Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[C:4]1[CH2:17][N:16](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15][CH2:14][C:5]=1[NH:6]2.CC1C(B2OC(C)(C)C(C)(C)O2)=CC=CC=1[N:53]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[N:55]=[CH:54]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:4][C:3]1[C:7]([N:53]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[N:55]=[CH:54]2)=[CH:8][CH:9]=[CH:10][C:2]=1[C:2]1[CH:10]=[CH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[C:3]=1[C:4]1[CH2:17][NH:16][CH2:15][CH2:14][C:5]=1[NH:6]2
Reactant: NC(=O)c1ccc(Br)c2c3c([nH]c12)CCN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C3
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2ccccc2c1=O
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: CCO
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Temperature: 90 °C
Reaction time: 15.75 h
Yield: 114.9 %

Procedure:
Alternatively, a mixture of 9-bromo-2-trityl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (78.3 mg, 0.146 mmol), 3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazolin-4(3H)-one (52.9 mg, 0.146 mmol), and 2 M aqueous sodium carbonate (0.219 mL, 0.438 mmol) in toluene (1.2 mL) and ethanol (0.3 mL) was degassed by bubbling with argon for ca. 5-10 min (1 minute with sonication). The mixture was treated with tetrakis(triphenylphosphine)palladium (8.4 mg, 0.007 mmol) and heated at 90° C. under argon. After 15.75 h, the mixture was cooled to room temperature and concentrated under vacuum. The residue was stirred in methanol, treated with a small amount of TFA and water and the resulting mixture was sonicated until the gummy insoluble material was replaced by a flocculent precipitate. The mixture was filtered and subjected to purification by preparative HPLC. Fractions containing the desired product by LCMS were combined, treated with saturated aqueous sodium bicarbonate and concentrated under vacuum to provide an aqueous suspension. The precipitate was collected by filtration, washed with water and dried under vacuum to provide the desired product as a white solid (37.7 mg, 56% yield). LCMS (M+H+) m/z 450.2. 1H NMR (400 MHz, DMSO-d6) δ 10.83-10.93 (1 H, m), 8.19-8.41 (2 H, m), 8.03 (1 H, br. s.), 7.86-7.97 (1 H, m), 7.79 (1 H, t, J=7.3 Hz), 7.58-7.70 (2 H, m), 7.41-7.57 (2 H, m), 7.23-7.41 (2 H, m), 6.74-6.88 (1 H, m), 3.02-3.28 (2 H, m), 2.90 (2 H, br. s.), 2.71 (2 H, br. s.), 1.76 (3 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[Cl:37])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccccc4Cl)cc3C)c2cc1OC
Yield: 73.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-chlorophenyl)methanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (112 mg, yield 68%).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Al+3].[Cl-:10].[Cl-].[Cl-].[CH:13]([Si](C)(C)C)=[CH2:14]>C(Cl)Cl>[Cl:10][CH2:13][CH2:14][C:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7]
Reactant: [Cl-]
Reactant: O=C(Cl)C1CCCC1
Reactant: C=C[Si](C)(C)C
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(CCCl)C1CCCC1
Temperature: 0 °C

Procedure:
A solution of cyclopentanecarbonyl chloride (10 g, 75 mmol) and AlCl3 (11.1 g, 83 mmol) in CH2Cl2 (100 mL) was cooled to −10° C. A solution of vinyltrimethylsilane (12 mL, 75 mmol) in CH2Cl2 (50 mL) was added drop wise over 30 minutes. The reaction was stirred for 20 additional minutes, and then poured over 200 g of ice. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and washed with saturated NaHCO3. The organic was then dried over Na2SO4, the solids were filtered away, and the product was purified by distillation (7.17 g, 60%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[NH3:16].[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:15]=[C:14]2[CH2:20][CH2:21][N:22]([CH3:23])[CH3:24]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(Br)cc12
Product: N
Temperature: 25 °C
Reaction time: 20 h
Yield: 3 %
Yield: 167.3 %

Procedure:
Benzoyl chloride (1.7 mL, 14.6 mmol) was added to a solution of 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1H-indole (Example 3a, 9.5 mmol) in dichloromethane (70 mL) containing triethylamine (4 mL, 28.7 mmol) and DMAP (206 mg, 1.7 mmol). The resulting solution was stirred at room temperature for 20 h. Dilution with dichloromethane (500 mL) was followed by sequential washing with water (200 mL) and brine (150 mL), drying over sodium sulfate and removal of the solvent in vacuo. Flash chromatography (silica gel, 3-5% 2M methanolic ammonia in dichloromethane) yielded 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (2.95 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[C:5]([C:7]1[CH:35]=[CH:34][C:10]2[N:11]([CH2:15][CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1)=O.[CH3:39][O:40][NH2:41].N1C=CC=CC=1>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[N:41][O:40][CH3:39])[C:7]2[CH:35]=[CH:34][C:10]3[N:11]([CH2:15][CH2:16][O:17][C:18]4[CH:19]=[CH:20][C:21]([CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[CH:32][CH:33]=4)[C:12](=[O:14])[S:13][C:9]=3[CH:8]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)C(=Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4cccc(Cl)c4)ccc32)cc1)C(=O)OC
Reactant: CON
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: CON=C(c1cccc(Cl)c1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(C=C(C(=O)OC)C(=O)OC)cc1

Procedure:
The compound obtained in Example 41 is dissolved in a minimum of methanol, and then 4 equivalents of O-methylhydroxylamine, previously dissolved in a few milliliters of water, and 4.5 equivalents of pyridine are added in succession. The reaction mixture is heated at reflux for 24 hours and then hydrolysed in water and filtered; the resulting precipitate is recrystallised from acetonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:15])[C:11]=2[O:13][CH3:14])[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])O.[Na+]>O1CCCC1>[NH2:15][C:10]1[C:11]([O:13][CH3:14])=[C:12]2[C:7]([CH2:6][CH2:5][C:4]2=[CH:3][CH2:2][NH:1][C:23](=[O:25])[CH3:24])=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(N)ccc2c1C(=CCN)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(N)ccc2c1C(=CCNC(C)=O)CC2
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
3-(2-Aminoethylidene)-4-methoxyindan-5-amine (15.3 mg, 0.076 mmol) and triethylamine (21.2 μL, 0.152 mmol) were dissolved in tetrahydrofuran (0.9 mL), a solution of acetic anhydride (7.18 μL, 0.076 mmol) in tetrahydrofuran (0.1 mL) was added under ice-cooling, and the mixture was stirred for 15 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) to give the title compound (16.2 mg, yield 87%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br:8][C:9]1[C:10]([OH:20])=[C:11]([NH2:19])[C:12](=[C:16]([Br:18])[CH:17]=1)[C:13]([OH:15])=[O:14].[O-]S([O-])(=O)=O.[Na+].[Na+].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Br:8][C:9]1[C:10]([OH:20])=[C:11]([NH:19][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:12](=[C:16]([Br:18])[CH:17]=1)[C:13]([OH:15])=[O:14]
Reactant: Nc1c(O)c(Br)cc(Br)c1C(=O)O
Reactant: O=Cc1cccs1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1c(Br)cc(Br)c(O)c1NCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A solution of 2-thiophenecarboxaldehyde (38 mg, 0.34 mmol) in dry methanol (0.8 mL) was added to a mixture of 4,6-dibromo-3-hydroxyanthranilic acid (105 mg, 0.34 mmol) and Na2SO4 (240 mg, 1.7 mmol) in methanol (2 mL). The reaction mixture was stirred overnight at room temperature. Sodium cyanoborohydride (32 mg, 0.51 mmol) was added, and the mixture was stirred for 2 days at room temperature. Conc. acetic acid (1 mL) was added, and the solvent was removed in vacuo. The residue was partitioned between brine and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The obtained material was purified by column chromatography (SiO2, CH2Cl2 -hexane-EtOAc-conc. HOAc 30:30:20:3). Preparative HPLC (H2O-acetonitrile-conc. HOAc 50:50:1) yielded the title compound as a yellowish solid (17 mg): 1H NMR (CD 3 OD-d4) 7.26 (dd, J=5 Hz, 1 Hz), 7.20 (s, 1H), 6.99 (m, 1H), 6.92 (dd, J=5 Hz, J=5 Hz, 1H), 4.54 (s, 2H); MS (TSP): m/z (rel. int.) 410/408/406 (M+1, 5/12/7), 234/232 (31/28), 154 (100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH:9]2[CH:7]([CH:8]2[N:11]([CH3:13])[CH3:12])[CH2:6]1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([OH:39])[CH:37]=3)[N:32]=[CH:31][N:30]=2)[CH:24]=[CH:25][C:26]=1[F:27]>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([O:39][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH:9]5[CH:7]([CH:8]5[N:11]([CH3:13])[CH3:12])[CH2:6]4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: CN(C)C1C2CN(CCCCl)CC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2C(C1)C2N(C)C
Temperature: 80 °C
Reaction time: 7 h
Yield: 44.2 %

Procedure:
A mixture of 3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-6-amine (0.70 g), K2CO3 (0.78 g) and 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.70 g) in 30 mL of DMF was stirred at 80° C. for 7 h, and cooled to rt. To this, 50 mL of ice-water was added, and the resulted mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (diluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.47 g, 35.00%), HPLC: 96.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.54 (s, 2H), 7.12 (d, J=4.2 Hz, 1H), 7.01 (t, J=8.0 Hz, 1H), 4.19-4.12 (m, 2H), 3.93 (s, 3H), 2.45-3.30 (m, 6H), 2.51 (s, 6H), 2.14-1.93 (m, 6H), 1.33 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([CH:8]1[O:12][C:11](=[O:13])[CH:10]=[C:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:25]1>>[CH2:1]([CH:8]1[O:12][C:11](=[O:13])[C:10]([CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:25]2[N:24]([CH3:23])[C:32]3[C:27]([C:26]=2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[C:9]1[OH:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)NCCc1cn(C)c2ccccc12
Reactant: O=C1C=C(O)C(Cc2ccccc2)O1
Product: CC(=O)NCCc1c(C(C2=C(O)C(Cc3ccccc3)OC2=O)c2ccccc2)n(C)c2ccccc12

Procedure:
Using general procedure C, 5-benzyl-4-hydroxy-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(1-methyl-1H-indol-3-yl)-ethyl]-acetamide to give N-(2-{2-[(5-benzyl-4-hydroxy-2-oxo-2,5-dihydro-furan-3-yl)-phenyl-methyl]-1-methyl-1H-indol-3-yl}-ethyl)-acetamide as red solid. MS: 493.3 ([M−H]−).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][C@@H:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:6][CH2:5][CH2:4]1.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].O>N1C=CC=CC=1>[S:25]([O:1][CH2:2][C@@H:3]1[O:8][C@@H:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:6][CH2:5][CH2:4]1)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)cc1
Yield: 94.2 %

Procedure:
A solution of 5.10 g of 1-[trans-β-(6-hydroxymethyltetrahydropyran-2-yloxy)-2,4-dichlorophenethyl]imidazole in 40 ml of dry pyridine was stirred overnight at room temperature with 2.88 g of tosyl chloride. The reaction mixture was poured into water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 20:20:1 by volume mixture of benzene, ethyl acetate and ethanol, to give 6.8 g of the title compound, as a colourless liquid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCCCc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1ccc2ccccc2c1
Reaction time: 21 h
Yield: 85.5 %

Procedure:
Compound 59-1 (4.33 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (6.69 g) and N-bromosuccinimide (4.54 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and further at room temperature for 21 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (4.95 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](O)=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].C([O-])([O-])=[O:14].[Cs+].[Cs+].Br[C:20]([CH3:25])([CH3:24])[C:21]([NH2:23])=[O:22]>O1CCOCC1.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:23][C:21](=[O:22])[C:20]([OH:14])([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)C(N)=O
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CCOc1ccc(NC(=O)C(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of 4-ethoxyphenol (511 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 2 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(4-ethoxyphenyl) -2-hydroxy-2-methylpropionamide as an off-white solid (536 mg, 2.40 mmol, 64.8% yield).: mp 146-148° C. 1H NMR (400 MHz, CDCl3) δ 8.59 (br s, 1H, N--H), 7.45 (dd, 2H, Ar--H, J=9.0, 2.2 Hz), 6.84 (dd, 2H, Ar--H, J=9.0, 2.2 Hz), 4.00 (q, 2H, CH2 -CH3, J=7.1 Hz), 2.73 (br s, 1H, O--H), 1.53 (s, 6H, C(CH3)2), 1.39 (t, 3H, CH2 -CH3, J=7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 174.0, 155.7, 130.6, 74.0, 63.7, 27.9, 14.8; IR (KBr pellet) 1604, 1647 (amide C=O stretches), 3256 (NH stretch), 3281 (OH stretch); MS (CI/CH4) 224;
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.NCCN(CCN)CCN>ClCCl>[I:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: OCCN1CCOCC1
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(OCCN1CCOCC1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A 8 mL vial was charged with 2-morpholinoethanol (200 μL, 1.63 mmol), dichloromethane (5 mL), polystyrene-linked diisopropylamine (4.90 mmol), and 4-iodobenzoyl chloride (479 mg, 1.80 mmol), and the reaction mixture was shaken at room temperature. After 16 hours, the reaction mixture was charged with polystyrene-linked tris(2-aminoethyl)-amine (1.63 mmol), and shaken at room temperature for 2 hours. The reaction was filtered, and the resin was washed with dichloromethane (3×10 mL), tetrahydrofuran (2×10 mL), and diethyl ether (2×10 mL). The combined filtrates were concentrated in vacuo to give 2-morpholinoethyl 4-iodobenzoate (434 mg, 1.19 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([Cl:11])=[CH:9][C:8](Cl)=[N:7][C:6]=1[CH3:13])[CH3:2].[CH2:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[C:18]=1B(O)O)[CH3:16].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:18]2[C:19]([CH2:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:15][CH3:16])=[N:7][C:6]=1[CH3:13])[CH3:2]
Reactant: CCc1cccc(CC)c1B(O)O
Reactant: CCOC(=O)c1c(Cl)cc(Cl)nc1C
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: Cc1ccccc1
Product: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Temperature: 25 °C

Procedure:
A mixture of 4,6-dichloro-2-methyl-nicotinic acid ethyl ester (1.2 g, 5.1 mmol), 2,6-diethyl-phenyl boronic acid (2.18 g, 12.2 mmol), sodium carbonate (2 M aqueous solution, 12.2 mL, 24.4 mmol), and Pd(PPh3)4 (284 mg, 0.26 mmol) is refluxed in toluene for 48 hours and then cooled to room temperature. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2×50 mL). The organic Layers are combined, dried, and solvent removed. The crude product is purified by flash column (hexanes/ethyl acetate 8:1) to give 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid ethyl ester. 1H NMR: (CDCl3) 7.26 (t, 1H), 7.18 (s, 1H), 7.13 (d, 2H), 4.47 (q, 2H), 2.62 (s, 3H), 2.28 (q, 4H), 1.44 (t, 3H), 1.04 (t, 6H).
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:24]([C:25]2[NH:29][CH:28]=[C:27]([CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1.[S:40]1[CH:44]=[CH:43][N:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46]>O1CCCC1.O>[F:18][C:19]1[C:24]([C:25]2[N:29]([S:45]([C:41]3[S:40][CH:44]=[CH:43][N:42]=3)(=[O:47])=[O:46])[CH:28]=[C:27]([CH2:30][N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH:26]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1nccs1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2nccs2)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a suspension of sodium hydride (60% in oil, 31 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.16 mL), a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (183 mg) in tetrahydrofuran (1 mL) and 1,3-thiazole-2-sulfonyl chloride (160 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 168 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][N:8]=1)(=[O:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:34][C:35]([F:44])([F:43])[CH2:36][CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl.O>[F:34][C:35]([F:44])([F:43])[CH2:36][CH2:37][CH2:38][S:39]([O:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:6][S:3]([C:2]([F:1])([F:14])[F:15])(=[O:5])=[O:4])[CH:12]=1)(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)CCCC(F)(F)F
Reactant: O=S(=O)(Oc1cc(O)ccn1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(CCCC(F)(F)F)Oc1ccnc(OS(=O)(=O)C(F)(F)F)c1

Procedure:
Under argon, 550 mg (2.26 mmol) of 4-hydroxy-2-pyridinyl trifluoromethanesulfonate (Example 39A) are suspended in 15 ml of dichloromethane at room temperature. 2 ml of a 40% strength solution of tetrabutylammonium hydroxide in water are added dropwise to this. Then 476 mg (2.26 mmol) of 4,4,4-trifluoro-1-butanesulfonyl chloride are added and allowed to react for 20 minutes. Working up takes place by adding water, extracting with ethyl acetate, washing, drying and evaporating in a rotary evaporator. The residue is purified by chromatography on 20 g of silica gel (0.04-0.063 mm) with cyclohexane/ethyl acetate 2:1 to 1:1).