Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10].CO.O.[OH-].[Na+]>C1COCC1>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][C:23]1[CH:22]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=2[CH3:1])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3C)cc(OCc3ccccc3C)c2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1COc1cc(OCc2ccccc2C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Yield: 94.5 %

Procedure:
Methyl 6-[(3,5-di-(2-methylbenzyloxy)benzoyl)amino]-3-pyridinecarboxylate (61 mgs) was stirred at ambient temperature in a mixture of THF (4 ml), methanol (1 ml) and water (1 ml) with 2M sodium hydroxide (0.3 ml, xs). After four hours the solvent was removed, under reduced pressure, water (5 ml) added and the pH adjusted to neutral. This gave a white precipitate which was filtered off, washed with water, dried to give the title compound (56 mgs, 94%). MS [MH]+ 483
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([Br:13])[CH:9]=[CH:10][C:11]=1[F:12]>OS(O)(=O)=O>[Br:13][C:8]1[CH:7]=[C:6]([F:5])[C:11]([F:12])=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: Fc1ccc(Br)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Fuming nitric acid (24 mL) was dissolved in concentrated H2SO4 in a round bottom flask. 3,4-Difluorobromobenzene (20 g, 104 mmol) was added dropwise via pipette with vigorous stirring. After addition was complete, the reaction was allowed to stir at room temperature for 2 hours. The reaction was poured into ice water and extracted 2×250 mL with Et2O. The organic layers were collected, combined, dried over MgSO4, filtered, and the solvent removed leaving a light yellow oil (24.02 g, 97% yield) of 1-bromo-4,5-difluoro-2-nitro-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)(O)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH3:33])[C:10](=[O:34])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.CO.C(Cl)(Cl)Cl.[NH4+:41].[OH-]>S(Cl)(Cl)=O>[NH2:41][C:18]([C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([C:19]1[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=1)[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:33])[C:10](=[O:34])[CH:9]=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [NH4+]
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Cn1cncc1C(N)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
4-(3-Chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-1H-quinolin-2-one (2 g, 4.08 mmol) was dissolved in 25 ml of thionyl chloride (SOCl2) and stirred at room temperature under an atmosphere of dry N2 for 2 hours. Thiony chloride was removed under reduced pressure. The crude chloride was taken up in toluene and concentrated under vacuum. The resulting solid was dissolved in THF (20 mL) and to this solution was bubbled ammonia gas (NH3) for 30 minutes. The reaction mixture was stirred at ambient temperature under an atmosphere of NH3 for 15 hours. After removal of THF, the product mixture was partitioned between CHCl3 and water. The organic layer was washed, dried over MgSO4 and concentrated under vacuum to give a brown solid. This was chromatographed on silica gel with CHCl3 then MeOH-CHCl3—NH4OH (1:99:0.1) as eluents to afford the titled compound as a white solid (1.065 g, 2.02 mmol, 50% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:30])OC(C)(C)C)[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1.[C:35](O)(C(F)(F)F)=O.C(Cl)Cl.CCN(CC)CC.C(C1NC=CN=1)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH3:35])[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([I:20])[CH:18]=2)[O:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(C)CCOc2ccc(I)cc21
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)c1ncc[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(C)CCOc2ccc(I)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a CH2Cl2 (5 ml) solution of tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-chromen-4-yl)amino]propylcarbamate (Diastereomer B). (0.47 g, 0.79 mmol), at r.t., was added 25 ml of 20% TFA/CH2Cl2. The mixture was stirred at r.t for 30 min. The solvent was removed in vacuo and the residue dissolved in CH2Cl2 (75 ml) and washed with aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield a white foam. The residue was dissolved in CH2Cl2 (5 ml) and chilled to 0° C. followed by the addition of Et3N (0.24 ml, 1.7 mmol) and acetyl imidazole (0.10 g, 0.90 mmol). The mixture was then warmed to r.t. and stirred overnight. The reaction mixture was diluted with CH2Cl2 (25 ml) and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield a white foam (0.35 g, 84%) after flash chromatograph 5% MeOH/CHCl3 (Biotage 40 S). Rf=0.29. HRMS (ESI+) calcd for C22H25N2O3IF2+1H calcd m/z 531.0958; found 531.0958 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([C:7]1([C:16]([F:19])([F:18])[F:17])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)[C:3]([F:6])([F:5])[F:4].[N+:20]([O-])([OH:22])=[O:21].S(=O)(=O)(O)O>C(Cl)Cl>[N+:20]([C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([CH:2]([Cl:1])[C:3]([F:6])([F:5])[F:4])([C:16]([F:19])([F:18])[F:17])[O:11][C:10]=2[CH:12]=1)([O-:22])=[O:21]
Reactant: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
613 g of 2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 2a were dissolved in 1.2 l of methylene chloride, and the solution was added dropwise at 0° to 10° C. to a mixture of 400 ml of 65% strength nitric acid and 400 ml of concentrated sulphuric acid. The mixture was stirred at room temperature for a further 2 hours. It was then added carefully to 2 l of ice-water and extracted with methylene chloride. The combined organic phases were washed 2 times with water, dried and concentrated. The yield was 652 g (93% of theory). The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.4 and -79.2 ppm; 1H-NMR: 4.81 ppm.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:11]2[O:10][C@@H:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)Cc2scc(-c3ccccc3F)c2O1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A mixed solution of tert-butyl (2S)-8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (681 mg) obtained in Example 12, steps 1-4, (2-fluorophenyl)boronic acid (356 mg), dichlorobis(triphenylphosphine)palladium (68 mg) and potassium carbonate (809 mg) in DME-water (1:1, 20 mL) was stirred at 85° C. for 4 hr under a nitrogen stream. The reaction solution was cooled to room temperature, and water was added. The mixture was filtered through celite, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 5→15% ethyl acetate/hexane) to give the title compound (694 mg, 98%) as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:5]=2[O:4]1.O.[OH:16][CH2:17][CH:18](CO)[OH:19]>>[OH:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1[O:11][CH2:3][CH:18]([OH:19])[CH2:17][OH:16]
Reactant: OCC(O)CO
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC(O)CO)c(O)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
0.3 mol (19.8 g) of 85% by weight potassium hydroxide pellets is dissolved in 210 ml of glycerol, and 0.25 mol (41.75 g) of 3,4-methylenedioxynitrobenzene is then added, with stirring. After heating for one and a half hours in the region of 110° C., the reaction medium is poured into 1.5 liters of iced water. The mixture is filtered in order to remove a small quantity of starting material. The filtrate is acidified to pH=4 with hydrochloric acid and then treated with 10 g of vegetable charcoal. After stirring for a few minutes at ambient temperature and removal of the vegetable charcoal by filtration, the solution is left to stand overnight at 0° C. and the expected product which has crystallized is then filtered off. After recrystallization from ethanol and drying in vacuo, the product melts at 148° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl[S:28]([OH:31])(=[O:30])=[O:29].C(=O)([O-])[O-].[K+:36].[K+]>N1C=CC=CC=1>[S:28]([O-:31])([O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1)(=[O:30])=[O:29].[K+:36]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cccnc2Nc2ccc(OS(=O)(=O)[O-])cc2)cc1
Reaction time: 72 h

Procedure:
2.0 g (5.38 mmol) of the compound of Example 6 was dissolved in 20 ml of pyridine. 800 mg (6.87 mmol) of chlorosulfonic acid (95%) was added dropwise thereto at -15° to -10° C. The temperature was slowly elevated to room temperature and the mixture was stirred for 3 days. A 1N aqueous potassium carbonate solution was added to the reaction mixture to adjust the pH to 8 to 9. The solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue and an aqueous layer thus formed was separated, concentrated, purified by silica gel column chromatography and precipitated with methanol/dichloromethane to obtain 1.58 g of the title compound.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](=[O:12])([O-])[O-:10].[K+].[K+]>CN(C)C=O.[Cu]I>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[C:9]([OH:10])=[O:12])=[CH:1][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)cc1
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 90.3 %

Procedure:
To a solution of 5.95 g of p-cresol and 7.83 g of 2-chlorobenzoic in 50 mL of dimethylformamide at 25° was added, in portions, 14.50 g of anhydrous potassium carbonate. The resulting mixture was heated to 80°, and 0.10 g of copper(I) iodide was added. The reaction mixture then was refluxed for 16 hours. While still hot the mixture was poured onto water-ice. The resulting suspension was filtered, and the filtrate was adjusted to pH 3.0 using aqueous hydrochloric acid. The precipitate was recovered by filtration. The crude solid was dissolved in an aqueous sodium hydroxide solution. This solution was acidified to pH 6.0 using hydrochloric acid, filtered, and then acidified to pH 3.0. Filtration provided 5.67 g of 2-(4-methylphenoxyl)benzoic acid which was employed in the following reaction without further purification. NMR (200 MHz, CDCl3): δ 8.15 (d of d, 1H); 7.42 (d of d of d, 1H); 7.23-7.12 (m, 3H); 6.97 (d, 2H); 6.80 (d, 1H); 2.37 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1.Cl>ClCCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccccc1N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
(RK1-1-22) I A solution of 4-nitrobenzenesulfonyl chloride (200 mg, 0.90 mmol), o-toluidine (106 mg, 0.99 mmol), and pyridine (79 mg, 0.08 ml, 0.993 mmol) in 5.0 mL 1,2-dichloroethane was heated to 150° C. for 10 minutes in the microwave. A 1M HCl solution was added until the pH of the mixture indicated pH=2, and the acidified aqueous layer was separated and extracted with CH2Cl2 (3×10 mL). The combined organic fractions were washed successively with brine and water then dried over Na2SO4 and evaporated to dryness to afford the title compound as a peach solid (127 mg, 47%). Mp=139-142° C. (lit. 157-159° C., Tetrahedron 62(25), 6100-6106; 2006); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=9.0 Hz, 2H), 7.89 (d, J=9.0 Hz, 2H), 7.28-7.27 (m, 1H), 7.20-7.12 (m, 3H), 6.30 (br s, 1H), 2.01 (s, 3H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4]([O:7][C@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([C:14]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])=O)[CH2:9]1)(=[O:6])=[O:5].CO>O1CCCC1.C(OCC)(=O)C>[CH3:3][S:4]([O:7][C@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([CH2:14][N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:9]1)(=[O:5])=[O:6]
Reactant: CN1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCNC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CN1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNC1=O
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a solution of sodium borohydride (0.60 g) in tetrahydrofuran (25 ml) was added dropwise boron trifluoride ether complex (5.8 ml) under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. To the mixture was added a solution of (2S,4R)-4-methanesulfonyloxy-1-methyl-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (2.3 g) in tetrahydrofuran (15 ml) and the mixture was stirred at the same temperature for 5 hours. To the reaction mixture was added dropwise methanol (15 ml) under ice-cooling. The mixture was filtered off and the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (50 ml) and conc. hydrochloric acid (2 ml) and the solution was stirred at ambient temperature overnight The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (50 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-methyl-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.89 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: Nc1ccc(CCO)cc1
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A mixture of 2-chloro-5-methylsulfonylnitrobenzene (Kavalek, J.; et al. Collect. Czech. Chem. Commun, 1971, 36, 209., 2 g, 8.5 mmol), 4-aminophenylethyl alcohol (1.4 g, 10.2 mmol) and Na2CO3 (1.4 g, 12.7 mmol) in ethanol was stirred at 100° C. for 16 h. The insoluble matter was removed by filtration and washed with ethanol (100 mL). The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:4) to afford 960 mg (34%) of the title compound as yellow solids: 1H-NMR (CDCl3) δ 9.84 (1H, br.s), 8.82 (1H, d, J=2.1 Hz), 7.79 (1H, dd, J=2.1 Hz, 9.1 Hz), 7.36 (2H, d, J=8.4 Hz), 7.22-7.38 (3H, m), 3.94 (2H, br.s), 3.07 (3H, s), 2.93 (2H, t, J=6.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[NH2:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[NH:14][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NC1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A solution of 2.0 g (10.4 mmol) of 7-nitro-1,2,3,4-tetrahydro-1-naphthylamine in 35 ml of THF was treated with ice-cooling with 4.2 g (41.6 mmol) of triethylamine and 1.3 g (11.4 mmol) of methanesulfonyl chloride and then stirred at RT for 2 hrs. After addition of 20 ml of water, the mixture was concentrated in vacuo down to a 10 ml residue, then treated with a further 20 ml of water, and the precipitated product was filtered off with suction. After drying in vacuo, 2.5 g of N-(7-nitro-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide were obtained; m.p. 150-152° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@:7]([CH3:17])([C:14]([NH:34][CH2:33][CH2:31][OH:32])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(C(=O)NCCO)O2
Yield: 77.2 %

Procedure:
Following the amide coupling procedure described in protocol A, 5.06 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (20.2 mmol), 3.68 g CDI (22.7 mmol) and 2.44 g ethanolamine (39.52 mmol) produced 4.576 g of (S)-6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a white powder.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10][CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1.[OH2:26].[OH:27]OS([O-])=O.[K+]>ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:27])=[O:26])=[N:8][CH:9]=1
Reactant: O
Reactant: O=S([O-])OO
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cn2)c2ccncc2)c1
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cn1)C(c1ccncc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 26 %

Procedure:
To a methanol (6 ml) solution of 5-chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl)thio]pyridine (239 mg, 0.68 mmol) was added a water (12 ml) solution of oxone (potassium peroxomonosulfate compound, 2KHSO5.KHSO4.K2SO4) (631 mg, 1.03 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 3 days, dichloromethane was added thereto. The resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (using a mixed solvent system of water/acetonitrile/formic acid). The solid thus obtained was washed with hexane/diisopropyl ether and then collected by filtration to give the title compound (67 mg, 0.18 mmol, 26%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:12]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.200 g; 1.32 mmol), benzeneboronic acid (0.323 g; 2.65 mmol), copper acetate (0.481 g; 2.65 mmol) and pyridine (0.214 mL; 2.65 mmol) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 40% ethyl acetate in heptane) to yield 0.164 g (54%) of the title compound as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:25]=[C:24]2[C:26]3=[C:27]4[C:17]([CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[CH:23]2)=[CH:16][CH:15]=[C:14]3[CH:13]=1.Br[CH2:29][C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>C(#N)C>[Br-:10].[CH:13]1[C:14]2[C:26]3=[C:27]4[C:17](=[CH:16][CH:15]=2)[CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[CH:23][C:24]3=[CH:25][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:29][C:30]2[CH:39]=[N:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)[CH:4]=1
Reactant: BrCc1cnc2ccccc2n1
Reactant: BrCc1cc2ccc3cccc4ccc(c1)c2c34
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2cc3ccc4cccc5ccc(c2)c3c45)cn1Cc1cnc2ccccc2n1
Product: [Br-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)pyrene (2.95 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. 2-(Bromomethyl)quinoxaline (2.23 g, 10.0 mmol) will be added to the filtrate and the mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure to yield the product