Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2](N(CC)CC)C.CO.[C:11]([C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([OH:24])([CH2:17]3)[CH2:15]1)[CH2:21]2)([OH:13])=[O:12]>CN(C=O)C>[CH3:2][O:12][C:11]([C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][C:16]([OH:24])([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:13]
Reactant: CCN(CC)CC
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: [Cl-]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-adamantanol obtained by the method of Example 2 was dissolved in 10 ml of DMF. To the mixture, 15 mmole of tionyl chloride was added dropwise over 30 minutes while heating the mixture to the reflux temperature so as to begin to reflux at about the time the addition is finished. After refluxing for 2 hours, the mixture was cooled. To the mixture, 20 mmole of triethylamine was added and 11 mmole of methanol was added dropwise over 30 minutes while keeping the temperature of the solution at 10° C. or below, and the mixture was stirred for another 2 hours. As a result, the conversion of 1-carboxy-3-adamantanol was 99%, and 1-methoxycarbonyl-3-adamantanol (yield 95%) was formed.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.[NH2:15][CH:16]([CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([NH:15][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH2:24][CH3:25])[CH:21]([CH3:22])[CH3:23]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc2ccccc2c1
Product: CCC(NC(=O)Cc1ccc2ccccc2c1)C(=O)OCC(C)C

Procedure:
Following General Procedure I above and using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH2:13][CH3:14])[C@:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1.ClC1N=C(N2CC(CC)C(C3CC3)(C#N)C2=O)C=CN=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([CH2:13][CH3:14])[C@@:10]([CH:17]3[CH2:19][CH2:18]3)([C:15]#[N:16])[C:9]2=[O:20])[CH:5]=[CH:4][N:3]=1
Reactant: CC[C@@H]1CN(c2ccnc(Cl)n2)C(=O)[C@]1(C#N)C1CC1
Agent: CCC1CN(c2ccnc(Cl)n2)C(=O)C1(C#N)C1CC1
Solvent: CCCCCC
Solvent: CC(C)O
Product: CC[C@@H]1CN(c2ccnc(Cl)n2)C(=O)[C@@]1(C#N)C1CC1
Yield: 109.8 %

Procedure:
To a mixture of 3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (3.7 g) obtained in Step B of Example 376, 2,4-dichloropyrimidine (3.1 g), cesium carbonate (13 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.71 g) in tetrahydrofuran (55 mL) was added tris(dibenzylideneacetone)dipalladium(0) (0.38 g), and the mixture was stirred overnight at 85° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3SR,4RS)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) and (3SR,4SR)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g). (3SR,4RS)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.3 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (500 mg) having a shorter retention time and (3R,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (510 mg) having a longer retention time. (3SR,4SR)-1-(2-Chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (1.6 g) was resolved by HPLC (column: CHIRALCEL OD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=700/300) to give (3S,4S)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (560 mg) having a shorter retention time and (3R,4R)-1-(2-chloropyrimidin-4-yl)-3-cyclopropyl-4-ethyl-2-oxopyrrolidine-3-carbonitrile (600 mg) having a longer retention time.
Reaction SMILES: [C:1]([NH:4][C:5]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH:22]([NH2:25])([CH3:24])[CH3:23].[CH:26]1([NH:32][S:33](=[O:36])(=[O:35])[OH:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCOCC>O1CCCC1.CC(C)=O>[CH:26]1([NH:32][S:33](=[O:34])(=[O:35])[O-:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1.[C:1]([NH:4][C:5]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][NH:25][CH:22]([CH3:24])[CH3:23])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)NC1CCCCC1
Reactant: CC(C)N
Reactant: COC(=O)C(=Cc1ccc(OCC2CO2)cc1)NC(C)=O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc(OCC(O)CNC(C)C)cc1)NC(C)=O
Product: O=S(=O)([O-])NC1CCCCC1

Procedure:
15.6 g (0.05 mol) of 1-[p-(2-acetylamino-2-carbomethoxyvinyl)-phenoxy]-2,3-epoxy-propane are dissolved in 50 ml of absolute tetrahydrofurane, 4.25 ml (0.05 mol) of isopropylamine are added and thereafter the mixture is heated for 18 hours to the boil under a reflux condenser. It is then evaporated in vacuo and the resulting crude base is dissolved in ethyl acetate. The solution is extracted three times with 20 ml of 1 N hydrochloric acid at a time. The hydrochloric acid extracts are brought to pH 8 with sodium carbonate solution and the crude base which hereupon has separated out is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulphate and evaporated in vacuo. 17 g of crude base are obtained as a brownish oil. This is dissolved in 20 ml of acetone and mixed with a solution of 9 g of N-cyclo-hexylsulphamic acid in 70 ml of acetone. After addition of ether, the N-cyclohexylsulphamate of 1-[p-(2-acetylamino-2-carbomethoxy-vinyl)-phenoxy]-2-hydroxy-3-isoproylamino-propane, melting point 121°-125°C, is obtained.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:16]1[CH2:21][CH2:20][CH:19]([Mg]Cl)[CH2:18][CH2:17]1>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[O:16]1[CH2:21][CH2:20][CH:19]([C:2]2[C:3]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:18][CH2:17]1
Reactant: Cl[Mg]C1CCOCC1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1

Procedure:
To a round bottomed flask was added 4-(3-chloropyrazin-2-yloxy)aniline (1.2276 g, 5.54 mmol) dissolved in a mixture of THF (8.86 mL) and NMP (2.215 mL). Iron(iii) acetylacetonate (0.098 g, 0.277 mmol) was added and the temperature was brought to 0° C. (Tetrahydro-2H-pyran-4-yl)magnesium chloride (8.31 mL, 6.65 mmol) was added dropwise to the reaction mixture. Upon completion, the reaction was quenched with saturated ammonia chloride solution. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCN
Reactant: O=C1CCC(=O)O1
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CCC(=O)O

Procedure:
preparation from 1-(tert-butoxycarbonylamino)-4,7,10-trioxa-13-tridecanamine (5 g) and succinic anhydride (1.98) gave 7 g crude product. LCMS (Method 6): Rt 3.34 min; m/z (M+1) 421 Calcd: 421
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:26])[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:14]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]1)[CH:8]=[CH:7]2.[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH3:39])C(O)=O)=[CH:31][CH:30]=1.[CH2:42](Cl)CCl>COCCOCCOC>[CH3:24][C:21]([CH3:22])([CH3:23])[C:20]([NH:19][CH:16]1[CH2:17][CH2:18][N:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:3]4[N:26]=[C:42]([CH2:39][CH2:35][C:32]5[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:40])[F:41])=[CH:34][CH:33]=5)[O:1][N:2]=4)[CH:5]=3)[N:10]=2)[CH2:15]1)=[O:25]
Reactant: CC(C)(C)C(=O)NC1CCN(c2ccc3cc(C(=N)NO)ccc3n2)C1
Reactant: CC(C(=O)O)c1ccc(C(F)(F)F)cc1
Reactant: ClCCCl
Solvent: COCCOCCOC
Product: CC(C)(C)C(=O)NC1CCN(c2ccc3cc(-c4noc(CCc5ccc(C(F)(F)F)cc5)n4)ccc3n2)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of the product of Step E, (66 mg) in anhydrous diglyme (2 mL) was added 4-trifluoromethylphenylpropionic acid (1.1 eq.) and EDC (2 eq.). The reaction mixture was heated to 50° C. overnight. After approximately 18 h, the mixture was heated at 110° C. for 2 hr. The mixture was cooled to r.t., quenched with water and extracted with excess EtOAc. The combined extracts were dried over a drying agent filtered and the solvent removed under vacuum. The residue was purified by preparative TLC eluting with EtOAc to afford the product, MS: m/z 538.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C:3](=[O:11])[CH2:4][C:5](=[O:10])[C:6]([O:8]C)=O.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.C(O)(=O)C>O1CCOCC1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]2[CH:33]([C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[O:30][CH3:29])[C:4]([C:3](=[O:11])[C:2]([CH3:1])([CH3:20])[CH2:12][O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)=[C:5]([OH:10])[C:6]2=[O:8])=[CH:24][CH:23]=1
Reactant: COC(=O)C(=O)CC(=O)C(C)(C)COC1CCCCO1
Reactant: COc1ccccc1C=O
Reactant: Nc1ccc(Br)cc1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccccc1C1C(C(=O)C(C)(C)COC2CCCCO2)=C(O)C(=O)N1c1ccc(Br)cc1
Yield: 32.9 %

Procedure:
A mixture of methyl 5,5-dimethyl-2,4-dioxo-6-(tetrahydro-2H-pyrane-2-yloxy)hexanoate (4.29 g, 15 mmol), 4-bromoaniline (2.58 g, 15 mmol), 2-methoxybenzaldehyde (1.812 mL, 15 mmol), acetic acid (0.343 mL, 6 mmol) and dioxane (15 ml) was heated at reflux overnight. After the reaction was completed, the mixture was concentrated in vacuo and the resulting residue was purified on a silica gel column chromatography (ethyl acetate/n-hexane). The resulting aimed compound was triturated with ethyl acetate and n-hexane to give 1-(4-bromophenyl)-4-(2,2-dimethyl-3-tetrahydro-2H-pyrane-2-yloxypropionyl)-3-hydroxy-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (2.69 g, yield: 33%) as colorless solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NCc1ccccc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 62.4 %

Procedure:
To N,N-dimethylformamide 0.5 mL solution of benzyl bromide 41 mg were added tert-butyl 2-amino-4-phenylbenzoate 54 mg and potassium carbonate 55 mg at room temperature, and it was stirred at 80° C. for 9 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=100:1] to give tert-butyl 2-benzylamino-4-phenylbenzoate 45 mg of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>C1COCC1.CCOC(C)=O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]2[NH:10][C:11](=[O:12])[NH:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc2[nH]c(=O)[nH]c2c1
Yield: 79.6 %

Procedure:
After 4-amino-3-nitrobenzonitrile (3.26 g, 20 mmol) was treated with hydrogen in MeOH (300 mL) in the presence of 5% palladium on active carbon (1 g) at room temperature for 16 hours, the reaction mixture was filtered and the filtrate was concentrated to give 3,4-diaminobenzonitrile (2.4 g, 90% yield). A solution of 3,4-diaminobenzonitrile (2 g, 15 mmol) in THF (100 mL) was treated with carbonyldiimidazole (CDI, 3.2 g, 19 mmol) at room temperature for 18 hours. The mixture was diluted with EtOAc (150 mL), washed with 1N HCl (30 mL) and brine, and dried over MgSO4. Filtration and concentration gave 5-cyanobenzimidazolinone (1.9 g, 80%). 1H NMR (CD3OD) δ 7.40 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.34 (d, J=1.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H); MS: 160.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12](O)=[O:13].Cl.[CH3:21][NH:22][O:23][CH3:24].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[F:8][C:9]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:11][C:12]([N:22]([O:23][CH3:24])[CH3:21])=[O:13]
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.082 mL, 7.81 mmol) was added to a stirred solution of 4,4,5,5,5-pentafluoropentanoic acid (1.00 g, 5.21 mmol), N,O-dimethylhydroxylamine hydrochloride (0.559 g, 5.73 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.998 g, 5.21 mmol) in dry DCM (5.35 mL) at 25° C. under N2. The reaction was stirred at 25° C. overnight. The reaction was diluted with CH2Cl2 (60 mL) and washed consecutively with 1N aq. HCl (2×), satd aq. NaHCO3, dried (Na2SO4) and concentrated in vacuo to give the desired product, as a colorless liquid. 1H NMR (500 MHz, CHCl3-d): δ 3.72 (s, 3H); 3.21 (s, 3H); 2.74 (t, J=7.8 Hz, 2H); 2.51-2.37 (m, 2H). m/z=236.2 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[C:21](O)(=O)[C:22](O)=O.[C:27](#N)[CH3:28]>>[CH:21]1([CH2:22][N:11]2[CH2:12][CH2:13][C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:14])[CH2:10]2)[CH2:28][CH2:27]1
Reactant: CC#N
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC1(c2cccc(F)c2F)CCN(CC2CC2)C1

Procedure:
Preparation according to Example 51. Enantiomer E1 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.11 g, 0.55 mmol), acetonitrile (6 mL), potassium carbonate (0.140 g, 1 mmol) cyclopropylmethyl bromide (0.05 mL, 0.51 mmol). Flash chromatography on silica gel (Ethyl acetate/methanol, 10:1). Yield: 0.045 g. [α]D=+12.5°; The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether; Mp. 170-171° C.; MS m/z (relative intensity, 70 eV) 253 (M+, 27), 96 (bp), 97 (60), 55 (44), 141 (32), 98 (2).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:12]=[CH:11][C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=1>C(=S)=S>[Br:1][C:9]1[O:10][C:6]2[CH:5]=[C:4]([CH3:3])[CH:12]=[CH:11][C:7]=2[CH:8]=1
Reactant: BrBr
Reactant: Cc1ccc2ccoc2c1
Solvent: S=C=S
Product: Cc1ccc2cc(Br)oc2c1
Temperature: 150 °C
Yield: 98.8 %

Procedure:
A solution of bromine (8.4 g, 0.0525 mol) in carbon disulphide (75 cm3) was added dropwise to a stirred solution of 6-methylbenzofuran (7.64 g, 0.0516 mol) in carbon disulphide (125 cm3) at below 10° C. The solvent was removed and the residue was heated at 150° C. for 1.5 hr. under reduced pressure. The residue was subjected to column chromatography on silica using petroleum ether (b.p. 60°-80° C.) as the eluant. The solvent was removed from the appropriate fractions to give 2-bromo-6-methylbenzofuran (11.0 g, 0.051 mol; 98.2%) RF 0.80.
Reaction SMILES: [C:1]1(=O)[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[NH2:13]C(N)=O>O>[C:1]1(=[O:7])[NH:13][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: NC(N)=O
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: O
Product: O=C1Cc2ccccc2C(=O)N1
Yield: 52.8 %

Procedure:
Homophthalic anhydride (20 g) and urea (60 g) were reacted at 170° C. for 1 hr. The reaction mixture was cooled, water (500 ml) was added thereto, and then the resulting precipitates were collected by filtration. The precipitate were washed with water and dried in hot air, to give 10.5 g of homophthalimide as a white powder. (17-2) 1,3-Dichloroisoquinoline
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[NH2:1]/[C:2](/[CH3:11])=[C:3](/[C:21](=[S:22])[NH:20][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: C/C(N)=C(/C(=O)OC(C)(C)C)C(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
A mixture of t-butyl 3-aminocrotonate (65.3 g, 0.4 mol), benzoyl isothiocyanate (62.9 g, 0.4 mol), and diethyl ether (300 ml) was stirred at ambient temperature for 3 hours. The solid product was collected on a filter, washed with ether and dried to give 56 g (43.7 percent yield) of material melting at 107° to 110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[O-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:17]([NH2:18])=[O:16])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCC1OC(=O)c2cc(NC(N)=O)ccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a solution of 8.27 g (0.04 mol) of the compound obtained in Example 4 in 39.4 ml of glacial acetic acid there are added, with sting, 25 ml of water, and to this solution there is slowly added a solution of 6.54 g of potassium cyanate in 10 ml of water. Once a white precipitate appears, the remaining potassium cyanate solution is added in one portion immediately. The mixture is warmed at 55° C., and stirred for 1 hour, then put aside at room temperature for 3 hours. 50 ml of water are added and the mixture is cooled to 5° C.; the separated solid is collected and dissolved in 10% sodium carbonate solution. Any insoluble material is filtered off and the filtrate is acidified with dilute sulphuric acid. The solid is collected and washed with water and dried, giving the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C:2](C)=[CH2:3].[O:14]=[O+][O-].CSC>ClCCl.CO>[C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])[C:2]([CH3:3])=[O:14]
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: CC(=O)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of 25 mL (147.5 mmole) of benzyl methacrylate in 500 mL of dichloromethane and 125 mL of methanol was cooled to −78° C. and ozonized until the solution was pale blue, indicating excess ozone. The solution was purged with nitrogen until the blue color of ozone had dissipated, and then 14.1 mL (192 mmole, 1.3 equivalents) of dimethyl sulfide was added rapidly dropwise under nitrogen. After stirring for one hour more at −78° C. the solution was removed from the cold bath and allowed to stir at room temperature for 3 hours. The solution may be stored overnight in the freezer at this point. Volatiles were removed on the rotary evaporator at 40° C. and the residue was taken up in 100 mL of dichloromethane and washed with 100 mL of water to remove dimethyl sulfoxide. The water layer was back extracted with a small volume of dichloromethane. The combined organics were washed with water in this fashion twice more. The final organic layer was filtered through cotton, concentrated on the rotary evaporator, and high-vacuum dried leaving an essentially quantitative yield of benzyl pyruvate as a colorless liquid. A small amount of formaldehyde methyl hemiacetal and/or the methyl hemiacetal of benzyl pyruvate may be present but do not interfere in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28]O)=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1.[CH2:30]([N:32](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:27]([CH2:28][C:30]#[N:32])=[CH:26][CH:25]=[CH:24][N:23]=2)[O:17][N:16]=1
Reactant: CCN(CC)CC
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CO)on1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CC#N)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a mixture of [2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]methanol (1.47 g), triethylamine (760 mg) and ethyl acetate (150 mL) was dropwise added methanesulfonyl chloride (860 mg) under ice-cooling and the mixture was stirred at room temperature or 2 hrs. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (50 mL) was added an aqueous solution (5 mL) of sodium cyanide (280 mg) at room temperature and the mixture was stirred at room temperature for 12 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (1.40 g, 68%) of 2-[2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals (1.07 g, 71%). melting point: 110-111° C.