Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12](=[O:35])[C@H:13]([CH2:31][CH2:32][S:33][CH3:34])[NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>CN(C=O)C>[CH3:10][O:11][C:12](=[O:35])[C@H:13]([CH2:31][CH2:32][S:33][CH3:34])[NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:18][C:17]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CBr)cc1-c1ccccc1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a 0° C. suspension in DMF (2 mL) of sodium hydride (90% in mineral oil, 38 mg, 0.95 mmol) was added a solution of 3-hydroxypyridine (95 mg, 1.0 mmol) in DMF (2 mL) dropwise and the mixture was stirred for 0.5 hours. A solution of (4-bromomethyl-2-phenylbenzoyl)methionine methyl ester (218 mg, 0.5 mmol) in DMF (1 mL) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was poured into aqueous 2N sodium hydroxide and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were dried, filtered and concentrated in vacuo. Chromatography on silica gel (60% ethyl acetate-hexanes, then ethyl acetate) gave [4-(3-pyridyloxymethyl)-2-phenylbenzoyl]methionine methyl ester (58 mg). 1H NMR (300 MHz, DMSO-d6) δ 12.66 (bs, 1H), 8.58 (d, 1H), 8.38 (d, 1H), 8.17 (dd, 1H), 7.30-7.56 (m, 10H), 5.29 (s, 2H), 4.29 (ddd, 1H), 2.23 (m, 2H), 1.98 (s, 3H), 1.84 (m, 2H). MS (CI NH3) m/e 454 (M+NH4)+, 437 (M+H)+. Anal calcd for C24H24N2O4S (+0.41 H2O): C, 64.94; H, 5.64; N, 6.31. Found: C, 64.94; H, 5.35; N,S 6.14.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]2[NH:8][C:9](=[C:11]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[C:12]([NH2:14])=[O:13])[NH:10][C:6]=2[CH:5]=1)([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:60]1([CH2:66][CH2:67][CH2:68][NH2:69])[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1.[ClH:70]>CN(C)C=O.CC(=O)OCC.O1CCOCC1>[ClH:70].[N:60]1([CH2:66][CH2:67][CH2:68][NH:69][C:1]([C:4]2[CH:26]=[CH:25][C:7]3[NH:8][C:9](=[C:11]([C:15]4[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=4)[C:12]([NH2:14])=[O:13])[NH:10][C:6]=3[CH:5]=2)=[O:3])[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1
Reactant: NCCCN1CCOCC1
Reactant: NC(=O)C(=C1Nc2ccc(C(=O)O)cc2N1)c1nccc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC(=O)C(=C1Nc2ccc(C(=O)NCCCN3CCOCC3)cc2N1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a room temperature solution of 2-[5-carboxy-1H-benzimidazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (630 mg, 1.73 mmol) in dimethylformamide (20 mL) was added DIPEA (661 μL, 3.79 mmol, 2.2 eq.), HBTU (720 mg, 1.90 mmol, 1.1 eq.). After 5 min, 3-(4-morpholinyl)propan-1-amine (277 μL, 1.90 mmol, 1.1 eq.) was added and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with EA (50 mL) and washed three times with 5% aqueous sodium bicarbonate (50 mL each). The EA fraction was decanted, dried over magnesium sulfate, filtered, and concentrated under vacuum to give a yellow solid. About 2 mL of 4.0 M hydrogen chloride in dioxane was added, and the mixture was stirred for 15 min and then concentrated under vacuum to give 2-(5-{[3-(4-morpholinyl)propyl]aminocarbonyl}-1H-benzimidazol-2(3H)-ylidene)-2-(4-trifluoromethylpyrimidin-2-yl)acetamide hydrochloride (750 mg, 1.52 mmol, 88% yield) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15]Cl)[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:23][N:24]([CH3:29])[CH2:25][C:26]([OH:28])=[O:27]>C(#N)C>[CH3:23][N:24]([CH3:29])[CH2:25][C:26]([O:28][CH2:15][C:13]1[N:14]=[C:7]2[C:6]([NH:5][CH2:4][C:3]3[C:2]([CH3:1])=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:22])=[CH:11][CH:10]=[CH:9][N:8]2[C:12]=1[CH3:17])=[O:27]
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Reactant: CN(C)CC(=O)O
Solvent: CC#N
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(COC(=O)CN(C)C)nc12
Yield: 31.5 %

Procedure:
8-(2,6-dimethylbenzylamino)-2-chloromethyl-3-methylimidazo[1,2-a]pyridine (0.3 g, 1.0 mmol) and N,N-dimethylglycine (0.1 g, 1.0 mmol) were added to acetonitrile (10 ml) and the mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using, dichloromethane:methanol (10:2) as eluent. Recrystallization from acetonitrile gave 0.12 g (32%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:44])[CH2:27][N:28]3[C:36]4[C:35]([F:38])([F:37])[CH2:34][CH2:33][C:32]([F:40])([F:39])[C:31]=4[C:30]([CH:41]([F:43])[F:42])=[N:29]3)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=2)[CH:5]=[CH:4]N=N1.[O:55]1CCN(CCN)[CH2:57][CH2:56]1.BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:42][CH:41]([F:43])[C:30]1[C:31]2[C:32]([F:40])([F:39])[CH2:33][CH2:34][C:35]([F:38])([F:37])[C:36]=2[N:28]([CH2:27][C:26]([NH:25][C@H:15]([C:13]2[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=[C:9]([NH:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][O:55][CH2:56][CH2:57]3)[N:14]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:44])[N:29]=1
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Reactant: NCCN1CCOCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NCCN3CCOCC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (28) was prepared according to the method presented for the synthesis of compound 23F of Example 23 starting with 2-morpholinoethanamine and 23B. 1H NMR (400 MHz, CD3OD) δ 8.76 (d, J=7.8 Hz, 1H), 8.14 (s, 1H), 7.46-7.32 (m, 2H), 7.22 (dd, J=10.7, 8.5 Hz, 1H), 7.00-6.59 (m, 2H), 6.43 (d, J=6.2 Hz, 2H), 5.23 (m, 1H), 5.02 (q, J=16.6 Hz, 2H), 3.97 (m, 6H), 3.70-3.39 (m, 6H), 3.10-2.93 (m, 2H), 2.66-2.38 (m, 4H). MS (m/z) 785.29 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](O)(=[O:35])[CH3:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:33]([O:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10]1)(=[O:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(=O)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred mixture of (2S,4R)-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethy-4-hydroxypyrrolidine (21.7 g, 47.6 mmol), acetic acid (3.0 ml, 52.4 mmol) and PPh3 (12.5 g, 52.4 mmol) in THF (330 ml) was added DIAD (9.4 ml, 47.6 mmol) at room temperature under an atmosphere of nitrogen. After 2 h stirring the same temperature, the mixture was heated at 50° C. for 2 h . After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel [1 Kg, n-hexane/EtOAc(5/1)], to give (2S,4S)4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethypyrrolidine (23.3 g, 99%) as a colorless oil. 1H-NMR (CDCl3) δ 1.06 (s, 9H), 1.35 and 1.43 (s, 9H, amide isomers), 1.92 (br, 3H), 2.20–2.45 (m, 2H), 3.31–4.07 (m, 5H), 5.17–5.30 (m, 1H), 7.36–7.44 (m, 6H), 7.65–7.71 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18]([CH:20]([NH2:23])[CH2:21][CH3:22])[CH3:19].C([O-])(=O)C.[K+]>[Cu].O>[CH2:18]([CH:20]([NH:23][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Reactant: CCC(N)CC
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 180 °C

Procedure:
A Parr stainless steel high pressure reactor was charged with 1-chloroanthraquinone (24.3 g), 1-ethylpropylamine (17.5 g), potassium acetate (14.0 g), activated copper metal (0.7 g), and water (0.05 g). The reaction vessel was sealed and heated to a temperature of 180° C. in an oil bath for 12 hours. The oil bath was removed and the vessel was allowed to return to ambient conditions. The solid was extracted with methylene chloride and the insoluble materials removed by filtration. The solvent was removed and the solid recrystallized from hot methanol. The material was chromatographed on a silica gel column using toluene as the eluent.
Reaction SMILES: OC1C=CC(C2C=CC(O)=CC=2)=CC=1.[OH-].[K+].CC(CC)CBr.[CH3:23][CH:24]([CH2:45][CH3:46])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([O:39]CC(C)CC)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.Cl>C(O)C>[CH3:23][CH:24]([CH2:45][CH3:46])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: CCC(C)COc1ccc(-c2ccc(OCC(C)CC)cc2)cc1
Agent: CCC(C)CBr
Agent: Cl
Agent: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1

Procedure:
A mixture of 4,4'-dihydroxybiphenyl (500 g), ethanol (7.5 l) and KOH (302 g) was heated under reflux with stirring, and (+) 2-methylbutyl bromide (prepared from (-)2-methylbutanol with phosphorus bromide)(530 g) was dropwise added for 4 hours to react them, followed by distilling off ethanol, adding water (2 l), filtering, collecting an insoluble substance, and treating this insoluble substance with toluene to remove a soluble substance. This soluble part was recrystallized from ethanol to give scaly crystals of m.p. 80.5° C., which was confirmed to be di-(2-methylbutyloxy)-biphenyl. On the other hand, the above insoluble part was heated together with hydrochloric acid with stirring, followed by cooling, collecting the resulting solid substance and recrystallizing it from toluene and then from ethanol to obtain 4'-(2-methylbutyloxy)-4-hydroxybiphenyl of m.p. 137.5° C. (125 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.[S:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:43][C:39]3[S:38][CH:42]=[CH:41][N:40]=3)(=[O:24])=[O:25])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccs1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (INTERMEDIATE LLL) (425.75 mg, 0.775 mmol), thiazol-2-amine (78 mg, 0.775 mmol), and THF (3875 μl) was cooled in an ice-water bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (1627 μl, 1.627 mmol) was added drop wise. After 30 min, the mixture was warmed to room temperature and loaded onto a 25-g silica gel loading column with DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 40-g silica gel column with 0 to 10% MeOH/DCM to give a yellow solid. The mixture was concentrated from DCM (2×). The residue was then taken up in DCM, sonicated, filtered, washed with DCM (3×), and dried under a stream of N2 (g) to give a white solid. The white solid was crushed with a spatula then dried under high vacuum to give 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (271 mg, 0.582 mmol, 75% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.69 (d, J=5.7 Hz, 1H), 8.55 (d, J=1.8 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 7.87 (dd, J=1.9, 8.9 Hz, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.60-7.45 (m, 3H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.74 (s, 3H); m/z (ESI) 466.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccccn1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), potassium carbonate (0.77 g), 2-(bromomethyl)pyridine hydrobromide (1.06 g) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 69%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([N:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:22]([CH:24]([CH2:36][CH2:37][CH3:38])[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=[O:23])C1C=CC=CC=1>C1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:12][C:13]([C:22]([CH:24]([CH2:36][CH2:37][CH3:38])[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=[O:23])=[CH:14]2
Reactant: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2n1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CCCC(Cc1ccc(C(=O)OC)cc1)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h

Procedure:
To flask containing AlCl3 (1.57 g, 11.7 mmol) was added a solution of the title compound of Example 3 Step C (1.39 g, 2.94 mmol) in benzene (8.0 mL). After 1 h, the reaction mixture was quenched by addition of sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc, and organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25%, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS A, tr=4.03 min, m/z 384.3 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.68 (s, 1H), 7.40-7.28 (m, 4H), 7.07 (d, J=1.5 Hz, 1H), 3.92 (s, 3H), 3.63 (dddd, J=8.0, 8.0, 6.0, 6.0 Hz 1H), 3.22 (dd, J=14.0, 8.5 Hz, 1H), 2.93 (dd, J=14.0 Hz, 6.0 Hz, 1 H), 1.92-1.84 (m, 1H), 1.66-1.59 (m, 1H), 1.41-1.34 (m, 2H), 0.93 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7]Br.C([O-])(O)=[O:14].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[O:3][C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]=1[CH2:7][OH:14]
Reactant: O=C([O-])O
Reactant: BrCc1c(Br)oc2ccccc12
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1c(Br)oc2ccccc12
Temperature: 25 °C

Procedure:
2-bromo-3-bromomethyl benzofuran prepared from Step A (7.67 g, 26.45 mmol) was immediately dissolved in dioxane (30 mL), followed by a solution of NaHCO3 (2.67 g, 1.2 eq.) in water (30 mL). The mixture was refluxed for 1 h with vigorous stirring, cooled to room temperature, diluted with water (150 mL) and extracted with dichloromethane (5×100 mL). The extract was washed with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. The resulting orange oil was dissolved in chloroform (12 mL) and left to stand at −20° C. The resulting yellow prisms were filtered at −40° C., washed with chloroform, and filtered cold. Yield: 3.72 g (62%). MS (m/e): 228, 226 (M+), 211, 209, 183, 181, 171, 169, 147, 118, 102, 91. 1H-NMR (acetone-D6): 4.29 (t, 1H, J=6 Hz) 4.73 (d, 2H, J=6 Hz) 7.32 (m, 2H) 7.51 (d, 1H, J=8 Hz) 7.78 (dd, 1H, J=8 Hz, 2 Hz). 13C-NMR (acetone-D6): 54.74, 110.64, 119.96, 123.28, 124.57, 126.51, 128.12, 155.37.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:19]([CH3:20])[C:18]([C:21](=[O:23])[CH3:22])=[CH:17][C:16]=1[C:24]([N:26]1[CH2:29][CH:28]([OH:30])[CH2:27]1)=[O:25].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:18]1[N:19]([CH3:20])[C:15]([NH:14][C:8]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:7]=2[F:6])=[C:16]([C:24]([N:26]2[CH2:29][CH:28]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:27]2)=[O:25])[CH:17]=1)(=[O:23])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(C(=O)N2CC(O)C2)c(Nc2ccc(I)cc2F)n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(C(=O)N2CC(OS(C)(=O)=O)C2)c(Nc2ccc(I)cc2F)n1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
Methane sulfonyl chloride (0.026 ml, 0.33 mmol) was added dropwise at 0° C. to a stirred solution of Example 27 (102 mg, 0.22 mmol) and triethyl amine (0.047 ml, 0.33 mmol) in CH2Cl2 (1.2 mL). After stirring for 10 min at 0° C., the reaction mixture was allowed to warm up at room temperature. After stirring for 2 hours, the reaction mixture was washed with a saturated solution of NaHCO3, extracted with CH2Cl2. The organics were washed with and brine, dried (MgSO4), and concentrated. Purification by silica gel chromatography gave 100 mg (84%) of the title compound as beige solid. MS (ES) [m+H] calc'd for C18H19FIN3O5S, 536; found 536.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](Cl)(=[O:19])=[O:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:30]>>[CH2:1]([C:8]1[C:16]([S:17](=[O:19])(=[O:18])[NH2:30])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(Cc2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(OCc2ccccc2)c1Cc1ccccc1
Reaction time: 4.5 h

Procedure:
4-Benzyl-3-benzyloxy-5-chlorosulfonylbenzoic acid (1.0 g) is in portions added to conc. ammonium hydroxide (10 ml) while stirring at 10°-12° C. After additional stirring at room temperature for about 20 hours, the mixture is left in a refrigerator for 4-5 hours. The separated ammonium salt is then collected by filtration and washed with a small amount of ice-cold water. After drying, the salt is dissolved in hot water (20 ml), and the solution is clarified by filtration hot in the presence of decolorizing carbon. The solution is then acidified with 4 N HCl (2.0 ml) and, after cooling, the resulting precipitate is collected by filtration, washed with water and dried. After recrystallization twice from ethanol, 4-benzyl-3-benzyloxy-5-sulfamylbenzoic acid is obtained with a melting point of 249.5°-251° C.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C@@H:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.O>C1COCC1>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N[C@H]1CCc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(N[C@H]2CCc3ccccc32)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of cyanuric chloride (631 mg, 3.42 mmol) in THF (2.00 mL) at 0° C. was added (S)-(+)-1-aminoindan (0.385 mL, 3.00 mmol) and DIPEA (0.596 mL, 3.42 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction was then poured into H2O, extracted with DCM and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 20% EtOAc in hexanes to afford the title compound as a yellow solid (738 mg, 87%). LC/MS: Rt=1.99 min, ES+ 281 (FA standard).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])[N:7]=1
Reactant: Cc1cccc(N)c1C
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(Nc2nc(Cl)nc(Cl)n2)c1C
Temperature: 5 °C

Procedure:
A solution of cyanuryl chloride (18 g) in hot acetone (70 ml) is poured under stirring into water (40 ml). To the so obtained suspension is added, while keeping the temperature to 5° C., 2,3-xylidine (24 ml). Stirring is maintained for 1 hour at 5° C.; then the reaction mixture is filtered, the precipitate is washed with water to neutrality; it is dissolved in ethyl acetate; the solution is dried over Na2SO4. By concentration 16.8 g of the desired compound are obtained. M.p. 186°-188° C. (ethyl acetate/hexane).
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])=[CH:11][CH:10]=1)(=O)=O.O[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:20][C:19]([F:22])([F:21])[S:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][O:6][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)=[CH:10][CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(OCCc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 0.85 g (2.11 mmole) of 4-(trifluoromethylsulfonyloxy)phenethyl trifluoromethansulfonate, 0.27 g (2.2 mmole) p-hydroxybenzaldehyde and 0.72 g (2.2 mmole) cesium carbonate in acetonitrile was stirred at room temperature over night. The salts were filtered off and the solvent evaporated in vacuo. Purification by chromatography on silica gel using dichloromethane as eluent gave 0.6 g (yield 75%) of 4-[2-(4-formylphenoxy)ethyl]phenyl trifluoromethanesulfonate.