Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[F:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: Fc1cnc2[nH]ccc2c1I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(F)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To a stirring suspension of sodium hydride (0.595 g, 24.81 mmol) in N,N-dimethylformamide (74.2 ml) was added a solution of 5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (5 g, 19.08 mmol, Adesis) in N,N-dimethylformamide (10.60 mL). The mixture was stirred under nitrogen for about 30 minutes. para-Toluenesulfonyl chloride (4.00 g, 20.99 mmol) in N,N-dimethylformamide (10.60 ml) was added, and the reaction stirred at room temperature for about an hour. The reaction was quenched by the slow addition of the reaction mixture to a stirring ice-water solution (about 100 mL). The resulting mixture was filtered, and the solid was collected and dried under vacuum overnight to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.09 (d, 1H), 7.98 (d, 2H), 7.43 (d, 2H), 6.67 (d, 1H), 2.35 (s, 3H). MS ESI(+) m/z 416.31 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[N:2]1.OS(O)(=O)=O.[CH3:14]O>>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:14])=[O:7])=[N:2]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc[nH]n1

Procedure:
1H-Pyrazole-3-carboxylic acid (15 g, 133.8 mmol) was dissolved in MeOH (250 ml). Concentrated H2SO4 (30 ml) was added to the solution. The resulting mixture was refluxed for 12 h and concentrated. The residue obtained was quenched by saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was concentrated. Yield 12.05 g. 1H-NMR (400 MHz; CDCl3): δ 3.98 (s, 3H), 6.86 (d, 1H), 7.85 (d, 1H), 11.9 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)[CH:13]=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].C=O.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:32][C:27]1[CH:26]=[C:25]([C:19]2([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=[C:16]([C:14]3[CH:13]=[CH:12][C:3]([C:4]([NH:6][CH2:7][C:8]([F:10])([F:9])[F:11])=[O:5])=[C:2]([NH:1][CH3:35])[CH:15]=3)[CH2:20]2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
In a solution of 0.25 g of 2-amino-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-N-(2,2,2-trifluoroethyl)benzoic acid amide (Compound of the present invention No. 5-329) synthesized in Synthetic Example 12 and 0.06 g of 36% formaldehyde aqueous solution in 7 ml of 1,2-dichloroethane, 1.00 g of sodium triacetoxy borohydride was added with stirring at room temperature in three portions at 1 hour-interval, and continued to stir at the same temperature for further 2 hours. After the completion of the reaction, the reaction mixture was poured to 5 ml of ice water, the organic phase was collected, and the solvent was distilled under reduced pressure. The residue was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (0:1 to 1:3 gradient), and 0.13 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylamino-N-(2,2,2-trifluoroethyl)benzoic acid amide was obtained as pale yellow crystal, and 0.13 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-dimethylamino-N-(2,2,2-trifluoroethyl)benzoic acid amide was obtained as pale yellow resinous substance. 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylamino-N-(2,2,2-trifluoroethyl)benzoic acid amide;
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].NC[C@@H]1CCCN1CC.C(=O)C>>[CH3:14][S:15]([N:11]1[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: CC=O
Agent: CCN1CCC[C@H]1CN
Product: CS(=O)(=O)N1CC[C@H](N)C1

Procedure:
By using (S)-(−)-3-(t-butoxycarbonylamino)pyrrolidine (2.0 g) and methanesulfonyl chloride (1 ml) as starting materials, the title compound (1.03 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).
Reaction SMILES: [CH2:1]([N:8]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:9]([CH:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[N+:29]([O-])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[O:21][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([N:8]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(C(Cc1ccccc1)Oc1ccc(F)cc1[N+](=O)[O-])N(Cc1ccccc1)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)ccc1OC(Cc1ccccc1)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1

Procedure:
2.95 g (5.73 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-4-phenyl-butyric acid in 59 ml methanol were hydrogenated with 1.76 g Raney-Nickel. Filtration and removal of the solvent by distillation yielded 2.26 g (81%) racemic (2S,3R and 2R,3S)-3-(2-amino-4-fluoro-phenoxy)-2-dibenzylamino-4-phenyl-butyric acid as light yellow oil, MS m/e (%): 485.5 (M+H+, 100).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1.[O:29]([CH2:36][CH2:37][CH2:38]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:7][O:8][C:9]1[C:26]([O:27][CH3:28])=[CH:25][C:12]2[CH:13]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][N:15]([CH2:38][CH2:37][CH2:36][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17][C:11]=2[CH:10]=1
Reactant: COc1cc2c(cc1OC)C(Oc1ccccc1)CNCC2
Reactant: BrCCCOc1ccccc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)C(Oc1ccccc1)CN(CCCOc1ccccc1)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A mixture of 7,8-dimethoxy-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine of Example 35 (4.8 g, 16 mmole) and 3-phenoxypropyl bromide (4 g, 18 mmole) in 25 ml DMF containing potassium carbonate (milled, 4.4 g, 32 mmole) was stirred at 80° C. for two hours. After cooling, the mixture was stirred with 300 ml water and was extracted with ethyl acetate-ether. The organic extract was washed with water, saturated NaCl and was dried (anhydrous MgSO4), filtered and evaporated to 9 g of an oil. This oil was purified by HPLC (silica gel, 10% ethyl acetate/dichloromethane) to give 4.7 g (68%) of 7,8-dimethoxy-3-(3-phenoxypropyl)-1-phenoxy-2,3,4,5-tetrahydro-3-benzazepine solid, m.p. 95°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]=[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:9][CH:8]=1)[CH3:6]>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:11][CH:12]=1)[CH3:6]
Reactant: COC(=O)C=C(C)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC(C)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2'4'-difluoro-4-biphenylyl)-2-butenoic acid methyl ester in 20 ml. of ethanol is hydrogenated on 0.1 g. of 5% Pd-C under 1 atmosphere at 20° until the reaction has ceased. The mixture is filtered and the filtrate is evaporated to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(#N)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][O:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:12])[C:8]=2[CH:9]=[CH:10][CH:11]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a stirred mixture of 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (10.0 g, 61.7 mmol) and cesium carbonate (58.5 g, 180 mmol) in acetonitrile (300 mL) was added tert-butyl bromoacetate (29.0 g, 148 mmol) at room temperature under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered through a pad of Celite® (a diatomite filter), and washed with ethyl acetate (100 mL). The combined filtrates were concentrated under reduced pressure. The residue was partitioned between ethyl acetate (500 mL) and water (200 mL×3). The organic layer was concentrated under reduced pressure. Column chromatography (silica gel, 100-200 mesh, 5-10% ethyl acetate in hexane) gave (5-oxo-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (12.1 g, 71%). MS cald. for C16H20O4 276, obsd. 277 [(M+H)+].
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:3]1=[O:21].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C@:38](S(C)(=O)=O)([CH2:44][CH2:45][CH2:46][CH3:47])C(OCC)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([CH2:38][CH2:44][CH2:45][CH2:46][C@H:47]([NH:1][C@@H:2]2[CH2:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:3]2=[O:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:36][CH2:37]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: CCCC[C@](C(=O)OCC)(C1CCN(C(=O)OCc2ccccc2)CC1)S(C)(=O)=O
Product: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H]1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 90 °C
Yield: 47.4 %

Procedure:
A mixture of 0.32 g of tert-butyl (RS)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate and 0.2 g of ethyl (R)-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonylhexanoate is heated at 90° C. for 30 minutes. After cooled, the mixture is separated and purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give 0.14 g of tert-butyl 3(R)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate as colorless oil from the first fraction.
Reaction SMILES: [C:1]1([C:7]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:8][CH2:9][C@@H:10]2[O:16][C@H:15]([CH2:17][O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:13]([OH:14])[C@@H:11]2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:52](Br)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CO>CN(C)C=O>[C:53]1([CH2:52][O:14][C@H:13]2[C@H:11]([O:12][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@@H:10]([CH2:9][O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[O:16][C@H:15]2[CH2:17][O:18][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O[C@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: c1ccc(CO[C@H]2[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 165.7 %

Procedure:
A solution of 800 mg of 2,5-anhydro-1,6-bis-O-(triphenylmethyl)-D-glucitol in 16 ml of dry dimethylformamide was treated with 240 mg of freshly washed sodium hydride. The mixture was stirred 1.5 hours, then 1.30 g of benzyl bromide was added and stirring continued for 2.5 days. Methanol was added, the solvents removed in vacuo and the residue taken up in chloroform/water. The organic layer was washed with water and brine, then dried and evaporated, giving a yellow oil which was flash chromatographed, eluting with hexane:ethyl acetate (12:1), giving 847 mg of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:17]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:17]
Reactant: ClI
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3ccccc3s2)cc1I
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To a solution in acetic acid (35 ml) of 2-(4'-aminophenyl) benzothiazole (2.98 g, 0.0132 mol) prepared as above was added dropwise a solution of iodine monochloride (2.78 g, 0.0171 mol) in acetic acid (35 ml) over 10 minutes at room temperature, followed by stirring for 11/2 hours. After evaporation of the solvent, 60 ml dichloromethane was added to the residue and the resulting suspension was neutralised with sodium hydrogen carbonate. Then 300 ml of water was added. The organic layer was washed with 10% sodium hydrogen carbonate solution (150 ml), water (100 ml×2) and dried (mgSO4). The solvent was removed under reduced pressure, absorbed onto silica gel, and placed on top of a column of silica gel. Flash elution using ethyl acetate-hexane (2:5) yielded brown crystals (3.32 g, 69.6%), m.p. 143-144° C.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)=[O:5])[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](CS(=O)Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Sodium perborate tetrahydrate (42 mg, 0.27 mmol) was added as a solid to a stirred solution of (2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionic acid (150 mg, 0.27 mmol), in acetic acid (5 mL) at 40° C. This solution was stirred at 40° C. for 1 hour (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a 1:1 mix of diastereoisomers as a white solid (144 mg, 93%): Rf 0.25 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (1H, d, J=8 Hz, Ar—H), 8.15 (1H, dd, J=8, 1 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.87 (2H, d, J=9 Hz, Ar—H), 7.78 (4H, m, Ar—H), 7.52 (2H, m, Ar—H), 7.44 (4H, m, Ar—H, NH), 4.39 (1H, m, CHN), 4.05-4.27 (2H, m, PhCH2), 3.04 (1H, m, CHHCHN), 2.92 (1H, m, CHHCHN), 1.39 and 1.37 (both 4.5H, s, CMe3 diastereomers); ESI-LCMS e/z calcd for C33H31NO6S 569.675, found 570 (M+H)+, 592 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=2)[CH:16]=1)[O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C:18]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[C:20]([Cl:26])[CH:19]=2)[CH:16]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)COc1cc(Cl)cc(Oc2cc(Cl)cc(C#N)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2cc(Cl)cc(OCC(=O)O)c2)c1

Procedure:
221 mg (0.561 mmol) of tert-butyl [3-chloro-5-(3-chloro-5-cyanophenoxy)phenoxy]acetate (5-2) was treated with neat trifluoroacetic acid until an LC/MS analysis indicated that the reaction was complete. The reaction was concentrated in vacuo and no further purification was done on the resultant desired product 5-3 which was isolated as an oil. MS: M+1=338.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
A mixture of methyl (4-{[4-(methyloxy)phenyl]carbonyl}phenyl)acetate (151) (1.00 g, 3.52 mmol) and AlCl3 (1.90 g, 14.07 mmol) were refluxed in benzene (40 mL) for 1 h and then cooled to 0° C. in an ice bath. Water (35 mL) was added slowly, and the mixture was extracted with ether (2×50 mL, each contained 15 mL of EtOAc). The combined ethereal extract was washed with water, brine, and dried over Na2SO4. Concentration gave light brown oil, which was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to afford 0.86 g (90%) of compound 152 as colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 2H), 3.72 (s, 3H), 5.63 (br s, 1H), 6.89 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 8.24 (d, J=7.9 Hz, 1H). LCMS (ESI): m/z 271 (M+H)+, 269 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:22]=C)=[C:13]2[C:17]=1[N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:33].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=2[C:12]([CH:22]=[O:33])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c2c1ccn2S(C)(=O)=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CS(=O)(=O)n1ccc2c(C=O)ccc(OCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-benzyloxy-1-methanesulfonyl-4-vinyl-1H-indole (1.3 g, 3.9 mmol; Intermediate 84) in dioxane (25 ml), lutidine (900 μl, 7.9 mmol), sodium metaperiodate (3.37 g, 15.8 mmol) (in water (10 ml)) and osmium tetroxide (100 mg, 0.1 mmol) was added (in that order). A precipitate was almost immediately formed, and the mixture was stirred for 1 h at room temperature. Water was added. The precipitate was filtered off, and washed with water. The solid material was extracted with acetonitrile. The acetonitrile-solution was evaporated. The product was purified by strait phase chromatography using Biotage flash-chromatograph 5-40% EtOAc in petroleum ether 40-60° C. Obtained 0.40 mg. MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[C:7]([Br:18])[CH:6]=2.[CH3:19][O:20][CH2:21][CH2:22][C:23](Cl)=O>>[Br:18][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[C:23]([CH2:22][CH2:21][O:20][CH3:19])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Reactant: COCCC(=O)Cl
Product: COCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Yield: 37.6 %

Procedure:
The method described in Part A of Example 9 was used to react 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (29.0 g, 93.5 mmol) with 3-methoxypropionyl chloride (11.5 g, 93.5 mmol). The crude product was recrystallized from 2:1 ethyl acetate:hexane and then purified by flash column chromatography on silica gel (eluting sequentially with 60:40 acetone:toluene and acetone). The resulting solid was recystallized from 3:1 ethyl acetate hexane to provide 13.3 g of 1-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as translucent crystals.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:11][CH2:12][NH2:13].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:14](=[O:15])[NH:13][CH2:12][CH2:11][CH:3]12
Reactant: CC1c2ccccc2NC1CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1c2ccccc2N2C(=O)NCCC12
Temperature: 110 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
To a solution of crude 2-(2,3-dihydro-3-methylindol-2-yl)ethylamine (1.75 g) in tetrahydrofuran (12 ml) at room temperature was added in small portions 1,1'-carbonyldiimidazole (1.1 g). After being stirred for 2 hours, the reaction mixture was evaporated in vacuo. The oil obtained was dissolved in toluene (25 ml) and the solution was heated at 110° C. for 1.5 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography (1% methanol-chloroform) to give crystals. Recrystallization from chloroform-ethyl acetate-hexane gave 3,4,4a,5-tetrahydro-5-methylpyrimido-[1,6-a]indol-1(2H)-one (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][CH:19](C(O)=O)[CH2:18][CH2:17]1.S1(CCCC1)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[C:11]=1[CH:19]1[CH2:20][CH2:21][CH:16]([O:15][CH3:14])[CH2:17][CH2:18]1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C1C=C(Cl)C(=O)c2ccccc21
Reactant: COC1CCC(C(=O)O)CC1
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COC1CCC(C2=C(Cl)C(=O)c3ccccc3C2=O)CC1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-chloro-1,4-naphthoquinone (1.16 g), 4-methoxycyclohexane-1-carboxylic acid (1.3 g) and silver nitrate (0.3 g) were stirred at 65° C. in a mixture of acetonitrile (2.5 ml), sulpholane (7.5 ml) and water (17.5 ml) while a solution of ammonium persulphate (2.3 g) in water (5 ml) was added dropwise during 15 minutes. The reaction mixture was stirred for a further 15 minutes at 65° C., cooled in ice and extracted with ether. The ether extracts were washed with sodium bicarbonate solution, dried and evaporated. The crude product was recrystallised from acetonitrile to yield 2-chloro-3-(4-methoxycyclohexyl)-1,4-naphthoquinone, m.p. 110°-113° C.; the product so obtained (0.9 g) was dissolved in boiling methanol (25 ml) and a solution of potassium hydroxide (0.9 g) in water (9 ml) added dropwise during 10 minutes. The reaction mixture was then refluxed for a further 30 minutes, concentrated hydrochloric acid (5 ml) added dropwise and the mixture cooled in ice. Addition of an equal volume of water precipitated an oil which slowly turned to a semi-solid. Recrystallisation from acetonitrile yielded 2-hydroxy-3-(4-methoxycyclohexyl)-1,4-naphthoquinone, m.p. 152°-155°, shown by n.m.r to be the pure trans isomer.