Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30](CC5C=CC=CC=5)[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:40][C:41]3[CH:42]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=3)[C:19](=[O:20])[N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:55]=[CH:56][CH:57]=[CH:58][C:4]=2[NH:3]1
Reactant: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O[C@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)N1CCN(C2CCNCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 77 mg (0.09 mmol) of (R)-2-[4-(1-benzyl-piperidin-4-yl)-piperazin-1-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 51) in 10 mL MeOH was combined with 50 mg 10% Pd/C and shaken for 3 h at RT and 50 psi hydrogen. The catalyst was suction filtered, the solvent was evaporated down i.vac., the residue was combined with acetonitrile and water and lyophilised.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][C:12](=C)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:24]>>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH2:13][C:12](=[O:24])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=C1C[C@H](COCc2ccccc2)[C@H](c2cccc(F)c2)C1
Product: O=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(S)-(benzyloxymethyl)-4-(R)-(3-fluorophenyl)-1-methylenecyclopentane (0.77 g, 2.75 mmol) from Step A in methanol (30 mL) was cooled to −70° C. and ozone was bubbled through the solution until a blue color persisted. The excess ozone was removed with a stream of nitrogen and then di methyl sulfide (5 mL) was added and the reaction was allowed to warm to rt over 16 h. Several drops of 2N HCl were added and the solution was stirred for 15 min to convert any methyl ketal to the desired ketone. The methanol was removed in vacuo and the was residue diluted with water, aq. sodium bicarbonate and ether.). The layers were separated and the aqueous was extracted with ether. The organic layers were washed with water, then brine, dried over sodium sulfate and concentrated. The residue was purified by FC using 10% ethyl acetate in hexanes to afford the title compound (0.88 g).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.[CH2:28]=[C:29]([CH3:31])[CH3:30]>O.C1(C)C=CC=CC=1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20]([C:25]([O:27][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1
Reactant: C=C(C)C
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.03 h
Yield: 94.7 %

Procedure:
A 100-ml flask was charged with 5 ml of toluene, 0.24 g (2 mmol) of anhydrous magnesium sulfate and 0.11 ml (2 mmol) of concentrated sulfuric acid, and they were vigorously stirred. To this mixture was added 2.12 g (10 mmol) of 4′-methyl-2-biphenylcarboxylic acid, and isobutene gas (98 mmol) was introduced thereto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4′-methyl-2-biphenylcarboxylic acid disappeared by HPLC, 4 ml of deionized water was poured into the mixture, and sufficiently stirred. Thereafter, the mixture was allowed to stand to separate into layers. The upper toluene layer was taken out therefrom, and the toluene layer was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the toluene layer was concentrated by distilling off toluene by using a rotary evaporator, to give 2.54 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 95% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17]Cl)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:19])[CH2:17][O:34][C:31]2[CH:30]=[CH:29][C:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)CCl)cs1
Reactant: Oc1ccc(-c2ccc(Cl)cc2)cc1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(C(=O)COc2ccc(-c3ccc(Cl)cc3)cc2)cs1
Yield: 45.4 %

Procedure:
By an operation similar to that in Example 2-1 and using 2-{[4-(chloroacetyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.49 g) obtained in Example 1 and 4′-chlorobiphenyl-4-ol (772 mg), 2-[(4-{[(4′-chlorobiphenyl-4-yl)oxy]acetyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (864 mg) was obtained. By successive operations similar to those in Example 2-2 and 2-3 using 568 mg thereof, the title compound (299 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][C:26]([O:28]C)=[O:27])[CH:22]=[CH:23][CH:24]=3)=[O:17])[C:7]=2[CH:30]=1)#[N:2].O.[OH-].[Li+]>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)=[O:17])[C:7]=2[CH:30]=1)#[N:2]
Reactant: COC(=O)Cc1cccc(NC(=O)N[C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(CC(=O)O)c2)[C@@H]1O

Procedure:
A solution of (3S-trans)-3-[[[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]carbonyl]amino]-benzeneacetic acid, methyl ester (0.7 g, 1.7 mmol, title compound from Example 24) in methanol (15 ml) under argon was treated with lithium hydroxide hydrate (0.14 g, 3.4 mmol) and the reaction was stirred at room temperature for 16 hours. More lithium hydroxide (two equivalent) was added and the reaction mixture was stirred for 48 hours. It was concentrated in vacuo and the residue was diluted with water (50 ml) and extracted with ethyl acetate. Organic layer was discarded and aqueous layer was acidified to pH~1 with 10% hydrochloric acid and extracted with ethyl acetate (3×100 ml). It was washed with water (100 ml) and concentrated in vacuo. The residue was flash chromatographed on silica gel eluting with methylene chloride/methanol/acetic acid (1800:200:5) to give (3S-trans)-3-[[[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]carbonyl]amino]benzeneacetic acid as a colorless solid (0.5 g, 3.9%), m.p. 135°-138° C. (with foaming): 1H NMR (DMSO-d6) δ8.76 (s, 2H), 7.62 (m, 2H), 7.42 (m, 2H), 7.25 (m, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.90 (d, J=7.0 Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 4.77 (m, 2H), 3.76 (m, 2H), 1.51 (s, 3H), 1.28 (s, 3H); 13C NMR (CDCl3) 172.8, 156.3, 155.9, 140.3, 135.6, 132.7, 132.4, 128.6, 126.0, 122.4, 119.1, 118.8, 117.9, 116.2, 102.7, 80.3, 71.6, 49.4, 26.5, 18.9; IR (KBr) 1132.1, 1267.2, 1491.3, 1559.3, 1611.2, 1659.3, 1713.2, 2228.1, 2980.1, 3379.0 cm-1 ; [60 ]25D =-6.7° (c=0.683, DMF).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].C(Cl)(Cl)Cl>CN(C=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([Cl:11])[CH:8]=1)[O:4][CH2:3][CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of 1-(2-bromo-ethoxy)-3,5-dichloro-benzene (2.41 g, 8.93 mmol) and potassium phthalimide (2.00 g, 10.64 mmol) in DMF (7.6 mL) was heated at 85° C. for 1 h. The reaction was cooled to room temperature and chloroform was added. The organic solution was washed with 0.2 N aqueous NaOH followed by water. The organic solution was dried (Na2SO4), filtered, and concentrated. The residue was suspended in Et2O and the solid was collected by filtration to provide the title compound (2.21 g). 1HNMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.77 (m, 2H), 6.89 (m, 1H), 6.88 (m, 2H), 4.16 (t, 2H), 4.05 (t, 2H); MS 336 (M+).
Reaction SMILES: [C:1]([CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:5]([OH:7])=[O:6])([OH:3])=O.S(Cl)(Cl)=O.[NH2:21][CH:22]1[C:28](=[O:29])[N:27]2[CH:23]1[S:24][C:25]([CH3:34])([CH3:33])[CH:26]2[C:30]([OH:32])=[O:31].C(N(CC)CC)C.Cl>CN(C)C=O.C(OCC)(=O)C.CCOCC.O>[C:5]([CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:1]([NH:21][CH:22]1[C:28](=[O:29])[N:27]2[CH:23]1[S:24][C:25]([CH3:34])([CH3:33])[CH:26]2[C:30]([OH:32])=[O:31])=[O:3])([OH:7])=[O:6]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Reactant: O=C(O)C(C(=O)O)c1ccc2c(c1)CCO2
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC1(C)SC2C(NC(=O)C(C(=O)O)c3ccc4c(c3)CCO4)C(=O)N2C1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
α-Carboxy(2,3-dihydro-5-benzofuranyl)acetic acid (14 mmole) is added to 50 ml of ether. Thionyl chloride (14.5 mmole) is added along with 1 drop of dimethylformamide. This mixture is refluxed about 3 hours and then evaporated under reduced pressure at room temperature. The residue is added to 50 ml of ether which is added to an ice cold mixture of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid (14 mmole), 30 ml of water, 15 ml of ether and triethylamine (14 mmole). After stirring for 30 minutes the pH is adjusted to 1.5 with dilute hydrochloric acid and the layers separated. The ether layer is extracted with water. Evaporation of the ether gives a residue which is taken up in ethyl acetate, dried, filtered and evaporated to give the title compound.
Reaction SMILES: Cl[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[NH:7][CH2:6]2.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(#N)C>CS(C)=O>[N:20]1([CH:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[NH:7][CH2:6]3)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C1NCc2cc(C(Cl)c3ccccc3)ccc2N1
Reactant: c1c[nH]cn1
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C1NCc2cc(C(c3ccccc3)n3ccnc3)ccc2N1
Reaction time: 4 h
Yield: 58.1 %

Procedure:
A mixture of 3.6 parts of 6-(chlorophenylmethyl)-3,4-dihydro-2(1H)-quinazolinone, 5.3 parts of 1H-imidazole, 60 parts of acetonitrile and 27.5 parts of dimethyl sulfoxide was stirred for 4 hours at reflux temperature. After concentration, the residue was washed twice with water, dissolved in a mixture of trichloromethane and methanol (90:10 by volume), dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a 45 parts of ethyl acetate and a few drops of water. The product was filtered off, washed with ethyl acetate and 2,2'-oxybispropane and dried, yielding 2.3 parts (58.1%) of 3,4-dihydro-6-[(1H-imidazol-1-yl)phenylmethyl]-2(1H)-quinazolinone; mp. 222.5° C. (comp. 16).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.C(NC1C=CC(S([N:36]=[N+:37]=[N-])(=O)=O)=CC=1)(=O)C.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[N+:36](=[C:9]([C:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-:37]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccnc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(2-fluoropyridine-3-yl)-3-oxopropanoate (1.42 g, 6.71 mmol) was dissolved in anhydrous acetonitrile (20 mL), treated with triethylamine (0.781 mL, 1.15 equiv) and cooled to 0° C. To the mixture was added the 4-acetamidobenzenesulfonyl azide (1.77 g, 1.1 equiv) and after stirring 0° C. for 1 hour, the mixture was treated with sodium hydroxide (10 mL, 1 N aqueous). The mixture was poured into sodium carbonate (50 mL, aqueous saturated) and water (200 mL) and extracted with ethyl acetate (2×250 mL). The combined organic extracts were washed once with brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes:ethyl acetate), providing the titled compound as a light yellow oil.
Reaction SMILES: [CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC3C=CC=CC=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[CH:1]1([C:5]2[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:31]4[C:30]5[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=5)[N:34]=[CH:33][N:32]=4)[CH:42]=3)=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCC2)nn1-c1ccccc1)Oc1ccccc1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C5CCC5)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
1-(3-cyclobutyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea was prepared from phenyl 3-cyclobutyl-1-phenyl-1H-pyrazol-5-ylcarbamate and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) according to the procedure given in Example 352B. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 7.78 (s, 1H), 7.22-7.53 (m, 10H), 6.38 (m, 1H), 3.99 (s, 6H), 3.44 (m, 1H), 2.14-2.50 (m, 4H), 1.23-1.99 (m, 2H); LC-MS (ESI) m/z 553 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13]C=O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cu].[Cu](Br)Br>[CH:9]1[C:8]2[NH:13][C:2]3[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=3[O:4][CH2:5][O:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=CNc1ccccc1OCOc1ccccc1Br
Agent: Br[Cu]Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1ccc2c(c1)Nc1ccccc1OCO2
Temperature: 180 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
The above formamide (6.8 g, 21 mmol) was suspended in Dowtherm (75 ml), and potassium carbonate (3.9 g, 28 mmol) was added, followed by copper (1.1 g, 17 mmol) and copper bromide (1.5 g, 11 mmol). The reaction mixture was heated at 180° C. overnight. After cooling, the mixture was filtered, and the filtercake was washed with dichloromethane. Dowtherm and solvent was distilled off, and ethanol (200 ml) was added to the residue, which was left overnight. 4 M Sodium hydroxide (14 ml) was added and the mixture was heated at reflux temperature for 1 h. After cooling, the mixture was filtered and evaporated. The residue was suspended in ethyl acetate (200 ml) and water (100 ml). The phases were separated and the organic phase was washed with water (2×75 ml). The aqueous phases were extracted with ethyl acetate (100 ml) and the combined organic extracts were evaporated. The residue was suspended in warm cyclohexane (100 ml), and left cooling under stirring. The precipitated solid was filtered off and dried, affording 12H-dibenzo[d,g][1,3,6]dioxazocine (4.57 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cccc(C2(Cc3ccccc3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 23 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.16 g, 73.3%).
Reaction SMILES: C(OC([N:11]([C:23]1[C:24]([C:35]([O:37][CH3:38])=[O:36])=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[S:26][CH:27]=1)[C:12]([C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1)=[O:13])=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.ClCCl.[Pd]>[O:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=[C:14]1[C:12]([NH:11][C:23]1[C:24]([C:35]([O:37][CH3:38])=[O:36])=[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[S:26][CH:27]=1)=[O:13]
Reactant: COC(=O)c1c(N(C(=O)OCc2ccccc2)C(=O)c2cc3ccccc3o2)csc1-c1ccc(Cl)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1c(NC(=O)c2cc3ccccc3o2)csc1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
10% Pd/C (5.8 mg, 5 μmol, 20 mol % Pd) was added to compound 9 (14.8 mg, 27 μmol) in ethanol:ethyl acetate:dichloromethane (2:1:1, 1.5 mL). The mixture was degassed and placed under H2 (1 atm) and stirred for 30 min. The mixture was filtered through a 0.45 μm syringe filter and concentrated under reduced pressure to provide 10 (11.1 mg, 99%) as a solid: 1H NMR (500 MHz, d6-DMSO) δ11.12 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.78 (m, 2H), 7.55-7.50 (m, 5H), 7.39 (t, J=7.6 Hz, 1H), 3.69 (s, 3H); LRESIMS m/z 412.0 [M+H]+, calcd. for C21H15Cl1N1O4S1 412.0.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.[F:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15](=S)[NH:16][C:17](=[O:19])[O:18][C:13]=2[CH:12]=1.[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH2:44])[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]1)#[N:24].C(N(CC)C(C)C)(C)C>C1COCC1>[C:23]([C:25]1([NH:34][C:35](=[O:45])[CH:36]([NH:44][C:15]2[C:14]3[CH:21]=[CH:22][C:11]([F:10])=[CH:12][C:13]=3[O:18][C:17](=[O:19])[N:16]=2)[CH2:37][CH2:38][C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH3:33])[CH2:29][CH2:30]1)#[N:24]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CCC(C)(C)CC)CC1
Reactant: O=c1[nH]c(=S)c2ccc(F)cc2o1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCC(C#N)(NC(=O)C(CCC(C)(C)CC)Nc2nc(=O)oc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
2-Chloro-1-methyl pyridinium iodide (365 mg, 1.43 mmol, 1.00 eq) was added to a suspension of 7-fluoro-4-thioxo-3,4-dihydro-benzo[e][1,3]oxazin-2-one (280 mg, 1.42 mmol, 1.00 eq), 2-amino-5,5-dimethyl-heptanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (627 mg, 1.42 mmol, 1.00 eq), and N,N-diisopropyl ethylamine (1.00 mL, 5.74 mmol, 4.04 eq) in THF (10.0 mL). The reaction mixture was stirred at room temperature overnight, then concentrated, resuspended in ethyl acetate (50 mL) and washed with saturated Na2CO3 solution. The organic phase was dried (MgSO4) and concentrated and the resulting residue was chromatographed over silica gel using a gradient of methanol in dichloromethane as the eluant to provide 324 mg (47% yield) of the title compound; m/z calculated for C26H36F N5O3 485.6, found 486.5 (M+H)+.
Reaction SMILES: [Si]([C@@:8]1([OH:42])[C@@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C)C)[O:11][C@@H:10]([N:22]2[CH:29]=[C:28]([CH2:30][O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH:39]([CH3:41])[CH3:40])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:9]1)(C(C)(C)C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:31][CH2:30][C:28]1[C:26](=[O:27])[NH:25][C:23](=[O:24])[N:22]([CH:29]=1)[C@@H:10]1[O:11][C@H:12]([CH2:13][OH:14])[C@@H:8]([OH:42])[CH2:9]1)([CH3:41])[CH3:40]
Reactant: CC(C)c1ccccc1COCc1cn([C@H]2C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccccc1COCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compounds 3′,5′-O-bis-(tert-butyldimethylsilyl)-5-(2-isopropylbenzyloxy)methyl-2′-deoxyuridine (134 mg, 0.22 mmol) and (3′ or 5′)-O-(tert-butyldimethylsilyl)-5-(2-isopropylbenzyloxy)methyl-2′-deoxyuridine (98 mg, 0.19 mmol) were dissolved in THF (5 mL), and a solution of tetra-n-butylammonium fluoride trihydrate (323 mg, 1.05 mmol) in THF (2 mL) was added. The mixture was stirred at room temperature for one hour, then concentrated in vacuo and purified by silica gel column chromatography to give 5-(2-isopropylbenzyloxy)methyl-2′-deoxyuridine dU.n6 (108 mg, 67%).
Reaction SMILES: O[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].Cl[Si](C)(C)C.[I-].[Na+].C(#N)C>CCCCCC.O>[F:16][C:15]([F:17])([F:18])[C:11]1[CH:10]=[C:9]([CH:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(O)(CCCC#N)c1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CC#N
Product: CC(CCCC#N)c1cccc(C(F)(F)F)c1
Yield: 46.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 4.4 grams (0.017 mole) of 5-hydroxy-5-(3-trifluoromethylphenyl)hexanenitrile, 13 mL (0.102 mole) of chlorotrimethylsilane, 15.4 grams (0.102 mole) of sodium iodide, and 8.0 mL (0.153. mole) of acetonitrile in 30 mL of hexane was stirred for about 30 minutes. After this time, gas chromatographic analysis of the reaction mixture indicated that the reaction was complete. The reaction mixture was then stirred with 100 mL of water, and then it was extracted with 100 mL of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The methylene chloride eluate was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.9 grams of 5-(3-trifluoromethylphenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.