Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Cl)Cc1ccccc1Cl

Procedure:
2-Chlorophenylacetic acid (51 mg, 0.3 mmol) was dissolved in ethyl acetate (1.5 mL), the solution was added with thionyl chloride (26 μL, 0.36 mmol), and the mixture was refluxed by heating for 4 hours. The solvent was evaporated under reduced pressure to give 2-chlorophenylacetyl chloride. By using this compound and 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (190 mg, 0.6 mmol) obtained in Example 1, (3), the title compound (10 mg, yield 11%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5](=[O:8])[CH2:6]Br)([CH3:3])[CH3:2].[C:17]1([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5](=[O:8])[CH2:6][NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: COc1cccc(N(C(=O)CBr)C(C)C)c1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-Isopropyl-N-(3-methoxy-phenyl) bromoacetamide, prepared as in Part B, (12.0 g 41.9 mmol), N-phenyl phenylenediamine (7.7 g, 41.9 mmol) and potassium carbonate (5.79 g) in DMF (100 mL) is stirred at RT for 20 h. The reaction mixture is filtered through celite and the filtrate diluted with ethyl acetate (150 mL) and washed with water (2×100 mL), 2N hydrochloric acid (2×100 mL), 1N aqueous sodium hydrogen carbonate (100 mL), dried (K2CO3 /MgSO4), and concentrated in vacuo. Purification by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent gave 8.2 g of N-Isopropyl-N-(3-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide as a light brown foam: 1H NMR (300 MHz, CDCl3) δ7.43 (t, 1H, J=8.0), 7.3-7.1 (m, 3H), 7.02 (m, 2H), 6.9-6.6 (m, 7H), 6.36 (d, 1H, J=7.8), 5.3 (s, br, 1H), 4.95 (m, 1H, J=6.8), 3.88 (s, 3H), 3.53 (s, 2H), 1.06 (m, 6H).
Reaction SMILES: FC1C(O[C:9](=[O:31])[NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]3[S:18][C:19]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[C:20]([C:22]#[N:23])[N:21]=3)[CH2:12]2)=C(F)C(F)=C(F)C=1F.[CH2:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][NH:37]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:22]([C:20]1[N:21]=[C:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@@H:11]([NH:10][C:9]([N:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:36]3)=[O:31])[CH2:12]2)[S:18][C:19]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)#[N:23]
Reactant: c1ccc2c(c1)CNC2
Reactant: N#Cc1nc(N2CCC[C@@H](NC(=O)Oc3c(F)c(F)c(F)c(F)c3F)C2)sc1Nc1ccccn1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nc(N2CCC[C@@H](NC(=O)N3Cc4ccccc4C3)C2)sc1Nc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
A solution of crude {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-carbamic acid pentafluorophenyl ester (˜50 μmol) in tetrahydrofuran (1 mL) was cooled to 0° C. under an atmosphere of argon and isoindoline (12.6 mg, 106 μmol) and diisopropylethylamine (20 μL, 115 μmol) were added. The reaction mixture was stirred at 0° C. for 1 hour then warmed to ambient temperature and stirred for an additional hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL), poured into water (10 mL) and extracted with ethyl acetate (4×5 mL). The combined organic extracts were washed with brine (2×5 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography using a 12 g C-18 column gradient eluted from 10% acetonitrile in water up to 100% acetonitrile. The product containing fractions were combined and concentrated in vacuo to a yellow solid. The yellow solid was taken up in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a yellow viscous oil (11.3 mg, 50%).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12](OCC)=[O:13])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[BH4-].[Na+]>CC(O)=O>[C:1]1([C:7]2[S:11][C:10]([CH2:12][OH:13])=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OCc1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (350 mgs, 1.494 mmol) in anhydrous methanol (5 mL, 124 mmol) was added NaBH4 (226 mgs, 5.98 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. AcOH (2 mL) was added and the reaction was concentrated to dryness. The residue was dissolved in EtOAc, brine and water and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aqueous NaHCO3 and brine, and dried over anhydrous magnesium sulfate. After filtration and evaporation, the residue was triturated with ethyl ether to give the title material as a first crop (150 mgs, 52%). LC (Method B): 2.022 min, LCMS (APCI) calcd for C9H9N2OS [M+H]+ m/z 193.04. found 193.2. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.92-8.03 (m, 2H), 7.44-7.59 (m, 3H), 5.14 (br. d, J=3.90 Hz, 2H), 2.63 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:6]1[CH2:10][O:9]C(C)(C)[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:5])[CH3:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:9][CH2:10][CH:6]([NH:7][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:3]([O:2][CH3:1])([CH3:4])[CH3:5]
Reactant: COC(C)(C)C1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(C)(C)C(CO)NC(=O)OC(C)(C)C
Yield: 98.4 %

Procedure:
tert-Butyl 4-(1-methoxy-1-methylethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (2.5 g) obtained in Example 73a) was dissolved in methanol (45 ml), p-toluenesulfonic acid monohydrate (0.18 g) was added thereto, and mixed at room temperature for 20 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a colorless solid (2.1 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:9]1=[O:47].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>Cl>[NH:48]([C:13]1[N:12]=[C:11]2[N:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:23]=3)[C:9](=[O:47])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])[CH2:17][C:16]2=[CH:15][N:14]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: CC(C)(C)[Si](OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(S(C)(=O)=O)nc32)c1)(c1ccccc1)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Product: CC(C)(C)[Si](OCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1)(c1ccccc1)c1ccccc1
Temperature: 180 °C
Yield: 100 %

Procedure:
1.5 g (2 mmol) of 3-(2-bromophenyl)-1-[3-(tert-butyldiphenylsilyloxymethyl)phenyl]-3,4-dihydro-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 61(h)) was treated with 3 ml of aniline and the mixture heated at 180° C. for 20 minutes and cooled. The mixture was poured into 50 ml of 2M aqueous hydrochloric acid and the precipitated product filtered off, washed with water and dried to afford 1.5 g (100%) of 7-anilino-3-(2-bromophenyl)-1-[3-((tert-butyldiphenylsilyloxy)methyl)phenyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a light brown solid. [Mass spectrum (ESI) MH+ =741].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CCC(O)c1ccnc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1ccnc(Br)c1
Reaction time: 30 h

Procedure:
To a solution of 1-(2-bromopyridin-4-yl)-propan-1-ol (2.20 g 10.2 mmol) in dichloromethane (55 mL) is added Dess-Martin periodinane (5.6 g, 13 mmol). After 30 hours, the mixture is diluted with saturated aqueous sodium carbonate (40 mL) and partially concentrated to remove the dichloromethane. The crude material is filtered through filter agent and washed with EtOAc (100 mL). The aqueous layer is separated and extracted with EtOAc (40 mL). The combined organic layers are washed with saturated aqueous sodium carbonate (40 mL) and brine (40 mL). The material is dried over magnesium sulfate, filtered and concentrated to afford 1-(2-bromopyridin-4-yl)-propan-1-one as an oil which is used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:14])=[C:5]([C:10]([O:12]C)=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([I:14])=[C:5]([C:10]([OH:12])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: COC(=O)c1sc(SC)c(C#N)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1sc(C(=O)O)c(I)c1C#N
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of methyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (3.40 g, 10 mmol) in tetrahydrofuran (80 mL) and water (16 mL) was added a solution of 1.00M sodium hydroxide in water (30 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N hydrogen chloride in water (50 mL) and diluted with water (400 mL). The resultant precipitate was filtered, washed with water (2×100 mL) and dried in a vacuum oven to give 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylic acid (2.6 g, 79%) as a white solid. LCMS: (FA) ES+ 326.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1([CH3:18])[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]1=2.[N+:19]([O-])([OH:21])=[O:20]>>[CH3:6][C:7]1([CH3:18])[CH2:13][CH2:12][CH2:11][NH:10][C:9]2[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:17][C:8]1=2
Reactant: CC1(C)CCCNc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
H2SO4 (2.5 ml) was cooled in a brine/ice bath. 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 g, 6.3 mmol) was added drop wise. The resulting slurry was stirred for 30 min. HNO3 (0.26 ml, 6.3 mmol) and more H2SO4 (1.5 ml) were added slowly. The reaction was stirred at 0-15° C. for 2 h, poured into ice water, extracted with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated to give 5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[C:22]2[N:23]([N:27]=[C:28]([Cl:30])[N:29]=2)[CH:24]=[CH:25][CH:26]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O1CCOCC1>[Cl:30][C:28]1[N:29]=[C:22]2[C:21]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[O:32][CH3:31])=[CH:26][CH:25]=[CH:24][N:23]2[N:27]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1nc2c(Br)cccn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1-c1cccn2nc(Cl)nc12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
A Schlenck flask was charged with palladium acetate (0.0966 g, 0.430 mmol), triphenylphosphine (0.4513 g, 1.721 mmol), and 1,4-dioxane (6 mL) and the mixture was stirred for 5 min until it turned bright yellow. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol), 2-methoxybenzeneboronic acid (0.490 g, 3.23 mmol), N,N-dimethylformamide (10.00 mL), and 1.00 N sodium carbonate in water (4.3 mL, 4.3 mmol) were added successively and the reaction was heated at 80° C. overnight, cooled to room temperature, diluted with dichloromethane, filtered through diatomaceous earth and concentrated. The reaction was purified via chromatography (silica gel 10%→20% ethyl acetate in hexanes) and concentrated to give 2-chloro-8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.464 g, 83%). MS=260 (MH)+. 311b) To an oven-dried Schlenck flask under an atmosphere of argon was added 2-chloro-8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.460 g, 1.77 mmol), 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.558 g, 2.12 mmol), palladium acetate (0.0875 g, 0.390 mmol), 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.242 g, 0.443 mmol), cesium carbonate (1.44 g, 4.43 mmol), followed by 1,4-dioxane (12.00 mL) and was degassed under an atmosphere of argon for 5 min and heated at 100° C. overnight, cooled at room temperature, diluted with dichloromethane, filtered through diatomaceous earth and concentrated. The reaction was purified via chromatography (silica gel 20%-30% ethyl acetate/hexanes) and concentrated to give 7-[8-(2-methoxy-phenyl)[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.744 g, 87%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.35 (s, 1H) 7.15 (m, 1H), 7.05 (m, 3H), 3.74 (s, 3H), 3.48 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H): MS=486 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].Cl[C:15]1[C:16]2[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=2[N:18]=[CH:19][N:20]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[NH4+].O>O1CCOCC1>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25]([O:27][CH3:28])=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)=[C:3]([O:11][CH2:12][CH3:13])[CH:4]=1)(=[O:7])[NH2:8]
Reactant: CCOc1cc(C(N)=O)ccc1N
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(=O)OC)c(C)c12
Temperature: 25 °C

Procedure:
4-amino-3-ethoxy-benzamide (0.045 g, 0.25 mmol), methyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (0.061 g, 0.25 mmol, Fluorochem Ltd.) and para-toluene sulfonic acid (0.005 g, 0.025 mmol) were heated at reflux in anhydrous 1,4-dioxane (1.5 mL) for 16 hours. The solution was cooled to ambient temperature, ammonium hydroxide/water (1:4, 5 mL) added and the precipitate collected and washed successively with water and diethyl ether. The title compound was obtained as a yellow solid (0.057 g, 59%) after recrystallisation from MeOH.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.OO.S(=O)(=O)(O)[OH:13].CC1C=C(C)C=C(O)C=1O>CC(C)CC(=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[C:7]=1[OH:13]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=S(=O)(O)O
Agent: Cc1cc(C)c(O)c(O)c1
Agent: OO
Solvent: CC(=O)CC(C)C
Product: Cc1cc(O)cc(C)c1O

Procedure:
In a vessel used in Example 52 were placed 100 g. (819 m. moles) of 3,5-dimethylphenol, 3.61 g. (36.1 m. moles) of 4-methyl-2-pentanone, 2.88 g. (50.8 m. moles) of 60 percent hydrogen peroxide and 0.01 g. of sulfuric acid, and the mixture was reacted at 110° C. for 20 minutes in the same manner as in Example 52. The reaction mixture was analyzed with gas chromatography. As products, 3.19 g. (23.1 m. moles) of 3,5-dimethylcatechol and 2.24 g. (16.2 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 77.4 percent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40]([O:42]C)=[O:41])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.CO.O.[OH-].[Li+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40]([OH:42])=[O:41])=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1
Reactant: COC(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
To a suspension of methyl (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetate of Example 32 (0.585 g, 1.03 mmol) in 2:1 v/v methanol:water (12 mL) was added lithium hydroxide monohydrate (87 mg, 2.07 mmol) and the mixture heated to reflux for 90 minutes. The cooled reaction mixture was concentrated in vacuo to remove methanol and then diluted with water (10 mL). The aqueous phase was washed with ethyl acetate (2×10 mL) then slowly added to a mixture of 1 M aqueous hydrochloric acid (2.2 mL) in water (20 mL) and the resulting suspension cooled to 0° C. for 1 hour. Filtration afforded the title compound (0.381 g, 66%) as a tan solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17]2[CH2:18][CH:19]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]([CH:23]=2)[CH2:21][CH2:20]3)[CH:9]=1>CCOC(C)=O.[Pd]>[CH3:39][Si:36]([CH3:37])([CH3:38])[CH2:35][CH2:34][O:33][CH2:32][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:41])[CH3:40])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH:19]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]([CH2:21][CH2:20]3)[CH2:23]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4nccc4n3)CC1CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Temperature: 45 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]oct-3-ene-8-carboxylate (12.2 g, 20.3 mmol) and 10% Pd/C (2.1 g) in EtOAc (175 ml) was stirred at 45° C. under hydrogen (balloon pressure) for 16 hours. After filtration and concentration, the crude mixture of two isomers was purified by gradient column chromatography on silica eluting with EtOAc/Hexanes (0-35%) to give the slightly impure “endo” product (6.24 g, Rf=0.6 in 25% EtOAc/Hexanes) and the “exo” product (5.44 g, Rf=0.5 in 25% EtOAc/Hexanes) which was used in the following reaction sequences.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43](Cl)=[O:44].C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:43]([C:34]1[CH:35]=[CH:36][C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=1)=[O:44])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2c1
Yield: 64.3 %

Procedure:
A solution of 249 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, 106 mg of 2-naphthoyl chloride and 72 mg of diisopropylethylamine in 10 ml of dry dichloromethane was stirred at 20° C. for 20 hours. The gelatinous reaction mixture was partitioned between dichloromethane and water. The organic phase was evaporated and the resulting oil was crystallized from ethyl acetate/n-hexane to give 215 mg of N-[2(R)-hydroxy-3(S)-[[N-(2-naphthoyl)-L-asparaginyl]amino]-4-phenylbutyl]-L-proline tert.butyl ester, as a white solid; MS: m/e 603 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[C:3]=1[CH2:14][C:15]([OH:17])=[O:16].[CH3:18]S(O)(=O)=O>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[C:3]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CS(=O)(=O)O
Reactant: N#Cc1ccc2c(CC(=O)O)c(O)ccc2c1
Solvent: CO
Product: COC(=O)Cc1c(O)ccc2cc(C#N)ccc12
Temperature: 40 °C
Yield: 172.6 %

Procedure:
A solution containing 18.2 g of 2-hydroxy-6-cyano-1-naphthylacetic acid, 250 ml of methanol and 3 g of methanesulfonic acid was stirred at 40° C. to perform dissolution, followed by stirring at room temperature for 2 days. Then, 5 g of active carbon was added, followed by stirring for 30 minutes. Thereafter, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. To the residue was added 50 ml of 50% hydrous methanol, and then the precipitate was collected by filtration to obtain 13 g of the desired product.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]2[C:14](SC)=[N:15][C:16]3[S:20][CH:19]=[CH:18][C:17]=3[C:12]2=[N:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OC)(=[O:26])C=C.C[O-].[Na+].C(O)(=O)C>CO.ClCCl>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[N:11]([C:14]([O:26][CH3:23])=[N:15][C:16]3[S:20][CH:19]=[CH:18][C:17]=32)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: CSc1nc2sccc2c2nnc(SCc3ccccc3)n12
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc2sccc2c2nc(SCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Benzylthio-5-methylthiothieno[3,2-e][1,2,4]-triazolo[4,3-c]pyrimidine (19.2 g (57.2 mmol)was mixed with 100 mL of methanol and to this was added with stirring 7.7 mL (86 mmol) of methyl acrylate and 3.3 mL of 25 percent sodium methoxide in methanol. After 2 hours at ambient temperature, the mixture was heated to reflux for about 2.5 hours during which time another 10 mL of 25 percent sodium methoxide in methanol was added. The mixture was stirred at ambient temperature overnight and then another 5 mL of the 25 percent sodium methoxide in methanol was added and the mixture heated to reflux again for 2 hours. The resulting mixture was acidified with acetic acid and was then concentrated by evaporation under reduced pressure to obtain a tan solid. This was dissolved in 600 mL of dichloromethane and the solution obtained was washed 3×100 mL with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The tan, solid residue was flash chromatographed on silica gel (240-400 mesh, 5×20 cm (centimeter) column) eluting with mixtures of hexane and ethyl acetate ranging from 90:10 to 50:50. The second compound to elute was collected to obtain 12.6 g of the title compound as a nearly white solid melting at 160°-162° C. The proton NMR spectra of this was consistent with the assigned structure.