Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15]2[C:3]=1[CH2:4][C:5]1[C:6]3[CH:7]2[CH2:8][NH:9][CH2:10][C:11]=3[CH:12]=[CH:13][CH:14]=1.C1NCC2=CC=CC3=C2[C@@H]1C1C=C[C:34]([OH:37])=[C:33](O)C=1C3.C[N:40]1[CH2:49][C:48](=[O:50])C2C(=CC=CC=2)[CH2:41]1.C(OC(C1C(C)=CC=CC=1)=O)C.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[CH2:8]1[NH:9][CH2:10][C:11]2=[CH:12][CH:13]=[CH:14][C:5]3=[C:6]2[C@@H:7]1[C:15]1[CH:16]=[CH:17][C:18]([OH:19])=[C:2]([OH:1])[C:3]=1[CH2:4]3.[CH2:34]([O:37][C:48](=[O:50])[CH2:49][NH:40][CH3:41])[CH3:33]
Reactant: Oc1ccc2c(c1O)Cc1cccc3c1C2CNC3
Reactant: CN1CC(=O)c2ccccc2C1
Agent: CCOC(=O)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Product: CCOC(=O)CNC

Procedure:
One compound provided in accordance with the present invention is (±)-8,9-dihydroxy-2,3,7,11b-tetrahydro-1H-naphtho[1,2,3-de] isoquinoline denominated hereinafter as “dinapsoline.” Dinapsoline is synthesized from 2-methyl-2,3-dihydro-4(1H)-isoquinolone according to the procedure depicted generally in FIGS. 1 and 2. Side chain bromination of ethyl-o-toluate (5a) with NBS in the presence of benzoyl peroxide produced compound 5b. Alkylation of sarcosine ethyl ester with compound 5b afforded compound 6, which after Dieckmann condensation and subsequent decarboxylation on acidic hydrolysis yielded compound 7.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:7]O)=[O:6].C(C1NC=CN=1)(C1NC=CN=1)=O>C1COCC1>[F:12][C:11]1[CH:10]=[CH:9][C:4]2[C:5](=[O:6])[NH:7][O:13][C:3]=2[C:2]=1[F:1]
Reactant: O=C(NO)c1ccc(F)c(F)c1O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]oc2c(F)c(F)ccc12
Yield: 96.2 %

Procedure:
A mixture of 3,4-difluoro-N,2-dihydroxybenzamide (Intermediate 527, 7.91 g, 41.8 mmol) and carbonyl diimidazole (13.6 g, 83.7 mmol) in THF (200 ml) was heated at reflux for 90 min. The mixture was partitioned between EtOAC and water and acidified with conc. HCl. The solution was extracted 3 times with EtOAc, each extract being washed with water and brine. Drying (MgSO4) of the combined extracts and removal of solvent gave 6.88 g of product as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH3:24])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH3:24]
Reactant: CCOc1ccc(C=O)cc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: CCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 74.5 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-ethoxybenzaldehyde 1.33 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.55 g.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH:23]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])([CH3:25])[CH3:24].[Br:36][CH2:37][C:38](O)=[O:39]>CN(C)C=O>[Br:36][CH2:37][C:38]([NH:28][C:27]1[C:26]([CH:23]([CH3:25])[CH3:24])=[CH:32][CH:31]=[CH:30][C:29]=1[CH:33]([CH3:35])[CH3:34])=[O:39]
Reactant: O=C(O)CBr
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSC) (2.1 g, 11 mmols) and 1-hydroxybenzotriazole (HOBt) (1.49 g, 11 mmols) were added to an N,N-dimethylformamide (DMF) (30 ml) solution of 2,6-diisopropylaniline (1.97 g, 10 mmols) and bromoacetic acid (2.08 g, 15 mmols) and stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.26 g (42%) of 2-bromo-N-(2,6-diisopropylphenyl)acetamide as colorless needle-like crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])=[O:7].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[OH:30][CH:27]1[CH2:26][CH2:25][N:24]([C:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:16][C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[N:8]([CH3:31])[C:6](=[O:7])[C:5]2[CH:32]=[CH:33][C:34]([NH:35][C:36]([C:38]3[C:46]4[N:45]=[C:44]([CH2:47][NH:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[NH:43][C:42]=4[CH:41]=[CH:40][CH:39]=3)=[O:37])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:23])[CH2:29][CH2:28]1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(=O)CC2)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCC(O)CC2)ccc1NC(=O)c1cccc2[nH]c(CNC(=O)OC(C)(C)C)nc12
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-oxopiperidin-1-yl)carbonylpent-1-yloxy]phenyl]-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (150 mg) in methanol (5 ml) was added sodium borohydride (7.52 mg) under an ice bath cooling and the mixture was stirred at the same temperature for 1 hour. The mixture was diluted with chloroform and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give N-[2-[5-(4-hydroxypiperidin-1-yl)carbonylpent-1-yloxy]-4-methylphenyl]-3-methoxy-N-methyl-4-[2-(tert-butoxycarbonyl)aminomethyl-1H-benzimidazol-4-yl]carbonylaminobenzamide (150 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:42]2[S:43][C:39]3[C:38]([CH3:57])=[N:37][N:36]([CH3:35])[C:40]=3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(s1)c(C)nn2C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2cc(-c3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)sc12
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.301 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (265 mg, 0.601 mmol) and tetrakis(triphenylphosphine) palladium(0) (174 mg, 0.150 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-4-(1,3-dimethyl-1H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 15-65% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (95 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (br s, 2H), 1.43-2.03 (m, 6H), 2.33 (s, 3H), 3.83 (br s, 1H), 3.90 (s, 3H), 4.28 (br s, 1H), 4.39-4.51 (m, 2H), 7.09 (d, J=5.81 Hz, 1H), 7.79 (br s, 3H), 8.61 (s, 1H), 9.22 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H23FN6OS, 415. found, 415.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C[O:11][C:12](=O)[C:13]([OH:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:12](=[O:11])[C:13]([OH:26])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(CO)CC1
Reactant: COC(=O)C(O)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN1CCC(COC(=O)C(O)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1-Methyl-piperidin-4-yl)-methanol (2.58 g, 20 mmol) and hydroxy-diphenyl-acetic acid methyl ester (9.69 g, 40 mmol) are suspended in toluene (65 ml). Molecular sieve 4A (1 g) is added and the mixture is stirred at room temperature for 10 minutes. Sodium (0.08 g) is added and the reaction mixture stirred at 80° C. for 3 hours. Additional sodium (0.1 g) is then added and heating maintained at 80° C. for 18 hours. The reaction mixture is cooled to room temperature, solid filtered off, and washed with ethylacetate. The filtrate is washed once with saturated aqueous NaHCO3 solution (50 ml) and twice with aqueous HCl 1M (25 ml each). The combined acidic aqueous layers are basified with saturated aqueous NaHCO3 solution and solid NaHCO3, the resulting precipitate is removed by filtration, drying under vacuum gives the title product as a white solid (M+H)+:340.09.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:21]=[CH:20][C:10]2[N:11]=[C:12]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])[S:13][C:9]=2[CH:8]=1)(C)C.[OH-].[K+].Cl>CO.CCOC(C)=O>[C:6]([C:7]1[CH:21]=[CH:20][C:10]2[N:11]=[C:12]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])[S:13][C:9]=2[CH:8]=1)#[CH:5]
Reactant: CCNC(=O)Nc1nc2ccc(C#C[Si](C)(C)C)cc2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc2nc(NC(=O)NCC)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.6 %

Procedure:
A mixture of 1-(6-trimethylsilylacetylenyl-2-benzothiazolyl)-3-ethylurea (0.0710 g, 0.22 mmol) and 1M aqueous KOH solution (1.22 mL, 1.22 mmol, 5.5 eq) in 1.5 mL MeOH was stirred at room temperature for about 2 hours. The mixture acidified with 1 M HCl, then taken up in 20 mL AcOEt, and the aqueous phase was extracted with 10 mL AcOEt. The combined organic portions were dried (MgSO4), concentrated, and purified by HPLC to give the desired compound 0.003 g (5%). LC/MS 246 (M+1); LC retention time 2.84 min.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH:17]1([S:23](Cl)(=[O:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH2:8]([NH:9][S:23]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:25])=[O:24])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCc1ccccc1)C1CCCCC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 2-phenylethylamine (0.60 g, 4.97 mmol) in 45 ml CH2Cl2 at room temperature was added Et3N (0.83 ml, 5.97 mmol). The mixture was stirred for 5 min, and then cyclohexanesulfonyl chloride (1.0 g, 5.47 mmol) was added at this temperature.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([NH2:21])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.[C:41](O)(=[O:44])[CH:42]=[CH2:43]>ClCCl.O>[C:1]([NH:5][C:6]1[N:11]=[C:10]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([NH:21][C:41](=[O:44])[CH:42]=[CH2:43])=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH:9]=[N:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)O
Reactant: CC(C)(C)Nc1cncc(-n2cnc3cc(N)ccc32)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1ccc2c(c1)ncn2-c1cncc(NC(C)(C)C)n1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-[6-(tert-butylamino)pyrazin-2-yl]-1H-benzimidazol-5-amine (20 mg, 0.08 mmol) in anhydrous dichloromethane (2 mL) under N2 was added triethylamine (33 μL, 0.24 mmol), EDAC.HCl (22 mg, 0.12 mmol), 4-(1-pyrrolidino)pyridine (cat.) and acrylic acid (8 μL, 0.12 mmol). The resulting mixture then stirred at RT for 3 clays and was the diluted with H2O (10 mL), the organic phase separated and the aqueous phase extracted with CH2Cl2 (10 mL). The combined organic layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography using dichloromethane-methanol (98:2-92:8) as eluant to separate the pure product (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[S:10])=[C:4]([OH:19])[C:3]=1[S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21].[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[S:10])=[C:4]([O:19][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:3]=1[S:20]([N:23]([CH3:25])[CH3:24])(=[O:21])=[O:22]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a solution of N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-bromophenyl)thiourea (500 mg, 1.07 mmol) in THF (20 mL), tert-butyldimethylsilyl chloride (810 mg, 5.35 mmol) and imidazole (144 mg, 2.14 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30% Ethyl acetate/Hexane) gave desired product (240 mg, 40%) and recovered starting material (280 mg). EI-MS m/z 580 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][C:9]=1[CH3:17])(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([CH3:17])[CH:10]=1)#[N:16]
Reactant: Cc1cc(CC#N)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC#N)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
The compound (1.16 g) obtained in Example 520 was dissolved in methylene chloride (15 ml); to the solution, trifluoroacetic acid (4 ml) was added and the mixture was stirred at room temperature for 1 h. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with methylene chloride. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 480.5 mg of the titled compound (yield, 70%).
Reaction SMILES: [C:1]([O:9]CC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[Na+:22]>O1CCCC1>[C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:22]
Reactant: O=C(OCc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C([O-])c1ccccc1
Temperature: 25 °C
Yield: 322 %

Procedure:
The procedure of Example 1 was followed using benzyl benzoate (4.8 mL, 5 mmol), sodium trimethylsilanolate (2.82 g, 25 mmol), dry tetrahydrofuran (100 mL), and 6.25 h of heating at reflux. The reaction mixture was cooled to room temperature and sodium benzoate (2.32 g, 64% yield) was isolated as a white solid: 1H NMR (D2O) δ 7.0-8.0 ppm (m, Ar--H's, 5H). Anal. Calcd. for C7H5NaO: C, 58.34; H, 3.50; Na, 15.95. Found: C, 57.99, 57.94; H, 3.80, 3.83; Na, 16.38, 16.60.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67](O)=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67]([NH:5][CH2:4][CH2:3][F:2])=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: NCCF
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCCF)c3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 31, method B, using 2-fluoroethylamine hydrochloride (0.70 g, 6.98 mmol), N,N-diisopropylethylamine (2.13 ml, 12.3 mmol), HATU (1.46 g, 3.83 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (3.49 mmol) in DMF (90 mL). The crude product was purified by MPLC on silica gel using EtOAc to provide the title compound as white solid. Yield: 0.74 g (35%). 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.46 (m, 5 H), 1.51 (dd, J=13.28, 3.71 Hz, 2 H), 1.57 (s, 9 H), 3.52 (td, J=26.02, 5.15 Hz, 2 H), 3.86 (dd, J=11.52, 3.52 Hz, 2 H), 4.39 (d, J=7.81 Hz, 2 H), 4.43 (m, 2 H), 6.64 (dd, J=3.32, 1.56 Hz, 1 H), 7.26-7.28 (m, 1 H), 7.80-7.83 (m, 1 H), 7.87-7.93 (m, 2 H), 8.24 (d, J=1.17 Hz, 1 H); MS (APPI) (M+H)+=491.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([O:16]CC)=[O:15])[C:11](=[O:19])[N:10]([CH2:20][C:21]([NH:23][C:24]([CH3:36])([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH3:25])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11](=[O:19])[N:10]([CH2:20][C:21]([NH:23][C:24]([CH3:36])([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[CH3:25])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(C)(C)c2cccc(C(F)(F)F)c2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CC(=O)O)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
237 mg (0.45 mmol) of ethyl {3-(4-chlorophenyl)-1-[2-({1-methyl-1-[3-(trifluoromethyl)phenyl]-ethyl}amino)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}-acetate from Example 429 are dissolved in 3 ml of methanol and treated with 0.9 ml of 1 N aqueous lithium hydroxide solution. This is stirred for 24 hrs at RT. The reaction mixture is then concentrated under reduced pressure. 5 ml of water are added, and the mixture is acidified with 1 ml of 1 N hydrochloric acid and extracted twice with 10 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The product that remains is freed from solvent residues under high vacuum. 220 mg (97% of theory) of the target compound are thus obtained.
Reaction SMILES: O1CCCC1.[F-].[CH2:7]([N+:11](CCCC)(CCCC)CCCC)CCC.C(#N)C.Br[CH2:28][C:29]1[CH:34]=[C:33]([CH:35]([S:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])[C:32]([Cl:52])=[CH:31][N:30]=1>CCCCCC>[Cl:52][C:32]1[C:33]([CH:35]([S:44][C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=2)[C:36]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=2[F:43])=[CH:34][C:29]([CH2:28][C:7]#[N:11])=[N:30][CH:31]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(CBr)ncc2Cl)c1
Agent: [F-]
Solvent: CCCCCC
Solvent: CC#N
Solvent: C1CCOC1
Product: N#CCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Under an argon atmosphere, trimethylsilylnitrile (0.226 ml, 1.63 mmol) and a tetrahydrofuran solution (1M, 1.63 ml, 1.63 mmol) of tetrabutylammonium fluoride were added sequentially to an acetonitrile (10 ml) solution of 2-bromomethyl-5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (516 mg, 1.09 mmol) at room temperature. The resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=9:1 eluate was concentrated under reduced pressure to give the title compound (390 mg, 0.93 mmol, 85%) as a brown oil.
Reaction SMILES: [NH2:1][C:2]1([C:8](O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B(F)(F)F.CCOCC.B#B.[OH-].[Na+]>C1COCC1.O.C1COCC1>[NH2:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC1(C(=O)O)CCCCC1
Agent: B#B
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC1(CO)CCCCC1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
1-Amino-1-cyclohexanecarboxylic acid(51.5 g, Aldrich) was added to 150 ml of THF followed by boron trifluoride etherate(27 ml, Aldrich). The reaction mixture was heated to 40° C., stirred for 10 minutes and then a 1.0M solution of diborane(380 ml, Aldrich) was added. The mixture was refluxed for 2 hr, cooled and added THF/water (1:1,25 ml) followed by 6N NaOH(95 ml). The reaction mixture was refluxed for 2 hr, cooled to room temperature and the organic layer was separated, washed with brine, dried and concentrated to give a light yellow oil (34.0 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH:21]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:21]=[C:20]([CH:19]=[C:4]([CH:5]=[C:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH:3]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1
Reactant: Cc1cc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.1 %

Procedure:
To a solution of tert-butyl 4-(3-methyl-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.50 g, 0.0011 mol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.85 mL, 0.011 mol) slowly. The resulting mixture was stirred for 2 h at RT. The solution was concentrated under reduced pressure to give the title compound (445 mg).