Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A solution of 628 mg (1.76 mmol) of 1-(t-butoxycarbonyl)-4-(2,2-bis(carbethoxy)ethyl)piperidine (from EXAMPLE 32, Step B) in 8 mL of THF at 0° C. was treated with 2.0 mL of 1.0 M sodium bis(trimethylsilyl) amide solution in THF and stirred cold for 10 min. The resulting mixture was treated with 0.35 mL (2.9 mmol) of benzyl bromide then warmed to rt and stirred for 1 h. The reaction was quenched with 10 mL of sat'd NH4Cl and the quenched mixture was partitioned between 50 mL of ether and 25 mL of H2O. The layers were separated and the organic layer was washed with 25 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 30 g of silica gel using 4:1 v/v hexanes/ether afforded 760 mg (96%) of the title compound: 1H NMR (500 MHz) δ 1.08-1.16 (m, 2H), 1.23 (t, J=7.0,66H), 1.45 (s, 9H), 1.54-1.58 (m, 2H), 1.60-1.66 (m, 1H), 1.78 (d, J=6.0, 2H), 2.68 (app t, J=11.5, 21), 3.28 (s, 2H), 4.01 (br s, 2H), 4.15 (q, J=7.0, 4H), 7.06-7.25 (5H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:17])[CH2:15][CH3:16].CS(C)=O>O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:17][CH2:14][CH2:15][CH3:16])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCN
Solvent: O
Solvent: CS(C)=O
Product: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 7.1 parts of 4-fluoro-3-nitrobenzoic acid, 9.1 parts of 1-propanamine and 25 parts of dimethyl sulfoxide is stirred for 3 hours at 60° C. The reaction mixture is poured onto 150 parts of water. The precipitated product is filtered off, washed with water and dried, yielding 8.8 parts of 3-nitro-4-(propylamino)benzoic acid; mp. 208° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:29][CH:21]1[CH3:20])=[O:18]
Reactant: CC1Cc2ccccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 5 %

Procedure:
The product is prepared according to the procedure described in example 68, using 550 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 400 mg of 2-methylindoline and 500 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 320 μl of pyridine and 8.0 ml of N,N-dimethylformamide. 37 mg of 3-methyl-2-[2-(2-methyl-2,3-di hydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]1[CH2:37][NH:36][C:35](=O)[C@H:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]1[CH2:37][NH:36][C:35](=[S:10])[C@H:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Temperature: 90 °C
Reaction time: 1 h
Yield: 188 %

Procedure:
Lawesson's reagent [2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (2.90 g, 7.18 mmol) was added to a suspension of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (4.79 g, 14.1 mmol) in toluene (250 mL) and the mixture was heated to 90° C. After 1 h, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→85% dichloromethane/ethyl acetate) gave a white solid. This solid was repurified by silica gel chromatography (20% ethyl acetate/hexanes→30% ethyl acetate/hexanes) to give the title compound (4.81 g). MS 357.0 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.10-7.04 (m, 2H), 6.94-6.91 (m, 1H), 6.50 (d, J=6.1 Hz, 1H), 4.62 (dd, J=10.3, 3.7 Hz, 1H), 4.13-3.88 (m, 1H), 3.36 (dd, J=14.7, 7.1 Hz, 1H), 3.07 (t, J=11.2 Hz, 1H), 2.32-2.21 (m, 2H), 2.14-2.12 (m, 1H), 1.79-1.72 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.P([N:50]=[N+:51]=[N-:52])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:50]=[N+:51]=[N-:52])=[O:5]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)ccc1C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To 2-methyl-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoic acid (0.412 g, 1.134 mmol) in a 100 mL round-bottomed flask equipped with a stir bar under N2 was added isopropyl alcohol (11 mL), triethylamine (0.205 ml, 1.474 mmol) and diphenyl phosphorazidate (0.319 ml, 1.474 mmol). The reaction was stirred at room temperature overnight. The resultant solid was filtered, washed with isopropyl alcohol followed by hexanes and dried under vacuum providing the title compound as a white solid (0.294 g, 0.757 mmol, 67%): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.13 (s, 1H), 8.11-8.02 (m, 2H), 7.84-7.77 (m, 2H), 7.40 (d, J=8.6 Hz, 2H), 2.74 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 389 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH2:16][C:15](=[O:18])[N:13]3[C:14]1=[C:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=13)[CH2:5][CH2:4][CH2:3]2.[OH-:19].[Na+]>C(O)C>[CH3:1][C:2]1([CH2:17][CH2:16][C:15]([OH:19])=[O:18])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: CC12CCCc3c1n(c1ccccc31)C(=O)CC2
Agent: [Na+]
Solvent: CCO
Product: CC1(CCC(=O)O)CCCc2c1[nH]c1ccccc21

Procedure:
A solution of 1,2,3,3a,4,5-hexahydro-3a-methyl-6H-pyrido[3,2,1-jk]carbazol-6-one (0.5 g), described in Example 40, in ethanol (10 ml) and 10% sodium hydroxide solution (10 ml) is heated at reflux for 3 hr. The mixture is concentrated, diluted with water and washed with ether. The aqueous phase is rendered acidic with conc. HCl and extracted with chloroform. Concentration of the chloroform extract yields the title compound as a solid, mp 204°-206° C., identical to the product of Example 69.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[CH3:15][NH2:16].[O-2].[Ca+2]>C1COCC1>[Cl:14][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[Cl:13])[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:16][CH3:15]
Reactant: Clc1ccc(OCCCCBr)cc1Cl
Reactant: CN
Agent: [Ca+2]
Agent: [O-2]
Solvent: C1CCOC1
Product: CNCCCCOc1ccc(Cl)c(Cl)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A mixture of 4-(4-bromobutoxy)- 1,2-dichlorobenzene (0.03 mol), methylamine (20 g) and calciumoxide (7 g) in THF (100 ml) was stirred at 125° C. overnight in an autoclave. The mixture was filtered over dicalite and the filtrate was evaporated. The residue was taken up in DIPE and the mixture was filtered over dicalite. The filtrate was converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 6 g (70.3%) of 4-(3,4-dichlorophenoxy)-N-methyl-1-butanamine (intermediate 4, mp. 132° C.).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8][NH:7][N:6]=1)=[N+]=[N-].[H][H]>[Ni].C(O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[C:9]3[C:5](=[N:6][NH:7][N:8]=3)[CH2:4][N:1]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[CH:12]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1n[nH]nc1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Ni]
Solvent: CCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1n[nH]nc1-2
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A mixture of 3 g (8.9 mmole) of 4-azidomethyl-5-[4-chloro-2-(benzoyl)phenyl]-2H-1,2,3-triazole and about 3 teaspoonsful of Raney nickel in 150 ml of ethanol was shaken in a Parr bottle with an initial hydrogen pressure of 5 p.s.i. for 1 hr. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to give 2 g of gummy solid. The residue was chromatographed over silica gel using a 1:1 mixture of ethyl acetate and methylene chloride as eluent. Evaporation of the solvent gave a gum which crystallized from a small amount of ethyl acetate to give white crystals. Recrystallization from a mixture of ethyl acetate and petroleum ether gave colorless prisms, mp 203°-205° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.[OH-].[Na+]>C(O)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]1[NH:13][CH2:14][CH2:15][N:16]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:17]1
Reactant: CCOC(=O)Cl
Reactant: c1csc(C2CNCCN2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)N1CCNC(c2cccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of ethyl chloroformate (20.4 g, 0.19 mol) in acetic acid (150 ml) is added dropwise with stirring to a solution of 2-(2-thienyl)-piperazine (31.6 g, 0.19 mol; Preparation 1) in acetic acid (150 ml) at 65° C. under an atmosphere of dry nitrogen. After 1 h, the solution is allowed to cool to room temperature, and stirring is maintained for an additional 16 h. The reaction mixture is added to chilled 10N NaOH (750 ml) and ice is added to control the exothermic reaction. The mixture is extracted with methylene chloride (4×300 ml), the organic solution is dried(potassium carbonate), and the solvent removed under reduced pressure to give the carbamate (30.0 g) as a light brown oil. This material is dissolved in methanol (250 ml), and the solution added to a solution of maleic acid (18.6 g; 1 eq) in methanol (250 ml). The mixture is treated with charcoal and the solvent removed under reduced pressure to give an oil which crystallizes on trituration with ethyl acetate. The maleate salt melts at 165°-166° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2([CH3:23])[CH2:22][O:21]2)=[O:19])=[CH:13][C:12]=1[CH3:24])#[N:10]>>[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[C:20]([OH:21])([CH3:22])[CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:13][C:12]=1[CH3:24])#[N:10]
Reactant: Oc1ccc(F)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1C#N
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(F)cc2)ccc1C#N

Procedure:
N-(4-Cyano-3-methylphenyl)-3-(4-fluorophenoxy)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1 starting from 4-fluorophenol and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide. 1H NMR (DMSO-d6): 1.42 (3H, s), 2.44 (3H, s), 3.94 (1H, d, J=9.6 Hz), 4.18 (1H, d, J=9.6 Hz), 6.18 (1H, bs), 6.93 (2H, m), 7.08 (2H, m), 7.69 (1H, d, J=9.0 Hz), 7.78 (1H, dd, J=9.0 Hz and 2.1 Hz), 7.93 (1H, d, J=2.1 Hz), 10.02 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:29]([NH:31][NH2:32])[CH3:30].CCN(CC)CC>CCO>[CH2:29]([N:31]1[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:32]1)[CH3:30]
Reactant: CCNN
Reactant: N#Cc1cccc(C(=O)CC(=O)CCc2ccc(F)cc2)c1
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1nc(-c2cccc(C#N)c2)cc1CCc1ccc(F)cc1
Yield: 25.9 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (1.0 g, 3.39 mmol), ethyl hydrazine oxalate (763 mg, 5.08 mmol) and Et3N (709 □L, 5.08 mmol) in EtOH (50 mL) was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The organics were separated, washed with brine (50 mL), concentrated under reduced pressure, and the residue purified by column chromatography on silica eluting with 40% EtOAc/iso-hexanes to yield first 3-{1-ethyl-5-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-3-yl}-benzonitrile (280 mg, 26%) (by-product) and then 3-{1-ethyl-3-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-5-yl}-benzonitrile (380 mg, 35%).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C[N+](C)(C)C.[OH-]>[CH3:13][S:14]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: C=Cc1ccc(OS(C)(=O)=O)cc1
Temperature: 5 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
Approximately 100 gs (6.17×10-1 moles) of 4-acetoxystyrene was added slowly to a cooled stirred solution (480 mL) of 25% TMAH (the temperature was maintained below 25° C. during the addition.) After about 1/2 to 1 hour of stirring, a clear, yellowish solution was obtained. This solution was cooled to 5° C. and the methanesulfonyl chloride 79.5 gs (0.75×10-1 moles) was added with stirring while the temperature was kept below 15° C through cooling with an ice bath. The reaction mixture was stirred for 1/2 hour until neutral pH was observed in the solution. After this time the resulting crystals were filtered-off, washed with distilled water, and sucked dry. The crystals were dissolved in a minimal amount of methylene chloride and recrystallized by addition of hexane. In this way 76 gs (62% yield) of white crystals were recovered. Analysis of the product indicated:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[F:59][C:60]([F:70])([F:69])[O:61][C:62]1[CH:67]=[CH:66][C:65](Br)=[CH:64][CH:63]=1>C1(C)C=CC=CC=1>[F:59][C:60]([F:69])([F:70])[O:61][C:62]1[CH:67]=[CH:66][C:65]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:64][CH:63]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Temperature: 110 °C

Procedure:
Piperazine (0.588 g, 6.84 mmol), Pd(II)acetate (0.027 g, 0.123 mmol), sodium t-butoxide (0.837 g, 10.06 mmol) and BINAP (0.154 g, 0.286 mmol) were stirred at room temperature in 10 mL dry toluene for 15 min. 4-trifluoromethoxy bromo benzene (1.5 g, 6.22 mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction mixture was refluxed at 110° C. for 20 hrs. The reaction mixture was filtered through a celite bed, washed with toluene, concentrated, ethyl acetate added and then extracted with 1.5 (N) aqueous HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated to afford the product.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOC[N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:33])=[C:24]3[C:25](=[O:32])[C:26]4[C:31]([C:18]([C:19]=23)=[N:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=4.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([NH:33][C:23]1[CH:22]=[CH:21][C:20]2[NH:16][N:17]=[C:18]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25](=[O:32])[C:24]=1[C:19]=23)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCOCn1nc2c3c(c(N)ccc31)C(=O)c1ccccc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-5-aminoanthra[1,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0° C. The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate (×2). The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), washed with brine, dried, and evaporated. The residue is chromatographed on silica gel to furnish the desired amide as a yellow solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=1)[CH:13]=[CH2:14]>C(Cl)Cl>[C:21]([C:19]1[CH:20]=[C:15]([CH:16]=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:18]=1[OH:25])[CH2:12][CH:13]1[CH2:14][O:9]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCl
Product: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O

Procedure:
A solution of 22.4 g [0.11 mol] of m-chloroperbenzoic acid [85% strength] in 300 ml of dry methylene chloride is added dropwise to a solution of 24.6 g [0.10 mol] of 4-allyl-2,6-di-tert.-butylphenol of boiling point6 : 134°-36° C [manufactured according to the datain Journ. Org. Chem. USSR 1967, 95] in 175 ml of dry methylene chloride at room temperature, at a speed such that the temperature of the reaction solution does not exceed room temperature. Stirring is continued at room temperature until a sample of the reaction solution indicates that 1 equivalent of peracid has been consumed. Thereafter, excess peracid is destroyed by adding 10% strength aqueous sodium sulphate solution and the organic phase is successively extracted with 5% strength sodium bicarbonate solution and with water, dried over sodium sulphate and evaporated. Crude 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane is obtained as a brownish oil which, when recrystallized from petroleum ether, yields colorless crystals of melting point 86°-87° C.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>>[CH:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C1=CCCCC1
Product: O=C(O)c1ccc(C2C=CCCC2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 114, Step 1, and using 4-iodobenzoic acid (3.0 g, 12.10 mmol), and cyclohexene (12.3 mL) to give the product (0.40 g, 1.98 mmol, 16%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[S:12][CH3:13])[CH:7]=[O:8])[CH3:2].[OH:17]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:14][CH2:15][CH3:16])[C:11]=1[S:12]([CH3:13])=[O:17])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)cc(OCC)c1SC
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(C=O)cc(OCC)c1S(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 3,5-diethoxy-4-methylsulfanyl-benzaldehyde (0.28 g, 1.16 mmol, 1.0 equiv) in conc. acetic acid (5 mL) was added a solution of 35% hydrogen peroxide in water (0.13 mL, 0.15 g, 1.50 mmol, 1.3 equiv). After stirring the solution for 2 h at rt the reaction mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate (1% methanol) providing 0.25 g (84%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 6H), 3.11 (s, 3H), 4.15-4.26 (m, 4H), 7.07 (s, 2H), 9.93 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 14.50, 37.62, 65.34, 106.10, 125.13, 139.95, 159.53, 191.07. MS (ISP): 257.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH:7]([C:9]([F:12])([F:11])[F:10])O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH:7]([C:9]([F:12])([F:11])[F:10])[N:37]1[C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]2[C:33]1=[O:43])[CH3:2]
Reactant: CCOC(=O)CCC(O)C(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCC(N1C(=O)c2ccccc2C1=O)C(F)(F)F

Procedure:
To a solution of 30 mmole of 4-trifluoromethyl-4-oxobutyric acid ethyl ester in 20 ml of ethanol cooled to 0° C. is added 30 mmole of sodium borohydride. The reaction mixture is stirred at 0° C. for 4 hours then acidified with M HCl to a pH of 1. The solvent is evaporated under reduced pressure and the residue is partitioned between water and ether. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester. A mixture of 20 mmole of 4-trifluoromethyl-4-hydroxybutyric acid ethyl ester, 22 mmole of triphenylphosphine, 20 mmole of phthalimide and 22 mmole of diethyl azodicarboxylate in 60 ml of tetrahydrofuran is heated at reflux temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure, and the residue chromatographed on silica gel to give 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester. A suspension of 30 mmole of 4-trifluoromethyl-4-phthalimidobutyric acid ethyl ester in 20 ml of concentrated HCl is heated at reflux temperature for 24 hours. The solid which separates on cooling is filtered, and the filtrate concentrated under reduced pressure. The residue is dissolved in the minimum quantity of water, and the pH of the solution adjusted to 5 by the addition of sodium hydroxide. Acetone is added, and the precipitated 4-amino-4-trifluoromethylbutyric acid collected by filtration.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]2[O:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:3]1=[O:23].[H][H]>[Pd].C(O)C>[NH:15]=[C:16]([C:4]1[C:3](=[O:23])[N:2]([CH3:1])[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][C:5]=1[OH:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: CN1C(=O)c2c(-c3ccccc3)noc2CC1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C(C(=N)c2ccccc2)=C(O)CC1c1ccccc1

Procedure:
A mixture of 4 grams (0.013 mole) of 5-methyl-6,7-dihydro-3,6-diphenyl isoxazolo[4,5-c]pyridin-4(5H)-one, 0.44 grams palladium on carbon and 80 ml. ethanol is hydrogenated at 50 psi until the equivalent amount of hydrogen is absorbed. The catalyst is filtered and washed thoroughly with ethanol. The ethanol is evaporated in vacuo and the residue recrystallized to give 3-α-iminobenzyl-5,6-dihydro-4-hydroxy-1-methyl-6-phenyl-2(1H)-pyridone; m.p. 117° to 120° C.