Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:40]=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Yield: 88 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.04 mmol), 3-methoxy-phenylboronic acid (2.3 g, 15.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (425 mg, 0.6 mmol) in 1,4-dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15.4 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×40 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 10:1) afforded 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.3 g, 90%) as a white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.50 (d, 1H, J=4.8 Hz), 7.90 (d, 1H, J=4.8 Hz), 7.67 (d, 2H, J=7.5 Hz), 7.42 (t, 1H, J=7.5 Hz), 7.27-7.18 (m, 3H), 6.82 ((t, 2H, J=9.0 Hz), 6.65 (s, 1H), 6.55-6.46 (m, 2H), 6.18-6.15 (d, 1H, J=10.2 Hz), 3.67 (s, 3H), 2.69-2.66 (m, 1H), 1.15 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH2:37][CH:38]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([NH:37][CH:38]2[CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41]2)=[O:29])[CH:4]=[N:3]1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)NC2CN(C(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (2.18 g) and tert-butyl 3-amino-1-azetidinecarboxylate (793 mg) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (1.07 ml), and the mixture was stirred under reflux for 40 hours. To the reaction mixture was added methylene chloride, and the solution was washed successively with 10% aqueous citric acid solution, 10% aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% methanol/methylene chloride to give tert-butyl 3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-azetidinecarboxylate (1.52 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:7])[C:4]([OH:6])=O.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[C:19]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH:25][C:4](=[O:6])[C:3]([O:2][CH3:1])([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH3:7])=[CH:22][CH:21]=1)#[N:18]
Reactant: COC(C)(C(=O)O)c1cccc2ccccc12
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C)(C(=O)NCc1ccc(C#N)cc1)c1cccc2ccccc12

Procedure:
2-Methoxy-2-(1-naphtyl)propionic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-naphthalen-1-yl-propionamide. Colorless foam. MS 345.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[CH3:24]O>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: CO
Reactant: COc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(N)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.4 %

Procedure:
To a solution of 2.5 g (7.8 mmol) of (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of methanol was added 0.125 g (0.66 mmol) of p-toluene sulfonic acid monohydrate. The solution was stirred at room temperature for 2 days and then concentrated to a small volume. The residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to a solid. Recrystallization of this solid from hexane-ethyl acetate gave 2.48 g of methyl (E)-6-(1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 91°-93° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C[O-].[Na+].[C:12](O)(=[O:14])C>CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:14][CH3:12]
Reactant: N#Cc1ccccn1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 6 h

Procedure:
2-cyanopyridine (10.0 g, 96.1 mmol) was dissolved in methanol (50 ml). Sodium methoxide (0.26 g, 4.8 mmol) was added to the solution, and reaction was conducted for 6 hours at room temperature. After the reaction was completed, acetic acid (0.32 g, 5.3 mmol) was added to neutralize the reaction solution, and the solution was concentrated under reduced pressure. Diethyl ether (50 ml) was added to the concentrated residue, and diethyl ether insoluble products were removed by filtration. The filtrate was concentrated under reduced pressure to give the crude product of methyl 2 pyridinecarboximidate as a pale yellow oil in a yield of 7.5 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3]1.[CH:13](OC)=[O:14].CC([O-])(C)C.[K+]>C1COCC1>[CH:13]([CH:8]([CH2:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:14]
Reactant: COC(=O)CCc1cnn(C)c1
Reactant: COC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C=O)Cc1cnn(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
A solution of methyl 3-(1-methyl-1H-pyrazol-4-yl)propanoate (18.7 g, 111 mmol) and methyl formate (14.02 g, 233 mmol) in dry THF (20 ml) was added dropwise over 2 h to a stirred, ice-cooled suspension of t-BuOK (31.2 g, 278 mmol) in dry THF (160 ml) under argon. The mixture was then allowed to warm to room temperature and stirred for 16 h. The solvents were removed in vacuo, and the residue was dissolved in water (50 ml). The solution was extracted with ethyl acetate (30 ml×2), and the aqueous phase was neutralized with 1M HCl to pH ˜5. The solid was collected. The filtrate was extracted with ethyl acetate (40 ml×2), dried over Na2SO4, filtered and concentrated in vacuo. The solids were combined to give the title compound as a white solid (9.1 g, 39.8% yield). LCMS: rt=1.05 min, [M+H+]=197
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].CO[CH:7](OC)[CH:8]([N:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:11](=[O:13])[CH3:12])Cl.[OH-].[Na+]>ClCCCl>[C:11]([N:10]1[CH:8]=[CH:7][C:20]2[C:15](=[C:16]([Cl:1])[C:17]([Cl:21])=[CH:18][CH:19]=2)[CH2:14]1)(=[O:13])[CH3:12]
Reactant: COC(OC)C(Cl)N(Cc1cccc(Cl)c1)C(C)=O
Reactant: [Cl-]
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(=O)N1C=Cc2ccc(Cl)c(Cl)c2C1
Temperature: 0 °C

Procedure:
To a suspension of 91 g. (0.682 m.) of aluminum chloride in 1400 ml. of 1,2-dichloroethane was added a solution of N-acetyl-2,3-dichlorobenzylaminoacetaldehyde dimethyl acetal (45.5 g., 0.149 m.) in 230 ml. of 1,2-dichloroethane over an hour, the temperature staying below 30° C. The mixture was then cooled to 0° C. and 1000 ml. of 40% NaOH was added. The mixture was stirred and the layers separated. The aqueous fraction was extracted with 500 ml. of 1,2-dichloroethane and the combined organic layers were washed with 300 ml. of water and dried over magnesium sulfate. Evaporation and trituration with ether gave 2-acetyl-7,8-dichloro-1,2-dihydroisoquinoline.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[Na+].O>CS(C)=O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
10.4 g of 4-hydroxy-carbazole (57 mmol) were dissolved in 31.1 ml of DMSO. 6.9 ml of epichlorohydrin (88 mol) were added and next 57 ml of a 1 N sodium hydroxide solution. The mixture was stirred for 8 h at 40° C. It was cooled to 20° C. and 130 ml of water were added. The product was filtered under suction, and washed with 3×30 ml water. The crude material was recrystallized from isopropanol. The substance was dried at 60° C. for 12 h.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: BrCCc1ccccc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cnn(CCc2ccccc2)c1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (1.50 g, 12.87 mmol) in MeCN (30 mL), (2-bromoethyl)benzene (1.97 mL, 14.15 mmol) and Cs2CO3 (4.61 g, 14.15 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo to obtain 4-nitro-1-phenethyl-1H-pyrazole as a beige solid which was used in the next step without further purification. LC-MS conditions A: tR=0.92 min; [M+H]+=217.97.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: NCCc1ccc(O)cc1
Product: CCOc1ccc(-c2ccnc(NCCc3ccc(O)cc3)n2)cc1

Procedure:
Intermediate 47 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 336. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.2 (d, 1H), 8.0 (d, 2H) 7.0 (m, 4H) 6.6 (d, 3H), δ 4.0 (q, 2H), 3.4 (t, 2H), δ 2.7 (t, 2H), 1.3 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1Cl.[Cr]([Cl:15])([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([Cl:15])[CH:3]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: OCc1ccc(Br)c(Cl)c1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: OCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mL0 was stirred at 25° C. for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.12 g g, 81%). 1H NMR (300 MHz, d6-DMSO): δ 9.96 (s, 1H), 7.69 (d, J=8.1, 1H), 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(N)cc1
Yield: 53.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was treated with 10% palladium on activated carbon (500 g). The reaction mixture was shaken under 60 psi of hydrogen gas at 25° C. for 18 h. The catalyst was then filtered off through a pad of celite and was washed with ethyl acetate. The filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52 g, 53.3%) as a yellow oil: EI-HRMS m/e calcd for C16H23NO2 (M+) 261.1727, found 261.1727.
Reaction SMILES: [CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Cl:20][CH2:21][C:22]([O:15][C:14]1[C:2]([CH3:1])=[C:3]2[C:11](=[C:12]([CH3:17])[C:13]=1[CH3:16])[O:10][C:6]1([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH2:4]2)=[O:23]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC1(CCC1)O2
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1OC(=O)CCl)CCC1(CCC1)O2
Temperature: 0 °C

Procedure:
A solution of 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol (500 mg) in anhydrous CH2Cl2 (3 mL) was mixed with a 15% aq. NaOH solution (2.0 mL). The resulting mixture was cooled to 0° C. and stirred vigorously while being treated with slow addition of a solution of chloroacetyl chloride (0.534 mL) in CH2Cl2 (2 mL). The reaction mixture was allowed to warm up to ambient temperature and stirred for an additional 6 h. Upon layer separation, organic phase was collected and dried over Na2SO4, followed by solvent evaporation. Column chromatography (SiO2: hexane:EtOAc, 95:5 v/v) yielded 5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl chloroacetate as a pale yellow solid (204 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[CH:27][CH:26]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1

Procedure:
N-(4-Methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-methoxybenzylamine using method H. NMR; δH [2H6]—DMSO 9.07,(1H, t), 7.98,(2H, d), 7.89,(1H, dd), 7.76,(1H, d), 7.55-7.50,(3H, m), 7.26,(2H, d), 6.89,(2H, d), 4.43,(2H, d), 3.72,(3H, s), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.24 min, MH+ 414.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: O
Solvent: NCCO
Product: COc1ccc(OC)c(C=C2NC(=O)NC2=O)c1

Procedure:
A mixture of 2,5-dimethoxybenzaldehyde (2.504 g.) and hydantoin (1.507 g., 1 molar ratio) in water (15 ml) was heated to 70°. To this 2 layer liquid was added monoethanolamine (1.38 g., 1.5 molar ratio). The mixture was heated 4 hours at 90°-92° (bath temperature) with magnetic stirring. The title compound was isolated in the usual manner and obtained as a yellow solid (3.288 g.), m.p. 250°-252°. Crystallization from dioxane (96% recovery) gave m.p. 251°-252°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][NH:13][CH2:14][CH2:15][NH:16][C@H:17]([CH:25]([CH3:27])[CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:33](Cl)(Cl)=[O:34]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C@H:17]([CH:25]([CH3:26])[CH3:27])[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C:33]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)[C@@H](NCCNCc1cccc(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)[C@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(OCc3ccccc3)c2)C1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 62.2 %

Procedure:
t-Butyl (R)-2-(2-(3-benzyloxybenzylamino)ethylamino)-3-methylbutyrate (155 mg; 0.37 mmol) was dissolved in toluene (5 ml) and cooled to 0° C. NaOH (1N; 5 ml; 5 mmol) was added, as was phosgene (20% in toluene; 0.37 ml; 0.75 mmol). The mixture was stirred at 0° C. for 6 h, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (2×; 5 ml). The combined organic phases were dried over MgSO4, and the solvents were removed under reduced pressure. Purification of the residue by column chromatography (SiO2) resulted in t-butyl (R)-2-(3-(3-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (102 mg; 0.23 mmol). MS: 439.25 (M+H); Rt: 2.12 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: O=C(O)Cc1cc(=O)oc2cc(O)ccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(CC(=O)O)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To 9 (1 g, 4.53 mmol) was added 25 ml of acetic anhydride and 5 ml of pyridine, and the reaction was allowed to stir at RT for 30 minutes. Upon removal of solvent in vacuo, the residue was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford 10 (30% yield). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.9 Hz, 1H), 7.23 (d, J=5.6 Hz, 1H), 7.24 (s, 1H), 6.47 (s, 1H), 2.94 (s, 2H), 2.33 (s, 3H). MS (ESI): m/z 263.0 [(M+H)]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:26][OH:27])[CH:23]([CH3:24])[CH:22]([CH3:25])[O:21]2)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2([CH2:26][O:27][S:2]([CH3:1])(=[O:4])=[O:3])[CH:23]([CH3:24])[CH:22]([CH3:25])[O:21]2)=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1OC(CO)(c2ccc(Cl)cc2)C1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1OC(COS(C)(=O)=O)(c2ccc(Cl)cc2)C1C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
0.13 ml (1.68 mmole) of methanesulfonyl chloride, followed by 0.24 ml (1.708 mmole) of triethylamine were added at 0° C. to a solution of 123 mg (0.543 mmole) of 2-(4-chlorophenyl)-3,4-dimethyl-2-hydroxymethyloxetane in 10 ml of methylene chloride, and the resulting mixture was stirred for 4 hours, during which time the reaction temperature was allowed to rise to room temperature. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel, eluted with a 10:1 by volume mixture of hexane and ethyl acetate, to afford 107 mg (yield 65%) of the title compound.
Reaction SMILES: [CH2:1]=[C:2]([C:7]#[N:8])[C:3]([C:5]#[N:6])=[CH2:4].C(C#N)CC=[CH:12][CH2:13][CH:14]([C:18]#[N:19])[CH2:15][CH2:16][CH3:17]>C(Cl)Cl>[CH2:3]([C:5]#[N:6])[CH2:2][CH2:1][CH2:1][C:2]([C:7]#[N:8])=[C:3]([C:5]#[N:6])[CH2:4][CH2:12][CH2:13][CH:14]([C:18]#[N:19])[CH2:15][CH2:16][CH3:17]
Reactant: C=C(C#N)C(=C)C#N
Reactant: CCCC(C#N)CC=CCCC#N
Solvent: ClCCl
Product: CCCC(C#N)CCCC(C#N)=C(C#N)CCCCC#N

Procedure:
A further preparation employed 1,3-butadiene-2,3-dicarbonitrile in a condensation reaction with 9-oxatricyclo[4.2.12,5.0]non-3-ene-1,6-dicarbonitrile utilizing methylene chloride as diluent under room temperature conditions and a contacting time of about 5 days. By this method, a conversion of about 50 percent was obtained based on the 9-oxatricyclo[4.2.12,5.0]non-3-ene-1,6-dicarbonitrile, resulting in nearly 100 percent ultimate yields of 13-oxatetracyclo[8.2.12,9.0.03,8 ]tridec-5-ene-1,5,6,10-tetracarbonitrile.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:12]1[CH:17]=CC=C[CH:13]=1.CNC>>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]([CH3:17])[CH3:13])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CBr)cc1
Reactant: c1ccncc1
Agent: CNC
Product: CN(C)C(=O)c1ccc(CBr)cc1
Temperature: 23 °C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
A mixture of 4-bromomethyl-benzoyl chloride (7.0 g, 30.24 mmol), polyvinyl pyridine (9.6 g, 90.7 mmol) and dimethyl amine (15.9 ml, 31.8 mmol, 2.0 M in THF) was stirred at 23° C. for 15 h. The solution was filtered and the solvent removed to give 7.3 g (99% yield) of 4-bromomethyl-N,N-dimethyl-benzamide as a yellow solid.
Reaction SMILES: C([N:8]1[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]([C:19]([O:21][CH2:22][CH2:23][CH3:24])=[O:20])[N:10]=[C:9]1[CH2:25][O:26][CH2:27][CH2:28][CH3:29])C1C=CC=CC=1.Cl>>[CH2:27]([O:26][CH2:25][C:9]1[NH:10][C:11]([C:19]([O:21][CH2:22][CH2:23][CH3:24])=[O:20])=[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[N:8]=1)[CH2:28][CH3:29]
Reactant: CCCOCc1nc(C(=O)OCCC)c(C(=O)OCCC)n1Cc1ccccc1
Agent: Cl
Product: CCCOCc1nc(C(=O)OCCC)c(C(=O)OCCC)[nH]1

Procedure:
Following a procedure similar to that described in Preparation42(iv), but using 0.99 g of dipropyl 1-benzyl-2-propoxymethylimidazole-4,5-dicarboxylate [prepared as described in step (i) above] as the starting material, 0.83 g of the hydrochloride of the title compound was obtained as a syrup.