Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](O)=[O:24])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([O:40][NH:41][C:23](=[O:24])[CH2:22][O:21][C:20]1[CH:26]=[CH:27][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:1])([CH3:31])[CH3:32])=[C:7]([CH3:29])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NOCc1ccccc1
Reactant: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)(c1ccc(OCC(=O)NOCc2ccccc2)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of acid compound 6 (27.4 mg, 0.0622 mmol) in DMF (0.1 mL) was added BnONH2, (10.5 mg, 0.0653 mmol, 1.05 equiv.), followed by iPr2NEt (33 μL, 24 mg, 0.1866 mmol, 3.0 equiv.) and HBTU (25.6 mg, 0.0684 mmol, 1.1 equiv.). After 2 h, the reaction was quenched by the addition of brine and then extracted with EtOAc (×4). The combined organic phases were stirred with triethylamine resin, dried over Na2SO4 and concentrated in vacuo to give a crude product which was subsequently purified by preparative tlc (10:90 acetone/toluene). This afforded the title compound 7 (27.7 mg, 82%)
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CC(O)N1
Reactant: OCc1ccccc1
Product: O=C1C=CC(OCc2ccccc2)N1
Temperature: 60 °C

Procedure:
A mixture of 8 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 130 cm3 of benzyl alcohol and 4 g of Amberlite IR 120 H is heated for 3 hours at 60° C. The benzyl alcohol is distilled off at 65° C. under 0.3 mbar. then is drawn off under azeotropic form first with water and then with benzene. 13.6 g of the expected product is obtained, which is unstable on distilling.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.O>COCCOC>[O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:27])[F:28])=[CH:26][CH:25]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of ethyl 3-oxo-3-phenylpropionate (28.6 g, 145 mmol) in 1,2-dimethoxyethane (1.50 ml) was added sodium hydride (60% in oil, 5.65 g, 141 mmol) under ice-cooling and the mixture was stirred at room temperature for 1 hr. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (33.8 g, 141 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 2 hrs. The reaction solution was poured into water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-oxo-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate (45.4 g, 75%) as a yellow oil.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:19]C1C=C(Br)C=CC=1N.FC1C=C(Br)C=CC=1N>>[CH3:19][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: Cc1cc(Br)ccc1N
Agent: Nc1ccc(Br)cc1F
Product: Cc1cc(-c2ccccc2S(N)(=O)=O)ccc1N

Procedure:
This compound was prepared by the method described for 2-fluoro-4-(2 -aminosulfonylphenyl)aniline described in EXAMPLE 8 by starting with 2-methyl-4-bromoaniline rather than 2-fluoro-4-bromoaniline.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)[N:7]([CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:18])[N:7]([CH3:19])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(C)(C)C)cc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbamate (294 mg, 0.895 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.895 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 258 mg (74.8%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)=O.[OH2:31]>>[NH2:14][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:31])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: O
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: NCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Product: Nc1c(-c2ccc(-c3ccc(F)cc3)cc2)nc2ccc(Cl)cc2c1C(=O)O

Procedure:
A basic aqueous solution of 4.54 g of 5-chloroisatin in water was reacted with 9.0 g of 2-amino-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)ethanone hydrochloride by the procedure described in example 20, giving 6.2 g of the desired compound as a yellow solid, mp 255°-257° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>[N+](C1C=CC=CC=1)([O-])=O.CCOCC>[CH2:1]([O:3][C:4]([C:5]1[C:10]2[N:11]=[C:19]([C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][C:17]=3[C:23]([F:25])([F:24])[F:26])[NH:12][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:13])[CH3:2]
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)c1cncc(N)c1N
Solvent: CCOCC
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)c1cncc2[nH]c(-c3ccc(F)cc3C(F)(F)F)nc12
Temperature: 220 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
A mixture containing ethyl 4,5-diaminonicotinate (79; 0.9 g, 5 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (82; 1.0 g, 5.2 mmol) in nitrobenzene (50 mL) was stirred at 220° C. for 18 h. Upon cooling to room temperature, the reaction mixture was diluted with ether. The resulting solids were collected by filtration, washed with ether, and dried to provide 2-(4-fluoro-2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine-7-carboxylic acid ethyl ester 83 (600 mg, 39%).
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[CH2:29][CH:4]1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH2:12][C:13]([CH3:18])([CH3:17])[O:14]2)=[CH:9][CH:8]=1>C(O)C>[C:19]1([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH:4]([OH:3])[CH2:29][NH:2][CH3:1])=[CH:8][CH:9]=3)[O:14][C:13]([CH3:18])([CH3:17])[CH2:12]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CN
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
Methylamine (7 ml) was added to 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)chroman (3.3 g., 0.0092 moles) in ethanol (7 ml) and the solution left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as a dark coloured oil which was converted to the hydrochloride salt. Recrystallization from 1:1 petroleum ether:ether gave a grey solid (0.85 g., 24%) m.p. 96°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([NH:15][CH3:16])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:23]([NH:31][C:32](=[S:33])[N:15]([C:13]1[O:12][N:11]=[C:10]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)[CH3:9])[CH:14]=1)[CH3:16])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CNc1cc(C(C)c2ccc(-c3ccccc3)c(F)c2)no1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: c1ccncc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(N(C)C(=S)NC(=O)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution consisting of {3-[1-(2-fluoro-biphenyl-4-yl)-ethyl]-isoxazol-5-yl}-methyl-amine (4.06 g), pyridine (40 ml) and benzoyl isothiocyanate (2.5 g) was stirred overnight at room temperature. The solution was concentrated and the residue was purified by a silica gel column chromatography to obtain the desired compound (5.28 g).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[C:13]([F:31])[CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:21][CH2:22]2)=[C:13]([F:31])[CH:12]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)cc2F)CC1
Product: Fc1cc(Cl)ccc1C1CCN(CCCc2onc3c2CCCCC3)CC1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-2-fluorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[S:8][CH2:9][CH2:10][NH:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl[CH2:15][C:16](Cl)=[O:17].[CH3:19][NH2:20]>O1CCCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:19][NH:20][CH2:15][C:16]([N:11]1[CH2:10][CH2:9][S:8][C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]1=2)=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCS2
Reactant: O=C(Cl)CCl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNCC(=O)N1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (500 mg, 2.55 mmol) in tetrahydrofuran (4 mL) was added 2-chloroacetyl chloride (0.223 mL, 2.80 mmol). The resulting mixture was stirred at 60° C. for 10 minutes, at which time the reaction was cooled to 0° C. To the mixture was then added methylamine (2 M in tetrahydrofuran; 12.7 mL, 25.4 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was then diluted with water and saturated sodium carbonate then extracted with dichloromethane (3×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:4:5 (2M NH3 in methanol:ethyl acetate:dichloromethane, giving the desired product (511 mg, 75%) as a yellow solid. 1H NMR (DMSO-d6) δ 8.36 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 3.93 (t, J=5.1 Hz, 2H), 3.48 (s, 2H), 3.34-3.28 (m, 2H), 2.28 (s, 3H), 2.00 (brs, 1H); ESI-MS (m/z, %): 268 (MH+, 100).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:2]12[CH2:8][OH:9].[OH-:10].[Na+]>S(=O)(=O)(O)O.O1CCOCC1.O>[OH:10][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:1]
Reactant: [OH-]
Reactant: OCC12CCCCC1O2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCC1(O)CCCCC1O

Procedure:
A stirred mixture of 10.6 g of 1,2-epoxycyclohexanemethanol and 8 drops of concentrated sulfuric acid in 100 ml of p-dioxane and 100 ml of water was heated at 60°-70° for 18 hours. The reaction mixture was neutralized with sodium hydroxide, and evaporated under reduced pressure to a viscous residue. The residue was taken up in methanol and dried with sodium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to a residue. The residue was distilled to give 10.8 g of 1,2-dihydroxycyclohexanemethanol; bp 170°-240°/0.02 mm. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:14][CH:13]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(Oc3cccc(S(C)(=O)=O)c3)cc2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(Oc3cccc(S(C)(=O)=O)c3)cc2)CC1=O
Reaction time: 16 h

Procedure:
A solution of 1.8 g (4.3 mmol) of 2-propionyl-3-hydroxy-5-(4-(3-(methylsulfonyl)phenoxy)phenyl)-cyclohex-2-en-1-one in 5 mL of methylene chloride and 10 mL of absolute ethanol at room temperature was treated with 0.50 g (5.2 mmol) of ethoxyamine hydrochloride and 0.50 g (6.1 mmol) of anhydrous sodium acetate. After stirring under a nitrogen atmosphere for 16 hours, the mixture was poured into 100 mL of water and extracted thrice with 15 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel. Evaporation of the solvent left the above named product as a pale oil in a yield of 1.8 g (91 percent of theoretical). 1H NMR (CDCl3): δ1.09-1.48 (m, 6H, both --CH2CH3 's), 2.57-3.60 (m includes s at 3.02 for CH3SO2 --, 10H), 4.13 (q, J=7 Hz, 2H, OCH2), 6.92-7.75 (m, 8H, aromatics), 14.9 (broad s, H, enol 1H) (Compound 3).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH3:11])C=CC=CC=1.[C:24]([CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)#[N:25].C(=O)([O-])O.[Na+]>COC(C)(C)C>[CH3:9][O:10][CH:11]=[C:29]1[CH2:30][CH2:31][CH:26]([C:24]#[N:25])[CH2:27][CH2:28]1
Reactant: N#CC1CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC=C1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
9.6 g of triphenyl(methoxymethyl)phosphonium chloride were suspended in 50 ml of t-butyl methyl ether while gassing with argon and treated portionwise at -10° C. with 3.39 g of solid potassium t-butylate. After completion of the addition, the mixture was stirred at 0° to 5° C. for a further 30 minutes and then the deep orange, partially heterogeneous mixture was treated dropwise within 10 minutes with a solution of 2.30 g of 4-cyanocyclohexanone in 20 ml of t-butyl methyl ether. In so doing, the internal temperature should not exceed 5° C. After completion of the addition, the now yellow-orange mixture was warmed to 25° C. and stirred for a further 2 hours. 50 ml of a 2% sodium hydrogen carbonate solution were subsequently added and the separated, aqueous phase was extracted twice with 50 ml of diethyl ether each time. The organic phases were washed with 50 ml of saturated sodium chloride solution, dried over potassium carbonate and concentrated. The residual, semi-crystalline, orange oil was triturated with 400 ml of hexane, cooled to -20° C. and freed from precipitated triphenylphosphine oxide by filtration (rinsing with cold hexane). Low-pressure chromatography (0.4 bar) of the concentrated residue on silica gel using 10% ethyl acetate/petroleum ether as the eluant gave 1.60 g (56%) of 4-(methoxymethylene)cyclohexanecarbonitrile as a colourless oil (purity 97%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([C:29](=[O:33])[C:30]([OH:32])=O)[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C(Cl)=O.[NH:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][N:40]([C:30](=[O:32])[C:29]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1)=[O:33])[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:46]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 1.0 g (2.16 mmol) of 3,5-bis(decyloxy)-alpha-oxobenzeneacetic acid in 50 ml of anhydrous methylene chloride and 2 drops of DMF stirred in an ice bath was added 0.94 ml (10.8 mmol) of oxalyl chloride. The cooling bath was removed and stirring was continued at room temperature for 2 hours. The solvent was removed at reduced pressure and the residual acid chloride was dissolved in 40 ml of anhydrous methylene chloride and added dropwise to an ice bath cooled solution of 0.6 ml (3.2 mmol) of diethyl iminodiacetate and 0.6 ml (4.3 mmol) of triethylamine in 10 ml of methylene chloride. After stirring in the ice bath for 30 minutes and at room temperature for 18 hours, the reaction mixture was washed with NaHCO3, dried and concentrated at reduced pressure to an oil which was purified by chromatography on 25 g of 230-400 mesh silica gel using 20% ethyl acetate-hexane to give 1.2 g (91% yield) of N-[[3,5-bis(decyloxy)phenyl]-1,2-dioxoethyl]-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester as an oil. The nmr and mass spectra served to confirm the structure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[O:26]([C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[N:41][C:33]=3[O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3cccnc3Oc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-phenoxynicotinoyl chloride: ESMS m/e: 543.3 (M+H)+.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[NH2:18].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)([O-])=O.C(NC(C)C)(C)C>CN(C)C=O.CO.[Pd]>[NH2:20][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:3](=[O:19])[C:4]3[C:5](=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:8][CH:9]=3)[NH:18][C:30]2=[O:31])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1N
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)Nc1ccc2c(=O)n(-c3ccc(N)cc3)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of 2-amino-4-(tert-butoxycarbonylamino)-benzoic acid methyl ester (6.3 g, 23.6 mmol) and 4-nitrophenyl isocyanate (7.8 g, 47.4 mmoles) in 100 mL dry dimethylformamide was stirred at room temperature for 20 hrs. To it was then added diisopropylamine (8.2 mL, 47.4 mmol), and the reaction mixture was heated in 80° C. bath for 2 hrs. It was cooled to room temperature and the solid precipitates were filtered off. The dimethylformamide filtrate was concentrated in vacuo to evaporate the solvent. To the residue was added 400 mL dichloromethane. After stirred and swirled, the solid was isolated by filtration. This solid was then dissolved in 100 mL dimethylformamide and 200 mL methanol. To it was added 1.0 g 10% Pd/C, and the mixture was subjected to standard hydrogenation using a balloon for 20 hrs. It was filtered through a celite bed. The filtrate was concentrated in vacuo and purified using flash column to afford the title compound (4.1 g, 44%). ES+ MS showed 397 m/z, the correct mass for the product.
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].[C:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[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:42](=[O:43])[CH2:41][CH2:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[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(O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 64 h
Yield: 22.3 %

Procedure:
A solution of 270 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester and 98 mg of 4-phenylbutyric acid in 10 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 81 mg of hydroxybenzotriazole, 69 mg of N-ethylmorpholine and 136 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using System G for the elution to give 79 mg of N-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(4-phenylbutyryl)-L-asparaginyl]amino]butyl]-L-proline tert.butyl ester as a white solid; MS: m/e 595 [M+H]+.