Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(N)cc1OC
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)Nc1ccc(OC)c(OC)c1
Temperature: 12 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of 919 g (6 mol) of 3,4-dimethoxyaniline in 5 L of methylene chloride was treated with 3.3 L of 2N sodium hydroxide. The reaction mixture was cooled to 12° C. and 603 mL (6.3 mol) of ethyl chloroformate was added at a rate to keep the temperature between 25°-30° C. The reaction mixture was stirred at room temperature for 2 hr and the layers were separated. The aqueous layer was extracted with 3×1500 mL of methylene chloride and the combined organic layers were dried over sodium sulfate and treated with Darco*. Evaporation gave an oil to which 3 L of ethyl acetate and 1 L of hexanes were added to crystallize the product. After cooling at 4° C. for 3 hr, the product was filtered and washed with 3×1 L of hexanes. Drying under vacuum gave 1133 g (84%) of the product, mp 75°-78° C. NMR (CDCl3) δ 1.30 (t, 3H, J=7 Hz, OCH2 --CH3), 3.83 (s, 6H, OCH3), 4.18 (q, 2H, J=7 Hz, OCH2 --CH3), 6.58 (br s, 1H, NH ), 6.70 (m, 2H, ArH), 7.12 (m, 1H, ArH).
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:21].C(Cl)(Cl)Cl>ClCCl>[CH:3]12[O:21][CH:4]1[CH2:5][N:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2OC2C1
Temperature: 46 °C

Procedure:
Benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (11.0 g, 54.1 mmol, commercially available from Aldrich) and 3-chlorobenzoperoxoic acid (17.3 g, 70.4 mmol) were added to 150 mL of chloroform and heated to 46° C. for 20 hours. The mixture was cooled, dichloromethane was added, and the reaction was washed with a saturated solution of NaHCO3 and Na2S2CO3. The combined organic layers were dried over MgSO4, filtered and concentrated to give 10.5 g (88% isolated yield) of the desired compound as an oil, which was used directly in the next step.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[C:21]([F:22])=[C:20]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH3:26])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:35])[CH2:3][CH2:2]1.Cl.[C:37](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[C:21]([F:22])=[C:20]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[CH3:37])[CH3:26])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:35])[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1F)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-7-fluoro-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (1.28 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/methanol, and the solution was subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was recrystallized (hexane/ethyl acetate) to give the title compound as white crystals (477 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=O)[NH:8]2)=[CH:4][CH:3]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:27]2[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: CCCn1cc(Br)cn1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCn1cc(-n2ccc3ccc(Cl)cc32)cn1
Temperature: 140 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
To a stirred solution of 6-chloro-1H-indole 1 (1.0 g, 6.62 mmol) in toluene (25 mL) under inert atmosphere were added N,N′-dimethylethylene diamine (233 mg, 2.64 mmol), potassium phosphate (3.50 g, 16.55 mmol) and 4-bromo-1-propyl-1H-pyrazole (Intermediate B; 1.23 g, 6.62 mmol) at RT and then degassed under argon for 15 min. To this, CuI (126 mg, 0.66 mmol) was added and sealed the tube. The reaction mixture was heated to 140° C. and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 2 (1.5 g, 88%) as yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.68 (s, 1H), 7.62 (s, 1H), 7.55 (d, J=10.0 Hz, 1H), 7.35 (s, 1H), 7.17 (d, J=3.5 Hz, 1H), 7.11 (d, J=10.0 Hz, 1H), 6.59 (d, J=3.5 Hz, 1H), 4.17 (t, J=7.5 Hz, 2H), 2.00-1.96 (m, 2H), 1.00 (t, J=7.5 Hz, 3H); LC-MS (ESI): 93.3%; m/z 260.2 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.04 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([Cl:17])[CH:6]=[C:7]([O:15][CH3:16])[C:8]=2[O:13][CH3:14])[N:3]=1.C[O-:19].[Na+]>CO>[Cl:1][C:2]1[N:11]=[C:10]([OH:19])[C:9]2[C:4](=[C:5]([Cl:17])[CH:6]=[C:7]([O:15][CH3:16])[C:8]=2[O:13][CH3:14])[N:3]=1
Reactant: C[O-]
Reactant: COc1cc(Cl)c2nc(Cl)nc(Cl)c2c1OC
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)c2nc(Cl)nc(O)c2c1OC
Yield: 9 %

Procedure:
A mixture of 2,4,8-trichloro-5,6-dimethoxyquinazoline (2.0 g, 0.0068 moles), sodium methoxide (0.367 g, 0.0068 moles) and methanol (100 ml) was stirred at reflux for 3 hours. The solvent was removed in vacuo and the residue was treated with water (50 ml), followed by acidification with glacidal acetic acid. The resulting aqueous mixture was extracted with dichloromethane (3×100 ml) and the combined organic extracts were dried over anhydrous sodium sulfate. After filtration and removal of solvent in vacuo the residue was recrystallized twice from methanol. The crystals were dried under vacuum at 40° C. to afford the product (0.168 g), mp 252°-253° C.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:5])=[CH2:4].[C:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])(=[O:8])[CH3:7]>>[CH3:5][C:3](=[CH2:4])[CH2:2][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:6](=[O:8])[CH3:7]
Reactant: CC(=O)Nc1ccccc1O
Reactant: C=C(C)CCl
Product: C=C(C)COc1ccccc1NC(C)=O
Yield: 85.5 %

Procedure:
The compound (1.74 g, 85%) was prepared from 3-chloro-2-methylpropene (1.09 g, 11.9 mmol) and 2-acetamidophenol (1.50 g, 9.92 mmol) analogously to that described in Example 8(i).
Reaction SMILES: COCCC[O:6][C:7](=[O:21])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:9]=1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([OH:21])=[O:6])=[CH:9][C:10]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCCOC(=O)c1ccc(Cl)c(OCCCOC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCCCOc1cc(C(=O)O)ccc1Cl

Procedure:
A solution of 4-chloro-3-(3-methoxy-propoxy)-benzoic acid 3-methoxy-propyl ester (1.58 g, 4.99 mmol) in aqueous 2N NaOH (3.23 mL, 6.48 mmol) and dioxane (10 mL) is stirred at room temperature for 3.5 hrs. The mixture is acidified by addition of 2N HCl, the volatiles are removed by evaporation and the obtained suspension is filtered. The precipitate is washed with ice-cold water and dried in vacuo to give the title compound as white solid. MS: 243.0 [M−H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.93 min. 1H-NMR (DMSO-d6): δ 2.00 (m, 2H), 3.27 (s, 3H), 3.34 (s, br, 1H), 3.53 (m, 2H), 4.19 (m, 2H), 7.5-7.6 (m, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(C)s1)C(=O)OCC

Procedure:
A 215 g (1.71 moles) sample of 5-methyl-2-thiophenecarboxaldehyde, 258 ml (1.71 moles) diethyl malonate, 25 ml piperidine, 0.52 g benzoic acid, and 1.5 L toluene were placed into a round bottom flask and heated to reflux for four hr. with azeotropic removal of water. The reaction was cooled and water was added. The toluene layer was washed with sodium bicarbonate solution. 3N hydrochloric acid, water, brine and dried (MgSO4). The solvent was evaporated in vacuo. The residue was washed with methylcyclohexane. The washings were collected, the solvent removed in vacuo and the residue was recrystallized from methylcyclohexane. The solid materials were combined to give 299.86 g of diethyl 2-[(5-methyl-2-thienyl)methylene]propanedioate, mp 53°-56° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]3[N:15]([C:18]4[CH:32]=[CH:31][C:21]([O:22][CH:23]5[CH2:26][CH:25]([C:27](OC)=[O:28])[CH2:24]5)=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1.[BH4-].[Na+].CO>C1COCC1>[OH:28][CH2:27][CH:25]1[CH2:24][CH:23]([O:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[C:14]4[CH:33]=[CH:34][C:11]([C:9]([NH:8][CH2:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[O:10])=[CH:12][C:13]=4[N:17]=[CH:16]3)=[CH:32][CH:31]=2)[CH2:26]1
Reactant: COC(=O)C1CC(Oc2ccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OC2CC(CO)C2)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-1H-benzimidazol-1-yl}phenoxy)cyclobutanecarboxylate (150 mg, 0.33 mmol) and sodium borohydride (25 mg, 0.66 mmol) were dissolved in THF (3 mL), put under a N2 atmosphere, and heated to 60° C. Methanol (13 μL, 0.33 mmol) was then added and the reaction was stirred at 60° C. for 48 h. The reaction was cooled to rt and concentrated in vacuo. Methanol (2 mL) was then added followed by sodium hydroxide (3M, 5 mL) and the methanol was removed in vacuo. The resultant aqueous solution was extracted with ethyl acetate (3×), dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was purified using the Waters mass-directed HPLC purification system to provide 1-(4-{[3-(hydroxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as a white solid. MS (ES+): m/z 429 (90) [MH+].
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]#[N:23])[N:11]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:10]=1[C:32]#[N:33])C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][C:9]1[C:13]([OH:14])=[C:12]([C:22]#[N:23])[N:11]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[C:10]=1[C:32]#[N:33]
Reactant: COc1ccc(-n2c(C#N)c(OCc3ccccc3)c(OCc3ccccc3)c2C#N)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc(-n2c(C#N)c(O)c(O)c2C#N)cc1
Yield: 14.7 %

Procedure:
3,4-Bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarbonitrile (14) (70 mg, 0.16 mmol) in THF (5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1.5 mL/min at 25° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford the crude product. The compound was purified by preparative HPLC (C-18 column, 21.2 mm i.d.×100 mm, 5 micron particle size, gradient 5-95% MeCN in 0.1% aqueous formic acid over 16 min) to afford 3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarbonitrile (UL1-034) (6 mg, 14%) as a yellow powder: m/z 254 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.44-7.36 (m, 2H), 7.14-7.05 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[C:22](=[O:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:17][N:18]1[CH:22]([OH:23])[CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C:19]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)N(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)C1=O
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-4-oxoazetidin-2-yl)methyl)-2,4-dioxoimidazolidine-1-carboxylate (170 mg, 0.390 mmol) in EtOH (10 mL) at 0° C. was added sodium borohydride (30 mg, 0.78 mmol). After 3 h at 0° C., the mixture was quenched with saturated NH4Cl (aq) and partially concentrated in vacuo. The bilayer was extracted with DCM and the organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was used as such in step 5. LCMS: m/z=457.1 (M+Na).
Reaction SMILES: [O-:1][O-:2].[Na+].[Na+].[C:5]([N:9]=[N:10][C:11](Cl)([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([N:9]=[N:10][C:11]([O:1][OH:2])([CH2:13][CH:14]([CH3:16])[CH3:15])[CH3:12])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Reactant: [O-][O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(C)(N=NC(C)(C)C)OO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1.56g (.02 moles) of sodium peroxide in 30 ml. of 75% aqueous methanol in a 50 ml. erlenmeyer flask immersed in a cold water bath, was added 4.1g (.02 moles) of 2-t-butylazo-2-chloro-4-methylpentane dropwise. After the addition was complete, the reaction mixture was stirred for an additional 45 minutes and poured into ice water containing 0.02 moles of HaSO4. The product was extracted with pentane and washed with cold solutions of ammonium sulfate and sodium bicarbonate, washed with water, dried over anhydrous sodium sulfate, filtered and the pentane stripped off under reduced pressure while the flask was immersed in an ice bath. The yield was 2.7 grams (67% of theory) and the product began to decompose when allowed to warm to room temperature. The infrared spectrum showed the characteristic hydroperoxide absorption at 3300-3400 cm-1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30](=[O:37])[NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)[CH2:25][CH2:24]4)=[C:17]3[N:16]=2)=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:39][C:18]3=[N:19][CH:20]=[C:21]([Br:38])[C:22]([N:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]([NH:31][C:32]5[S:33][CH:34]=[CH:35][N:36]=5)=[O:37])[CH2:27][CH2:28]4)=[C:17]3[N:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109 %

Procedure:
To (4-{6-bromo-7-[4-(thiazol-2-ylcarbamoylmethyl)-piperazin-1-yl]-3H-imidazo[4,5-b]pyridin-2-yl}-benzyl)-carbamic acid tert-butyl ester (0.053 g, 0.08 mmol) in dichloromethane (4 ml) was slowly added trifluoroacetic acid (0.5 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was run trough a 2 g SCX cartridge and eluted with 0.1M NH3 in methanol to give the title compound as a pale yellow solid (0.046 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]2[O:18][CH:17]=[CH:16][C:15]=2[CH:19]=1.C(N(CC)CC)C>CCO>[O:18]1[C:14]2[CH:13]=[CH:12][C:11]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:19][C:15]=2[CH:16]=[CH:17]1
Reactant: Brc1ccc2occc2c1
Reactant: OB(O)c1cccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1cncc(-c2ccc3occc3c2)c1
Yield: 63.7 %

Procedure:
A solution of 5 pyridin-3-ylboronic acid (390 mg, 3.18 mmol), 5-bromobenzofuran (500 mg, 2.54 mmol), palladiumdichlorobis(triphenylphosphine) (111 mg, 0.16 mmol) and triethylamine (8.8 mL, 63.5 mmol) in EtOH was irradiated in the microwave at 100° C. for 1200 s. Removal of the solvents followed by dissolving in CH2Cl2 and filtering gave the residue after concentration of the solvent under reduced pressure. The compound was purified on ISCO to afford 316 mg of the title compound as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.60 (d, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H) 7.38 (dd, 1H), 6.85 (dd, 1H). MS (ESI) m/z: Calculated: 195.07; Observed: 196.30 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([CH:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:51][CH2:52][C:53]1[C:54]([OH:61])=[N:55][C:56]([CH3:60])=[CH:57][C:58]=1[CH3:59])=[O:6]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)cc2F)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
The 2-fluoro-4-(1-phenoxyethyl)benzoic acid (150 mg, 0.514 mmol), 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (353 mg, 0.84 mmol) was dissolved in 20 mL dichloromethane, and then added triethylamine (2 mL). After the mixture was stirred at room temperature for 10 minute, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.514 mmol, 96 mg) was added. The mixture was stirred at room temperature for 12 hours then washed with water (10 mL), extracted with dichloromethane (20 mL). The organic layer were concentrated and s purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 2-fluoro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide (70 mg, 47%). LCMS (M+H+) m/z: calcd 394.17. found 394. 1H NMR (300 MHz, CD3OD) δ 7.69 (t, J=6.1 Hz, 1H), 7.28-7.13 (m, 4H), 6.86-6.81 (m, 3H), 6.06 (s, 1H), 5.43-5.41 (m, 1H), 4.47 (s, 2H), 2.34 (s, 3H), 2.22 (s, 3H). 1.57 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:14][CH:13]=4)=[CH:4][CH:3]=1.I[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:14][CH:13]=4)=[CH:4][CH:3]=1
Reactant: COc1ccc(I)cc1
Reactant: Cc1ccc(-c2ccc3[nH]c4ccc(-c5ccc(C)s5)cc4c3c2)s1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2c3ccc(-c4ccc(C)s4)cc3c3cc(-c4ccc(C)s4)ccc32)cc1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
The obtained 3,6-bis(5-methylthiophen-2-yl)carbazole (8.07 g, 22.4 mmol), 4-iodoanisole (21.00 g, 89.7 mmol), copper powder (0.71 g) and potassium carbonate (12.40 g) were mixed together. The mixture was refluxed in a nitrogen atmosphere for 6 hours and cooled to 100° C. Next, toluene (80 mL) was added thereto, and the resultant mixture was filtrated using a filtration aid to remove insoluble matter. Thereafter, the solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride, and the solution was washed with water and dried to obtain a brown liquid. Next, the obtained liquid was purified through silica gel column chromatography using as an eluent a solvent mixture of methylene chloride/hexane (3/7 by volume), to thereby obtain 4.39 g of 3,6-bis(5-methylthiophen-2-yl)-9-(4-methoxyphenyl)carbazole.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].[Pb](=O)=O>C(Cl)(Cl)Cl>[CH3:9][C:5]1[C:6](=[O:7])[CH:8]=[C:2]([CH3:1])[C:3](=[O:11])[C:4]=1[CH3:10]
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=[Pb]=O
Solvent: ClC(Cl)Cl
Product: CC1=CC(=O)C(C)=C(C)C1=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 2.0 g of trimethylhydroquinone in 300 ml of chloroform was added 10 g of lead (IV) oxide, and the mixed solution was stirred at room temperature for 30 hours and then lead (IV) oxide was filtered off and the reaction solution was concentrated under reduced pressure. The concentrate was combined with 150 ml of hexane, washed with 50 ml of a 0.5% sodium bicarbonate solution and then 50 ml of water, dried over anhydrous sodium sulfate, then concentrated under reduced pressure. After cooling in a freezer, the precipitating crystal was filtered and washed with a small amount of cold hexane to give 2,3,5-trimethylbenzoquinone as a yellow needle crystal. The yield was 1.6 g (82%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[N+](C1C=C(S(O[CH2:26][C@@:27]2([CH3:30])[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O>>[CH3:26][C@:27]1([CH2:30][O:1][N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH2:29][O:28]1
Reactant: C[C@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: C[C@]1(CON2C(=O)c3ccccc3C2=O)CO1

Procedure:
Prepared from N-hydroxyphthalimide and [(2R)-2-methyloxiran-2-yl]methyl 3-nitrobenzenesulfonate (Chen, J.; Shum, W., Tetrahedron Letters, 1993, 34(48), 7663-6) by the method of Example 93 Step I.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:29]=[CH:28][S:27][C:26]=1[CH:30]=O>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][N:19]([CH2:30][C:26]5[S:27][CH:28]=[CH:29][C:25]=5[CH3:24])[CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1ccsc1C=O
Reactant: O=c1[nH]c2cc(Br)ccc2n1C1CCN(C2CCNCC2)CC1
Product: Cc1ccsc1CN1CCC(N2CCC(n3c(=O)[nH]c4cc(Br)ccc43)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 18, using 5-bromo-1-[1-(piperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one and 3-methyl-2-thenaldehyde.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:30])[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Reactant: O=C(CCl)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CC(=O)Nc3ccccc3)C2=O)CC1
Yield: 14 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 2-chloro-N-phenylacetamide, to give the desired product as a white solid (14%).