Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10][CH2:9][C:8]=2[CH:21]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH:11]1[CH2:10][CH2:9][C:8]2[CH:21]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=2[O:12]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(COC1CCCCO1)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Yield: 100 %

Procedure:
A mixture of 34 parts of 3,4-dihydro-6-nitro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 31 parts (100%) of 3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-amine as an oily residue (intermediate 10).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:20])[N:4]2[C@H:21]([C:25](O)=[O:26])[CH2:22][CH2:23][CH2:24][N:3]12.C(OC([NH:34][C@H:35]1[CH2:39][C:38](=[O:40])[O:37][CH:36]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O)C=C.C([SnH](CCCC)CCCC)CCC.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:42]([O:41][CH:36]1[CH:35]([NH:34][C:25]([CH:21]2[N:4]3[C:5](=[O:20])[CH:6]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:7][CH2:8][C:2](=[O:1])[N:3]3[CH2:24][CH2:23][CH2:22]2)=[O:26])[CH2:39][C:38](=[O:40])[O:37]1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O=C(CCc1ccccc1)N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O
Reactant: C=CCOC(=O)N[C@H]1CC(=O)OC1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC1CCC(=O)N2CCCC(C(=O)NC3CC(=O)OC3OCc3ccccc3)N2C1=O
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 81 %

Procedure:
To a solution of (1S, 9S) 6,10-dioxo-octahydro-9-(3-phenyl-propionylamino)-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid (45a) (662 mg; 1.773 mmol) in dry dichloromethane (9 ml) and dry dimethyl formamide (3 ml) at room temperature was added bis(triphenylphosphine)palladium chloride (30 mg) and (3S, 2RS)-3-allyloxycarbonylamino-2-benzyloxy-5-oxotetrahydrofuran (Chapman, Biorg. Med. Chem. Lett., 2, pp. 613-18 (1992)) (568 mg; 1.95 mmol) followed by dropwise addition of tri-n-butyltin hydride (1.19 g; 4.09 mmol). 1-Hydroxy-benzotriazole (479 mg; 3.546 mmol) was added to the mixture and the mixture was cooled to 0° C. before addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (408 mg; 2.128 mmol). The mixture was stirred at room temperature for 3.25 h then diluted with ethyl acetate (50 ml), washed twice with dilute hydrochloric acid (20 ml), twice with saturated sodium bicarbonate (20 ml), once with brine then dried (MgSO4) and concentrated. The resulting oil was purified by flash chromatography (0-100% ethyl acetate/chloroform) to afford 810 mg (81%) of 46a as a mixture of anomers: mp. 92°-94° C.; IR (KBr) 3311, 1791, 1659, 1651, 1536; 1H NMR (CDCl3) δ 7.49, 6.56 (1H, 2d, J=6.7, 7.8), 7.29 (10H, m), 6.37, 6.18 (1H, 2d, J=7.7, 7.6), 5.56, 5.34 (1H, d, s, J=5.2), 5.08-4.47 (6H), 3.18-2.80 (5H), 2.62-2.28 (5H), 2.04-1.53 (5H). MS (FAB, m/z), 563 (M+ +1), 328, 149, 91.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[N:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH2:67][C:68]([OH:70])=O)[C:56]([C:71]([F:74])([F:73])[F:72])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C=O)C>[NH2:7][C:68](=[O:70])[CH2:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[CH2:60][CH2:59][C:57]1[C:56]([C:71]([F:74])([F:72])[F:73])=[CH:55][N:54]=[C:53]([NH:52][C:49]2[CH:48]=[CH:47][C:46]([CH:43]3[CH2:44][CH2:45][N:40]([C:38]([O:37][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:39])[CH2:41][CH2:42]3)=[N:51][CH:50]=2)[N:58]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
HOBt (50 mg, 0.37 mmol), EDCl.HCl (78 mg, 0.41 mmol) and DIPEA (0.11 mL, 0.63 mmol) were added to a stirred solution of 2-(2-(2-(2-((6-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (A46) (74 mg, 0.13 mmol) in dry DMF (5 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (121 mg, 1.26 mmol) was added in one portion and the resulting mixture was stirred for 18 hours at room temperature. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic layers were washed with brine (10 mL) and dried over Na2SO4. The volatiles were removed in vacuo and the residue purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridges, 0-100% EtOAc in petroleum benzine 40-60° C. followed by 0-25% MeOH in EtOAc) to give the title compound A47 as clear oil (58 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.54 (s, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.30-7.22 (m, 4H), 7.17 (d, J=8.5 Hz, 1H), 5.78 (s, 1H), 5.62 (s, 1H), 4.25 (s, 2H), 3.74 (s, 2H), 3.11 (s, 4H), 2.83 (m, 3H), 1.92 (d, J=12.3 Hz, 2H), 1.79-1.60 (m, 2H, peak obscured), 1.48 (s, 9H). LCMS-A: rt 5.549 min; m/z 585 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2=[N:17][CH:18]=[C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)[N:20]=[C:15]2[CH:14]=1.O1CCOCC1.Cl>CCOC(C)=O>[NH:21]([C:19]1[N:20]=[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[N:30]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:16]2=[N:17][CH:18]=1)[NH2:22]
Reactant: COc1ccc2c(c1)c(-c1cc3nc(NNC(=O)OC(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(NN)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 60 °C
Yield: 85.8 %

Procedure:
To a round bottom flask were added tert-butyl 2-(6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarboxylate (0.272 g, 0.505 mmol) and 1,4-dioxane (5 mL). To the mixture was added HCl (4 N in 1,4-dioxane, 1.26 ml, 5.05 mmol) and the reaction mixture was heated to about 60° C. for about 1 h. The reaction mixture was cooled to room temperature and was diluted with EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 2-hydrazinyl-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.19 g, 84%): LC/MS (Table 1, Method d) Rt=1.55 min; MS m/z: 439 (M+H)+.
Reaction SMILES: [OH:1]C(C)CC(O)=O.O[C@H:9]([CH2:14][CH2:15][CH2:16]CCC)[CH2:10][C:11]([OH:13])=[O:12]>>[OH:1][C@H:10]1[CH2:9][CH2:14][C@@H:15]([CH3:16])[O:12][C:11]1=[O:13]
Reactant: CCCCCC[C@@H](O)CC(=O)O
Reactant: CC(O)CC(=O)O
Product: C[C@@H]1CC[C@H](O)C(=O)O1

Procedure:
When the above procedures were repeated in the same manner except that β-hydroxybutanoic acid synthesized in Referential Example 2 was used instead of (R)-β-hydroxynonanoic acid, (2S,5R)-2-hydroxy-5-methyl-δ-valerolactone was obtained.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16](=O)[CH:17](OC)[O:18]C.CC(=O)C.Cl>C(O)C>[CH:17]([C:16]1[N:2]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)[N:3]=[CH:14][CH:15]=1)=[O:18]
Reactant: COC(OC)C(=O)/C=C/N(C)C
Reactant: N#Cc1ccc(NN)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: N#Cc1ccc(-n2nccc2C=O)cc1
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A solution of 4-hydrazinylbenzonitrile hydrochloride (10.14 g, 59.78 mmol, 1.00 equiv), (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (17.6 g, 101.61 mmol, 1.70 equiv), propan-2-one (30 mL) and 6N hydrochloric acid (30 mL) in ethanol (300 mL) was stirred at 78° C. for 3.5 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. Water (300 mL) and ethyl acetate (200 mL) were added to dissolve the residue. The resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic layers was washed with water (1×100 mL) and brine (1×100 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 4 g (34%) of 4-(5-formyl-1H-pyrazol-1-yl)benzonitrile as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 9.87 (s, 1H), 8.09-7.98 (m, 3H), 7.85-7.83 (m, 2H), 7.36 (d, J=1.5 Hz, 1H) ppm. LCMS (method A, ESI): RT=1.28 min, m/z=198.0 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@H:17]([CH3:19])[C@H:16]([C:20]#[N:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])O.[Na+]>C(OCC)C>[CH2:7]([N:14]1[CH2:18][C@H:17]([CH3:19])[C@H:16]([CH2:20][NH2:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@H]1C#N
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Lithium aluminum hydride (80%, 3.89 g) was suspended in diethyl ether (90 mL). While the suspension was cooled on an ice bath, a diethyl ether solution (25 mL) of cis-1-benzyl-4-methyl-3-pyrrolidinecarbonitrile (4.11 g) was added dropwise and the mixture was stirred at room temperature for 1 hour. While the reaction mixture was cooled on an ice bath, a saturated aqueous solution of sodium hydrogen carbonate (8 mL) was carefully added dropwise. Following dilution with diethyl ether (100 mL), insoluble materials were collected by filtration and were washed with diethyl ether. The filtrate and the washing solution were combined and the combined solution was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (hexane:ethyl acetate=1:1 shifted to ethyl acetate: methanol=10:1) to give 2.35 g of cis-1-benzyl-4-methyl-3-aminomethylpyrrolidine as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1CC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](C)NC(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)(C)C>[C:1]([O:5][C:6](=[O:39])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)CN1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
0.45 g (0.84 mmol) of N-[[N-[N-(benzyloxycarbonyl)-L-alanyl]-L-phenylalanyl]methyl]-L-proline tert.butyl ester, prepared as described in Example 5, was reduced in 15 mlof isopropanol in the presence of 80 mg of sodium borohydride as described in Example 7. After working-up the two isomers were separated by chromatography on silica gel using System A for the elution. There were obtained 70 mg of isomer 1 of N-[3(S)-[[N-(benzyloxycarbonyl)-L-alanyl]amino]-2(R or S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester in the form of a gum;Rf (System A): 0.38; MS: m/e 540 [M+H]+, and 50 mg of isomer 2 in the form of a gum; Rf (System A) 0.21; MS: m/e 540 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].O.O.O.[C:15]([O-:18])(=[O:17])[CH3:16].[Na+].C=CCCCCCCCC.[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>>[C:15]([O:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:17])[CH3:16]
Reactant: CCCCCCCCCCBr
Reactant: CC(=O)[O-]
Agent: C=CCCCCCCCC
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: O
Product: CCCCCCCCCCOC(C)=O
Temperature: 105 °C

Procedure:
A reaction mixture containing 55 grams of 1-bromodecane (0.25 mole), 270 grams of sodium acetate trihydrate (1.98 moles) 12.5 ml of 1-decene and 10grams of tricaprylylmethylammonium chloride was heated to 105° C for2 hours with mechanical stirring. The progress of the reaction was followedby periodic sampling and gas liquid partition chromatography analysis of the organic layer. The reaction forming decyl acetate was essentially complete after 1 hour. A plot of the data showed reasonably good first-order kinetics.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[Sn](Cl)Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(F)c(-n2ccnc2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(F)c(-n2ccnc2)c1
Yield: 61.5 %

Procedure:
1-(2-Fluoro-5-nitrophenyl)-1H-imidazole (300 mg, 1.45 mmol) was reduced as described in Example 37, step b, using tin(II) chloride (1.14 g, 6.0 mmol) in ethanol (10 ml) to yield the title compound (158 mg, 62%): 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.22 (1H, s), 7.18 (1H, s), 7.02 (1H, dd, J 10.2, 8.8 Hz), 6.68-6.54 (2H, m); MS (ES+) m/z 178 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[O:12][CH2:13][C:14]#[N:15].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[NH:16]1[C:14]([CH2:13][O:12][C:3]2[C:2](=[O:1])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH:4]=2)=[N:15][N:18]=[N:17]1
Reactant: N#CCOc1coc2ccccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(OCc2nnn[nH]2)coc2ccccc12
Temperature: 125 °C
Yield: 59.4 %

Procedure:
A mixture of [(4-oxo-4H-1-benzopyran-3-yl)oxy]acetonitrile (2.0 g, 0.01 mole), sodium azide (0.715 g, 0.011 mole) and ammonium chloride (0.56 g, 0.012 mole) in DMF (10 ml) is heated at 125° C. for 7 hrs. under nitrogen. The reaction is cooled overnight and then poured into excess cold water. The aqueous is acidified with 5N hydrochloric acid and the insoluble product is filtered, washed with fresh water and sucked dry. Recrystallization from absolute ethanol gives beige colored crystals (1.45 g, 60%), mp 194°-196° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=3)[CH:19]=[CH:18]2)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(CCl)cc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1ccc(Cn2ccc3ccc(CC(=O)O)cc32)cc1

Procedure:
The titled compound (21 mg) as a reddish brown solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-methylbenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(OC)ccc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(OC)ccc1Nc1ccc(O)cc1
Reaction time: 8 h
Yield: 122.6 %

Procedure:
A mixture of 6 g of ethyl 2-(4-benzyloxyphenylamino)-5-methoxybenzoate, 30 ml of acetic acid, 270 ml of ethanol and 500 mg of 10% palladium-on-carbon catalyst was hydrogenated on a Parr apparatus for eight hours. The mixture was filtered, the filtrate stripped of solvent and the residue partitioned between ether and saturated sodium bicarbonate solution. The ether solution was dried over anhydrous magnesium sulfate and the solvent removed to give 5.6 g of ethyl 2-(4-hydroxyphenylamino)-5-methoxybenzoate as a yellow solid, m.p. 134°-136° C. when recrystallized from toluene.
Reaction SMILES: [CH2:1]([C:4]1([CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[C:5]1=[O:24])[CH:2]=C.CSC.CC(C)=[O:33]>>[F:21][C:20]([F:23])([F:22])[C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=1)[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:1][CH:2]=[O:33])([CH:25]([CH3:27])[CH3:26])[C:5]1=[O:24]
Reactant: CC(C)=O
Reactant: C=CCC1(C(C)C)CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Solvent: CSC
Product: CC(C)C1(CC=O)CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1=O
Temperature: 25 °C

Procedure:
A solution of 3-allyl-1-(3,5-bis(trifluoromethyl)-benzyl)-3-isopropylpyrrolidin-2-one (1.0 g, 2.54 mmol) in acetone (9 mL) was cooled to −78° C. O3 was bubbled through this solution until the color had changed from colorless to blue (30 min). At this point nitrogen gas was bubbled through the solution for 5 minutes, and dimethyl sulfide (1.88 mL, 25.4 mmol) was added. The solution was allowed to warm to room temperature over 2 h, and then concentrated in vacuo to yield impure 2-(1-(3,5-bis(trifluoromethyl)benzyl)-3-isopropyl-2-oxopyrrolidin-3-yl)acetaldehyde as a clear oil. Key non-solvent resonances in 1H-NMR (400 MHz, CDCl3) δ=9.81 (s, 1H), 8.0-7.8 (m, 3H), 5.2-5.0 (m, 1H), 4.7-4.5 (m, 1H), 3.4-3.1 (m, 2H), 2.2-1.8 (m, 5H), 1.0-0.8 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:18])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[F-].[Cs+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:8]3[C:14](=[O:15])[CH:13]4[CH2:12][CH2:11][CH:10]([CH2:17][CH2:16]4)[C:9]3=[O:18])[CH:7]=2)=[CH:24][CH:23]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(CC2)C1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2CCC(CC2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 3-(5-bromo-2-ethylphenyl)bicyclo[3.2.2]nonane-2,4-dione (0.13 g, 0.39 mmol) and 4-chlorophenylboronic acid (0.087 g, 0.55 mmol) in anhydrous dimethoxyethane (5 ml) is stirred at room temperature under an atmosphere of nitrogen. The reaction mixture is then evacuated and flushed with nitrogen (degassing cycle repeated 4 times). Cesium fluoride (0.178 g, 1.17 mmol) is added, and the suspension is stirred at room temperature for 45 minutes. Next [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.048 g, 0.06 mmol) is added in one portion, and the reaction mixture is heated at 80° C. for 23 hours. After cooling to room temperature the suspension is filtered through diatomaceous earth, then washed with 2M hydrochloric acid (20 ml) and dichloromethane (20 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (10 ml×2). All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a brown gum. The crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio), then further purified by preparative reverse-phase HPLC to afford to afford 3-(4′-chloro-4-ethylbiphen-3-yl)bicyclo[3.2.2]nonane-2,4-dione.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:15]([CH3:16])=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:13]=[C:12]([CH3:27])[CH:11]=1>CS(C)=O.C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[CH:11]=[C:12]([CH3:27])[N:13]=[C:14]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:15]=1[CH3:16])[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6 %

Procedure:
To a solution of 3-pentanol (0.2 ml, 0.5205 mol) in DMSO (1 ml) was added 60% sodium hydride in oil (30 mg) in a portionwise. After stirring at room temperature for 5 min, a solution of 4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenoxy)-pyridine (98 mg) in 0.5 ml of dry THF was added and the resulting mixture was heated at 130° C. for 5 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 20% chloroform in hexane to chloroform as eluent to give 7 mg of the title compound as white crystals, mp 72.5–74° C. 1H NMR (CDCl3) δ 6.84 (s, 2H), 6.26 (s, 1H), 4.16 (m, 1H), 2.27 (s, 3H), 2.17 (s, 6H), 2.04 (s, 6H), 1.69 (m, 4H), 0.95 (t, 6H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][C:23]=1[NH:32][CH2:33][C:34]1[N:35]=[N:36][N:37]([CH3:39])[N:38]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:32]([C:23]3[CH:24]=[C:25]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=[CH:27][C:22]=3[CH3:21])[CH2:33][C:34]3[N:35]=[N:36][N:37]([CH3:39])[N:38]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(C)c(NCc2nnn(C)n2)c1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(=O)c1ccc(C)c(N(Cc2nnn(C)n2)[C@H]2c3cc([N+](=O)[O-])ccc3O[C@](C)(C(OC)OC)[C@@H]2O)c1
Yield: 51 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (420 mg, 1.48 mmol) obtained in step 1 of example 2 and N-(2-methyl-5-(methoxycarbonyl)phenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (520 mg, yield: 51%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>ClCCl>[OH:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(Oc2ccc(C#N)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(Oc2ccc(O)cc2)cc1
Yield: 74.4 %

Procedure:
Following the general procedure for Example 11 (step 2), boron tribromide (1.0 M solution in dichloromethane, 5.73 mL, 5.73 mmol) was added to the product from step 1 (0.43 g, 1.91 mmol) in dichloromethane (10 mL) to afford the title compound (0.30 g, 74%) as an off-white solid.