time: 3 h

Procedure:
Dimethyl sulphate (24.4 g.) was added over 5 minutes to a stirring solution of 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline (23.6 g.) and potassium hydroxide (16.3 g.) in a mixture of water (50 ml.) and tetrahydrofuran (50 ml.) at room temperature. After stirring for a further 3 hours at this temperature the solid product was collected. The filtrate was extracted with dichloromethane (3×200 ml.). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to give a second crop of the solid. The combined solids were purified by high pressure liquid chromatography over silica gel, eluting with isopropanol:dichloromethane 10:90 at a flow rate of 200 ml. per minute. The same solvent was used for applying the product to silica gel. This procedure gave the novel 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4-quinolone, m.p. 172°-175°.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.O[CH2:37][C:38]1([CH:42]([OH:44])[CH3:43])[CH2:41][CH2:40][CH2:39]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:43][CH:42]1[O:44][C:32]2([CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:35][CH2:37][C:38]21[CH2:41][CH2:40][CH2:39]2
Reactant: CC(O)C1(CO)CCC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCC2(CCC2)C(C)O3)c2ncnn12
Temperature: 25 °C

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (12.67 g), 1-[1-(hydroxymethyl)cyclobutyl]ethanol (4.26 g), p-toluenesulfonic acid hydrate (0.57 g) and toluene (300 mL) was refluxed with heating for 5 hr while dehydrating with a Dean-Stark trap. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (13.64 g, 87%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:12](=[O:28])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:15]([NH2:27])[CH:14]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[Br-].[Br-].[Br-].[In+3]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][C:4]([C:12]([C:13]2[CH:14]=[C:15]3[C:16]([CH:19]=[C:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:27]3)=[CH:17][CH:18]=2)=[O:28])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccccc3)c(N)c2)sc1Br
Agent: [Br-]
Agent: [In+3]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Yield: 85.3 %

Procedure:
To a solution of 3 (25 mg, 0.05 mmol) in EtOAc (5 mL) was added stannous chloride dihydrate (58 mg, 0.26 mmol). The resulting mixture was refluxed for one hour under N2. The reaction mixture was poured onto ice (5 g), and basified with a saturated NaHCO3 solution to pH 8. The white milky mixture was filtered through a Celite pad to remove tin oxides. The organic layer from the filtrate was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave the desired intermediate methyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)thiophen-3-yl)acetate as a yellow foam (21 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H), 7.50 (s, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.38 (m, 3H), 7.17 (m, 2H), 4.40 (brs, 2H), 3.73 (s, 3H), and 3.66 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 186.7, 170.3, 148.1, 143.4, 138.1, 135.9, 135.1, 132.4, 131.8, 129.0, 128.7, 122.9, 122.8, 118.8, 114.5, 112.3, 97.6, 85.3, 52.6, and 35.0; HRMS-ESI calcd C22H16BrNO3S [M+Na] 475.9926. found 475.9923. To a 250 mL flask containing freshly distilled toluene (50 mL) was added methyl (2-bromo-5-(3-amino-4-(phenylethynyl)benzoyl)thiophen-3-yl)acetate (2.93 g, 6.45 mmol) and indium tribromide (1.14 g, 3.22 mmol) under N2. The resulting mixture was refluxed for one hour. The solvent was removed in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave 4 as a yellow solid (2.50 g, 85%). 1H NMR (400 MHz, CDCl3) δ 9.38 (brs, 1H), 7.98 (s, 1H), 7.69 (d, J=7.8 Hz, 2H), 7.58 (m, 2H), 7.47 (s, 1H), 7.40 (t, J=7.5 Hz, 2H), 7.30 (m, 1H), 6.80 (s, 1H), 3.65 (s, 3H), and 3.59 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 187.4, 170.5, 144.2, 142.3, 136.5, 135.7, 134.9, 133.3, 131.8, 130.9, 129.4, 128.8, 125.9, 121.9, 120.4, 113.5, 100.3, 52.6, and 35.2.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[Br:42]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([Br:42])[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(Br)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (51 mg; 0.086 mmol) in methylene chloride (1.2 mL) was added N-bromosuccinimide (63 mg; 0.354 mmol) and triphenylphosphine (97 mg; 0.369 mmol). The reaction was stirred at room temperature for 16 hours. Reaction was directly purified over 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-45% ethyl acetate in heptane) to give 27 mg (48% yield) of the title compound as a colorless gum. MS (ES+): Calc: 657.1, Found: 658.3 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.71 (d, J=8.30 Hz, 1H), 7.65 (s, 2H), 7.59 (d, J=8.30 Hz, 1H), 7.28 (s, 1H), 4.99 (d, J=9.96 Hz, 1H), 4.91 (d, J=15.35 Hz, 1H), 4.68 (q, J=15.77 Hz, 2H), 4.68 (d, J=16.26 Hz, 1H), 4.24 (s, 3H), 2.34 (d, J=12.86, 1H), 2.00 (m, 1H), 1.80 (d, 13.28 Hz, 1H), 1.63 (t, J=10.35 Hz, 2H), 1.39-1.22 (m, 2H), 1.14 (m, 2H), 0.98 (m, 1H), 0.76 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](Cl)=[O:8].[NH3:10]>>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:10])=[O:8]
Reactant: O=C(Cl)c1ccsc1Br
Reactant: N
Product: NC(=O)c1ccsc1Br
Yield: 90.8 %

Procedure:
Add 2-bromothiophene-3-carbonyl chloride (540 mg, 2.39 mmol) to a solution of aqueous ammonia (25%, 3 mL, 17.44 mmol) with stirring. Stir the mixture for 30 minutes. Concentrate the mixture. Collect the resulting precipitate via filtration and wash the solids with water. Dry the white precipitate in vacuo to obtain the title compound (450 mg, 2.17 mmol).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16](=[O:19])[CH2:17]Br)([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]1([S:7][CH2:8][CH2:9][O:10][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCCSc1ccccc1

Procedure:
2-Phenylthioethanol (6.1 g), t-butylbromoacetate (7.9 ml), tetrabutylammoniumbromide (1.3 g), toluene (80 ml), and 75% aqueous sodium hydroxide (40 ml) were stirred together for 72 hours. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organics were washed with brine, dried (MgSO4) and the solvent was removed in vacuo to provide the subtitle compound (12.07 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:22])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6].COC1C=CC=C(OC)[C:30]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(B2OC(C)(C)C(C)(C)O2)=CCC1>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:32][C:31]1([CH3:30])[C:36]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([F:22])[C:11]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:35][CH2:34][CH2:33]1
Reactant: COC(=O)c1cc(F)c(OCc2ccc(OC)cc2)c(Br)c1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CCC=C1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(F)c(OCc2ccc(OC)cc2)c(C2=CCCC2(C)C)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 331.1 %

Procedure:
A stirred mixture of 66.49C (1.63 g, 4.420 mmol), ground S-Phos (0.36 g, 0.88 mmol), palladium acetate (0.10 g, 0.45 mmol), and potassium phosphate tribasic (2.35 g, 11.06 mmol) in DMF (13 mL) and water (0.4 mL) was purged with argon and placed under vacuum and the process repeated three times. Before heating, 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (66.6C) (1.47 g, 6.63 mmol) was added via syringe and then the mixture was heated to 75° C. After 18 hours, the reaction was cooled to room temperature, diluted with water, and extracted three times with EtOAc. The organic layers were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified on a 40 g column of silica gel (0-10% EtOAc in hexanes) to afford 66.49D as a white solid (1.12 g, 66% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (1H, dd, J=11.7, 2.3 Hz), 7.57 (1H, dd, J=2.0, 1.2 Hz), 7.31 (2H, m), 6.88 (2H, m), 5.56 (1H, t, J=2.5 Hz), 5.01 (2H, s), 3.91 (3H, s), 3.82 (3H, s), 2.42 (2H, td, J=7.0, 2.7 Hz), 1.86 (2H, t, J=7.2 Hz), 1.06 (6H, s).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:16]=[CH:15][C:11]2[CH2:12][CH2:13][O:14][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:8]2[C:16](=[CH:15][C:11]3[CH2:12][CH2:13][O:14][C:10]=3[CH:9]=2)[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCC2
Reactant: O=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)NC(c2ccccc2)c2cc3c(cc21)OCC3

Procedure:
A solution of 8.0 g. of 1-Isopropyl-1-(2,3-dihydro-6-benzofuranyl)urea, 3.6 ml. of benzaldehyde, 5 drops of methanesulfonic acid and 200 ml. of toluene is stirred and refluxed under a water separator for 20 hours. The resulting solution is cooled and the cooled solution is washed twice with 150 ml. water, dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is dissolved in a minimum amount of chloroform and chromatographed on silica gel (200 g.) using chloroform as an eluent to give an oil of 1-isopropyl-4-phenyl-3,4,6,7-tetrahydro-furo[3,2-g] quinazolin-2(1H)-one and an oil of 6-isopropyl -9-phenyl-2,3,8,9-tetrahydro-furan[2,3-f]quinazolin-7(6H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30].[K+]>CC(CC)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][I:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccccc2)C1
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-methylsulfonyloxymethyl-4-t-butyldimethylsilyloxypyrrolidine (108.5 g) in methylethylketone (1100 ml), potassium iodide (73.5 g) was added, and the resultant mixture was refluxed for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove the solvent. The residue was diluted with ethyl acetate, washed with aqueous sodium chloride solution, aqueous sodium hypochlorite solution and aqueous sodium chloride solution in order and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:39]=[CH:38][C:15]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[C:19]([C@@H:27]3[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]3[OH:29])=[CH:18]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[C@@H:27]1([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[N:17]([CH2:16][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:39][CH:38]=3)[CH:18]=2)[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]1[OH:29]
Reactant: Cc1ccc2c(c1)c([C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)cn2Cc1ccc(OCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)c([C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)cn2Cc1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
1-{4-[2-(Benzyloxy)ethoxy]benzyl}-3-(β-D-glucopyranosyl)-5-methyl-1H-indole (32 mg) was dissolved in a mixed solvent of methanol (1 mL) and ethyl acetate (2 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure to give the title compound (17 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=2)[C:3]1=[O:25].[C:26]([C:30]1[CH:31]=[C:32]2[C:37](=[C:38]([F:40])[CH:39]=1)[C:36](=[O:41])[N:35]([C:42]1[N:49]=[CH:48][CH:47]=[C:46](Cl)[C:43]=1[CH:44]=[O:45])[N:34]=[CH:33]2)([CH3:29])([CH3:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:26]([C:30]1[CH:31]=[C:32]2[C:37](=[C:38]([F:40])[CH:39]=1)[C:36](=[O:41])[N:35]([C:42]1[N:49]=[CH:48][CH:47]=[C:46]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[N:19]=4)[C:3](=[O:25])[N:2]([CH3:1])[CH:7]=3)[C:43]=1[CH:44]=[O:45])[N:34]=[CH:33]2)([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1nccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)n1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cc1nccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)n1
Temperature: 100 °C
Yield: 36 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 114b (236 mg, 0.69 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (250 mg, 0.69 mmol), PdCl2(dppf) (29 mg, 0.035 mmol), K3PO4 (296 mg, 1.39 mmol), sodium acetate (114 mg, 1.39 mmol), acetonitrile (15 mL), and water (1 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 114c (134 mg, 36%) as a yellow solid. MS-ESI: [M+H]+ 540.2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]1[CH:21]2[CH:16]([CH:17]3[CH2:22][CH:20]2[CH2:19][CH:18]3O)[CH2:15][CH2:14]1.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:13]1[CH:21]2[CH:16]([CH:17]3[CH2:22][CH:20]2[CH2:19][CH:18]3[N:28]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:29])[CH2:15][CH2:14]1
Reactant: OC1CC2CC1C1CCCC21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C1CC2CC1C1CCCC21
Reaction time: 8 h

Procedure:
With stirring, 1.7 g of diethyl azodicarboxylate, diluted with 5 ml of THF, were added to a solution of 1.66 g of octahydro-4,7-methanoinden-5-ol, 1.47 g of phthalimide, and 2.62 g of triphenylphosphine in 15 ml of THF. The reaction mixture was allowed to stand overnight and then concentrated, the residue was stirred with ether, the precipitate was filtered off with suction, and the filtrate was concentrated. The residue was purified over silica gel using toluene. This gave 1.36 g of a yellow oil.