Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](O)[CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:16]([C:15]1[CH:10]=[CH:11][C:12]([O:8][C:7](=[O:9])[CH2:6][CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:14]=1)([O-:18])=[O:17]
Reactant: CC(=O)SCCC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(=O)SCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred ice cold solution of ethyl acetate (75 ml.) containing 3-(acetylthio)propanoic acid (7.4 g. 50 mmol.) and p-nitrophenol (8.4 g., 60 mmol.) dicyclohexylcarbodiimide (10.3 g., 50 mmol.) is added in portions. After thirty minutes, the ice bath is removed and the solution stirred at room temperature overnight. The precipitated dicyclohexylurea is filtered off, ethyl acetate evaporated, and the residue dissolved in ethanol. The 3-(acetylthio)propanoic acid p-nitrophenyl ester crystallizes out, yield 8.6 g. (63.7%), m.p. 71°-73°.
Reaction SMILES: S([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[C:12]1[C:20]([O:22][CH2:23]C)=[O:21])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C1COCC1>[NH:11]1[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)c1cc2cnccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2cccnc2[nH]1
Temperature: 15 °C
Reaction time: 12 h

Procedure:
A mixture of compound 6-c (6 g, 17.4 mmol) and Cs2CO3 (CAS 534-17-8) (17 g, 52.2 mmol) in methanol (70 mL) and THF (140 mL) was stirred at 15° C. for 12 h. The solvent was removed under vacuum. H2O (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to yield product 6-d as a white powder (1.39 g, 46%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (1.0 g; 6.02 mmol), 0.502 ml (6.62 mmol) of 3-amino-propan-1-ol and 1.15 ml (6.62 mmol) of diisopropylethylamine in 5 ml THF is stirred at rt for 1 hr (temperature raises somewhat at the beginning). After concentration in vacuo the residue is dissolved in 50 ml of ethyl acetate, washed with 50 ml of 4% aqueous sodium hydrogen carbonate and brine, dried and concentrated. 1.32 g of pure title compound as a solid are thus obtained (99% yield).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8][C:9]([O:11]CC2C=CC=CC=2)=O)[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3]1.C[C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28](O[C:31](=O)[C:26]=12)=[O:29]>C(O)(=O)C.[Pd]>[CH3:31][C:26]1[CH:25]=[CH:35][CH:34]=[C:33]2[C:27]=1[C:28](=[O:29])[N:8]([CH:7]1[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:11]
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)C(=O)NC1=O
Reactant: Cc1cccc2c1C(=O)OC2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)OC1CC(N2C(=O)c3cccc(C)c3C2=O)C(=O)NC1=O
Reaction time: 3 h

Procedure:
A mixture of 2,6-dioxo-3-benzyloxycarbonylamino-5-acetoxypiperidine (9 g, 28.2 mmol) (U. Teubert et al, Arch. Pharm. Pharm. Med. Chem. (1998) 7-12), and Pd/C (10%, 0.9 g) in acetic acid (90 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with acetic acid. To the filtrate is added 3-methylphthalic anhydride (4.56 g, 28.2 mmol) and this mixture is heated at reflux for 18 hours. The solvent is removed in vacuo to give 3-(4-methyl-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which can be further purified by column chromatography.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:13][CH:11]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:48][C:49](=[O:52])[CH2:50]Br)C1C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[C:1]([O:9][C@@H:10]1[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:13][CH:11]1[O:12][CH2:50][C:49]([OH:52])=[O:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(OC[C@H]1OC(O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 46.25 g (100 mmol) of 2,3,5-tri-O-benzoylribofuranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 400 ml of methyl-tert-butyl ether, and 82.93 g (600 mmol) of potassium carbonate is cooled to 0° C. At 0° C., 22.91 g (150 mmol) of bromoacetic acid benzyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 500 ml of methyl-tert-butyl ether is added thereto, the organic phase is separated, and the aqueous phase is extracted twice with 200 ml of methyl-tert-butyl ether. The solvent of the combined organic phases is dried on sodium sulfate, dessicant is filtered out and distilled off in a vacuum. The residue is taken up in 500 ml of ethanol. 5 g of palladium (10%) on activated carbon is added thereto, and it is hydrogenated until hydrogen absorption is completed. Then, catalyst is filtered out, it is rewashed with a little ethanol and evaporated to the dry state in a vacuum. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 200 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[CH3:30][O:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cccc(CCc2ccccc2OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OC2CCNCC2)c1
Reaction time: 1 h
Yield: 90 %

Procedure:
379 mg of 1-t-butoxycarbonyl-4-{2-[2-(3-methoxyphenyl) ethyl]phenoxy}piperidine [prepared as described in step (a) above] were dissolved in 5 ml of a 4N solution of hydrogen chloride in dioxane, and the solution was allowed to stand at room temperature for 1 hour. The reaction mixture was then concentrated by distillation under reduced pressure, and the resulting oily residue was dissolved in 10 ml of ethyl acetate, after which it was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 290 mg (yield 90%) of the title compound as colorless crystals, melting at 121°-122° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([CH2:14][CH3:15])=[C:11]([CH3:13])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:14]([C:10]1[S:9][C:8]([NH2:7])=[N:12][C:11]=1[CH3:13])[CH3:15]
Reactant: CCc1sc(NC(=O)OC(C)(C)C)nc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1sc(N)nc1C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
The above prepared (5-ethyl-4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.394 g, 1.626 mmol) was dissolved in 8 mL of CH2Cl2 and treated with 1.5 mL of TFA. After 2 h at RT all starting material had disappeared. The reaction mixture was then poured onto icewater/NaHCO3, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/ethyl acetate=1/1) yielded 0.200 g of the title compound as light brown viscous oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Cl:23]CCCl>C(O)(=O)C.O.C(=O)(O)[O-].[Na+].S(=O)(O)[O-].[Na+]>[CH2:15]([O:14][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[C:4]([C:1](=[O:3])[CH2:2][Cl:23])[CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Reactant: ClCCCl
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(CCl)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Temperature: 65 °C
Reaction time: 4.5 h

Procedure:
5-acetyl-7-benzyloxy-1H-quinolin-2-one (7.0 g, 23.86 mmol) is dissolved in a mixture of 1,2-dichloroethane (147 mL), glacial acetic acid (43 mL), and water (7 mL) and combined with N-benzyltrimethylammonium-dichloriodate (19.0 g, 54.58 mmol). The mixture is stirred for 4.5 hours at 65° C., then diluted with sodium bicarbonate solution and 5% sodium bisulfite solution and stirred for 5 minutes. The precipitate formed is filtered off, washed with water (2×20 mL) and dried in the oven. Yield: 6.0 g (77%); mass spectroscopy:
Reaction SMILES: CO.C[O:4][C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)=[O:6].[OH-].[Li+].Cl>O>[O:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([C:5]([OH:6])=[O:4])=[CH:8]1
Reactant: COC(=O)c1coc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.3 %

Procedure:
To a methanol (30 mL) solution of 1-benzofuran-3-carboxylic acid methyl ester (5.25 g, 29.8 mmol) tetrahydrofuran (60 mL), water (30 mL) and lithium hydroxide (2.50 g, 59.9 mmol) were added at room temperature. The mixture was stirred for 15 hours at room temperature. 1N-hydrochloric acid (60 mL, 60 mmol) was added to the reaction liquor, and then methanol was distilled off under reduced pressure. 1N-hydrochloric acid (15 mL, 15 mmol) was added to the obtained aqueous layer, and solids generated therefrom were collected by filtration. The solids were washed with water, and then dried for two days at 50° C. with a vacuum pump, to obtain the title compound (4.41 g, 27.2 mmol, 91%) as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5]C)=[O:4].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:2][C:3]([OH:5])=[O:4])[CH2:10][CH2:9]1
Reactant: COC(=O)CCl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CCN(CC(=O)O)CC1
Temperature: 70 °C
Yield: 70 %

Procedure:
165 g of methyl 2-chloroacetate are dropped into a solution of 152 g of N-methylpiperazine and 212 ml of triethylamine in 1.5 l of toluene, with stirring and under inert gas atmosphere; then the reaction mixture is heated to 70° C. for 4 hours. After that, the reaction mixture is cooled to room temperature, the resulting precipitate is filtered and washed on the filter with 100 ml of toluene. The resulting organic solution is extracted with water (5×200 ml) and the combined organic extracts are refluxed for about 20 hours, then water is distilled off under reduced pressure. The residue is crystallized from isopropanol, to obtain 168 g of 2-(N-methylpiperazino) acetic acid, m.p. 160°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O:27]C)=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[OH-].[Na+:30]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O-:27])=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Na+:30]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C=CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 55 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 11 (5.2 g), 1 mol/L of an aqueous sodium hydroxide solution (42 mL), and methanol (150 mL), to give the captioned compound (2.9 g, 55%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1
Yield: 61.9 %

Procedure:
3-(4-Chlorophenyl)-5-methyl-1,2-benzisoxazole (12.2g.) and N-bromosuccinimide (9.6g.) were mixed in carbon tetrachloride (200ml.) and heated under reflux in the presence of UV light. (Hanovia medium pressure lamp 125 watts, emitting at 254,265,297,313,366 mp). On cooling, the mixture was filtered and the filtrate evaporated to dryness. The resulting solid was recrystallized from 33% toluene/60-80 petrol ether (150 ml.) to give the title compound as a white crystalline solid (10.0g) m.p. 142°C
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]5[CH:39]=[CH:38][C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[N:31]=5)=[CH:27][C:22]=4[N:21]=[C:20]3[CH2:40][C:41]3([C:46]([O:48]CC)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C1COCC1.[Li+].[OH-].Cl>C(Cl)Cl.O.CO>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]5[CH:39]=[CH:38][C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[N:31]=5)=[CH:27][C:22]=4[N:21]=[C:20]3[CH2:40][C:41]3([C:46]([OH:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH:13]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccc(NS(C)(=O)=O)cc3)c2)CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(-c2cccc(Cn3c(CC4(C(=O)O)CCCC4)nc4cc(OCc5ccc6ccccc6n5)ccc43)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 20 mL vial were added ethyl 1-((1-((4′-(methylsulfonamido)-[1,1′-biphenyl]-3-yl)methyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (117 mg, 0.17 mmol), THF (2 mL) and MeOH (2 mL) followed by LiOH (1 mL, 1 M). The reaction vial was capped and the mixture was stirred at RT for 16 h. The mixture was cooled to RT, water (5 mL) was added and the pH was adjusted to ˜4 using 1 M HCl. To the mixture was added DCM (5 mL) and the mixture was stirred for 1 h at RT. The organic layer was separated then concentrated to dryness. The resulting residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C38H36N4O6S, 660.24; m/z found, 661.3 [M+H]+. (500 MHz; DMSO-d6) δ 8.39 (d, J=8.5, 1H), 8.03 (d, J=8.2, 1H), 7.98 (d, J=8.2, 1H), 7.81-7.76 (m, 1H), 7.69 (d, J=8.5, 1H), 7.63-7.59 (m, 1H), 7.56-7.50 (m, 3H), 7.40-7.34 (m, 3H), 7.29-7.25 (m, 2H), 7.20-7.18 (m, 1H), 7.02-6.99 (m, 1H), 6.95-6.91 (m, 1H), 5.50 (s, 2H), 5.37 (s, 2H), 3.16 (s, 2H), 3.01 (s, 3H), 2.16-2.09 (m, 2H), 1.72-1.52 (m, 6H).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O.O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C@@H:33]([N:35]3[CH2:40][CH2:39][C@:38]([CH2:47][CH2:48][CH2:49][OH:50])([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[O:37][C:36]3=[O:51])[CH3:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1>CC(C)=O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C@@H:33]([N:35]3[CH2:40][CH2:39][C@:38]([CH2:47][CH2:48][C:49]([OH:3])=[O:50])([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[O:37][C:36]3=[O:51])[CH3:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(=O)O)(c2ccccc2)OC1=O
Reaction time: 8 h
Yield: 79.8 %

Procedure:
CrO3 (1 g) was added to H2SO4 (1 mL) and water was added to bring the total volume to 4 mL. (R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (600 mg, 1.4 mmol) was dissolved in 10 mL acetone, and cooled in an ice bath. The Jones reagent (0.5 mL) was slowly added to the mixture and stirred overnight. Solvent was removed in vacuo, the residue was dissolved in CH2Cl2 (10 mL) and water (10 mL). The layers were separated, and the aq layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanoic acid (500 mg, crude), which was not purified.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1.[NH:39](C(OC(C)(C)C)=O)[C@H:40]([C:43](O)=[O:44])[CH2:41][CH3:42].C(OP(ON1C(=O)C2C=CC=CC=2N=N1)(OCC)=O)C.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[NH2:39][CH:40]([CH2:41][CH3:42])[C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1)=[O:44]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(N)C(=O)Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 51E (59 mg, 0.1 mmol) and Boc-Abu-OH (22 mg, 0.11 mmol) in tetrahydrofuran (5 ml) was added 3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (36 mg, 0.11 mmol) and triethylamine (0.07 ml, 0.5 mmol). The mixture was stirred at room temperature for 16 hours then poured into saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and evaporated. To the residue was added dichloromethane (2 ml) and trifluoroacetic acid (2 ml) then stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by HPLC with NH4OH to provide the title compound. (62 mg, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.90 (t, J=7.54 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 1.48 (m, 1 H) 1.66 (m, 1 H) 1.90 (s, 3 H) 3.22 (m, 2 H) 7.02 (m, 2 H) 7.40 (d, J=8.46 Hz, 2 H) 7.52 (d, J=8.46 Hz, 2 H) 7.61 (d, J=8.46 Hz, 1 H) 7.72 (m, 5 H) 7.94 (s, 1 H) 8.52 (s, 1 H) 8.79 (s, 1 H) 10.33 (s, 1 H); MS (ESI+) m/z 670, 672 (M+H)+.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:28]([CH3:36])[C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][N:31]=1.O.OC1N=CN=C2C=1NC(S)=N2>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:28]([CH3:36])[C:29]([C:32]([O:34][CH3:35])=[O:33])=[N:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COC(=O)c1nnc(S)n1C
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: COC(=O)c1nnc(SC2=C(O)CC(CCc3ccc(OC)c(Cl)c3)(C3CCCC3)OC2=O)n1C

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and methyl 5-mercapto-4-methyl-4H-1,2,4-triazole-3-carboxylate, as shown in Example 21, Step 2, was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[O:15])[C:7]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.[BH4-].[Na+].CC(C)=O.ClCCl>C(O)C>[CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[OH:15])[C:7]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2CC(=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2CC(O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of 5-cyclopropyl-1-(2-(4-fluorophenyl)-2-oxoethyl)-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (65.0 mg, 0.170 mmol) from Example 5 in ethanol (1 ml) was added sodium borohydride (6.4 mg, 0.170 mmol) and the reaction mixture was stirred at room temperature over weekend. Then was added acetone (0.062 ml) followed by dilution with dichloromethane. The resulting solution was washed with water and the organic phase was dried over sodium sulfate and filtered. Evaporation gave the desired product (30 mg, 46%).
Reaction SMILES: Br[C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].[CH3:35]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl>[CH3:35][C:2]1[C:3]2[CH2:33][NH:32][C:31](=[O:34])[C:4]=2[C:5]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:6][C:7]=1[NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19]
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Br)c3c2C(=O)NC3)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(C)c3c2C(=O)NC3)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To an oven dry flask was added tert-butyl (1S,2R)-2-(7-bromo-3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (40 mg, 0.075 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (20.99 μL, 0.151 mmol), and potassium carbonate (31.3 mg, 0.226 mmol) in dioxane (1959 μL) and water (196 μL). The resulting tan solution was degassed with nitrogen for 5 min. Palladium chloride (dppf) (5.52 mg, 7.54 μmol) was added and the mixture was degassed for an additional 2 min. The vessel was capped and the reaction mixture was heated at 100° C. with stirring overnight. The reaction mixture was cooled to RT, diluted with EtOAc (5 mL), and washed with water (5 mL) and brine (5 mL). The organic layer was collected, dried over Na2SO4 and concentrated to give the title compound as a brown viscous oil, which was used without purification (45 mg). [M+H] calc'd for C26H35N5O3, 466. found, 466.