Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1OC[C@H](C(C)(C)C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.[Cl:22][C:23]([F:25])=[CH2:24].[N+](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N-]>C1CCCCC1.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:22][C:23]1([F:25])[CH2:24][CH:28]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1CCCCC1
Product: CCOC(=O)C1CC1(F)Cl
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Cyclohexane (76.6 g), 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] (64.8 mg, 0.22 mmol), and copper (II) trifluoromethanesulfonate (72.1 mg, 0.20 mmol) were charged in an autoclave, and then 1-chloro-1-fluoroethylene (76.8 g, 0.95 mol) was charged under elevated pressure. After the mixed solution was cooled to 10° C., a mixed solution containing 95% of ethyl diazoacetate (12.0 g, 100 mmol) and cyclohexane (50 g) was charged under elevated pressure over five hours. Cyclohexane (20 ml) was further charged under elevated pressure and stirring was continued at the same temperature for 1 hour, and then the internal pressure was released to give a solution of ethyl 2-chloro-2-fluorocyclopropanecarboxylate in cyclohexane (179.3 g). This solution was analyzed by gas chromatography to find that the content of the ethyl 2-chloro-2-fluorocyclopropanecarboxylate was 6.52% (yield based on ethyl diazoacetate: 70.1%), and the ratio of cis-isomer/trans-isomer was 64.4/35.6.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:13](O)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.C(N(CC)CC)C.[NH4+].[OH-]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:13]([NH2:25])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 18 h
Yield: 103.9 %

Procedure:
A mixture of 1,3-dibenzylpyrrolidine-3-carboxylic acid (Example A28, 4.0 g, 13.5 mmol), 1,1′-carbonyldiimidazole (2.42 g, 14.9 mmol), and triethylamine (2.08 mL, 14.9 mmol) in tetrahydrofuran (100 mL) is heated at reflux for 1.5 hours. The solution is cooled, poured into NH4OH (300 mL), and stirred for 18 hours. The mixture is extracted with chloroform, the organic layer is washed with water, dried, and concentrated to afford 4.13 g of the title compound as an oil; MS EI+: m/z 295 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[N:17]([CH2:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:18](=[O:22])[N:19]([CH3:21])[N:20]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH:24]1([CH2:23][N:17]2[C:18](=[O:22])[N:19]([CH3:21])[N:20]=[C:16]2[CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:32])[CH3:31])[CH:7]=[CH:6][CH:5]=3)[CH2:13][CH2:12]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1nc(CCN2CCN(c3cccc(N)c3)CC2)n(CC2CCCCC2)c1=O
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(N2CCN(CCc3nn(C)c(=O)n3CC3CCCCC3)CC2)c1
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of 5-{2-[4-(3-aminophenyl)piperazino]ethyl}-4-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (D16; 450 mg, 1.129 mmol) in dry pyridine (5 mL), acetic anhydride (0.112 mL, 1.185 mmol) was added at room temperature. The reaction mixture was stirred for 1 h, toluene (30 mL) was added and the solvents were removed in vacuo to afford a light-brown solid. Purification by preparative LC-MS afforded 133 mg (27%) of the title compound as a light brown powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1.ClCCl>[CH2:27]([O:26][C:24]([NH:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:25])[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1sc2cc(OC)ccc2c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)Nc1c(C(=O)OC)sc2cc(OC)ccc12
Yield: 87.7 %

Procedure:
A mixture of 27.4 g (0.115 mol) of methyl 3-amino-6-methoxybenzo[b]thiophene-2-carboxylate, 38 g (0.275 mol) of potassium carbonate and 13.2 ml (0.138 mol) of ethyl chloroformate in 330 ml of toluene is heated at reflux for three hours. 7 ml (0.069 mol) of ethyl chloroformate are then added and the mixture is left heating at reflux for a further seven hours, with stirring. The mixture is then diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. Recrystallization is carried out from a mixture of isopropanol and diisopropyl ether. 31.2 g of product are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])[CH3:2].[C:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[CH:17]=[CH2:18]>O.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]([CH2:17][CH2:18][N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: C=CC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CN(CCC(=O)OCc2ccccc2)c2ccccc2O1

Procedure:
2.3 mmol (0.9 ml) of 40% Triton B in water are added at 0° C. to 22.6 mmol (5 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) and 79 mmol (12.8 g) of benzyl acrylate in 17 ml of toluene. The reaction mixture is refluxed overnight, the solvent is evaporated off and the reaction mixture is heated again for 24 hours. After cooling, hydrolysis and extraction with ethyl acetate, the organic phase is concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (3/7) as eluant to yield the expected compound.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[F:1]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc(F)c1C
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(F)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(3-Fluoro-2-methylphenyl)acetamide (39 mmol) in acetic acid (50 mL) was added bromine (40 mmol) in dropwise fashion. After stirring at rt for 2 days, the precipitated product was filtered, washed with water, and dried under high vacuum. N-(4-Bromo-3-fluoro-2-methylphenyl)acetamide was obtained as a white solid.
Reaction SMILES: Cl.[C@@H:2]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[C:18](Cl)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[C:18]([O:8][CH2:7][C@H:6]1[O:9][C@@H:2]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[CH2:3][C@@H:4]1[OH:5])(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C[C@@H]1O

Procedure:
5'-O-palmitoyldeoxycytidine is synthesized by reacting deoxycytidine hydrochloride with 1.1 equivalents palmitoyl chloride in dry dimethylformamide.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](O)[CH3:27]>>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:17](=[O:18])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:1]2([O:8][CH2:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CCO
Product: CCOC1(c2ccccc2)c2cc(Cl)ccc2NC(=O)N1c1ccccc1
Yield: 88 %

Procedure:
A solution of 10.0 g (0.285 mole) of 1-(2-benzoyl-4-chlorophenyl)-3-phenylurea in 50 ml ethanol was refluxed for 18 hr, and then cooled. The solid that formed was collected on a filter and washed with ethanol to give 9.46 g (88%) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(1H)-quinazolinone as colorless crystals: mp 209°-211°. The 1H nmr spectrum shows the presence of an ethyl group in addition to aromatic hydrogens.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)CN2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.22 g, 0.4 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.20 g, 0.8 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7])=[N-].[C:9]1([CH3:19])[C:10]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>C(Cl)(Cl)Cl>[O:8]=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][O:18][S:15]([C:10]1[C:9]([CH3:19])=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:16])=[O:17]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCCC(=O)C=[N+]=[N-]
Solvent: ClC(Cl)Cl
Product: CCCC(=O)COS(=O)(=O)c1ccccc1C
Yield: 59.9 %

Procedure:
A 1.0 g quantity of 1-diazo-2-pentanone is dissolved in 50 ml of chloroform, and 2.2 g of o-toluenesulfonic acid is slowly added to the solution. The same procedure as in Example 1 is thereafter repeated to afford 1.37 g of 2-oxopentyl-o-toluene sulfonate in the form of a transparent colorless oil (Compound 29).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:28])[C:17]=2[CH2:16]1)=O)(C)(C)C>ClCCl>[CH3:28][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[CH2:26][CH2:27][NH:15][CH2:16][C:17]1=2
Reactant: Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c2c(c3ccccc31)CCNC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3.5 ml, 45.23 mmol) was added to a solution of 2-t-butoxycarbonyl-9-methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole (1.848 g, 6.461 mmol) in dichloromethane (25 ml) and stirred at room temperature for 3 hours, diluted with dichloromethane (125 ml), washed with 2M sodium hydroxide (2×50 ml), water and dried (MgSO4). The magnesium sulfate was collected by filtration and the filtrate evaporated in vacuo to give the title product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:2]([N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]1[CH:13]=[CH:14][C:8]([Br:7])=[C:9]([Cl:15])[CH:10]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN(CCCCC)c1ccc(Br)c(Cl)c1
Yield: 106.4 %

Procedure:
1-Bromopentane (0.42 mL, 3.4 mmol) was added to a mixture of 4-bromo-3-chloroaniline (200 mg, 0.9 mmol) and potassium carbonate (199 mg, 1.4 mmol) in DMF (20 mL) and the reaction was heated to 13 0˜˜C overnight. The mixture was cooled, diluted with water (20 mL) and extracted with petroleum ether (3×25mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography using 9:1 petroleum ether:ethyl acetate as eluent to give N,N-Dipentyl-4-bromo-3-chloroaniline (1) (332 mg, 68%). 1HNMR (CDCI3) 67.02 (d, IH, ArH); 3.12 (t, 4H, 2×NCH2); 0.95 (t, 6H, 2×CH3). MS; 347 (M+H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(=O)CC>[Cl:23][CH2:22][CH2:21][CH2:20][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(O)cc1)C1CC1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCCl)cc1)C1CC1
Temperature: 25 °C

Procedure:
Cyclopropyl(4-hydroxyphenyl)methanone (10 g, 61.7 mmol), K2CO3 (12.7 g, 91.9 mmol), and 1-bromo-3-chloropropane (10.74 g, 68.2 mmol) in 2-butanone (100 mL) were refluxed for 24 hours, allowed to cool to ambient temperature, filtered, and concentrated. The residue was heated at 40° C. under reduced pressure for three hours to provide the title compound of sufficient purity for subsequent use without further purification (13.25 g, 90%).
Reaction SMILES: [Mg].[CH3:2][C:3]([C-:5]1C=C[CH:7]=[CH:6]1)=O.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].C(Br)C=C.C[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[C-:10]1([C:6]([CH3:7])=[CH:5][CH:3]=[CH2:2])[CH:14]=[CH:13][CH:12]=[CH:11]1.[CH-:21]1[CH:22]=[CH:23][CH:24]=[CH:25]1.[Fe+2:15]
Reactant: CCCCCC
Reactant: CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [Mg]
Agent: c1cc[cH-]c1
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC=C(C)[c-]1cccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
72 mg (3.0 mmole) of magnesium metal was placed in a 50 ml round bottom flask. 228 mg (1.0 mmole) of ferrocenyl methyl ketone and 181.5 mg (1.5 mmole) of allyl bromide were dissolved in 15 ml of THF. The resulting mixture was poured into the round bottom flask containing the magnesium metal while stirring at room temperature for two hours. After two-hour stirring, the cover of the flask was opened, and the liquid portion of the reaction mixture was introduced into a silica gel column, which had been wetted with n-hexane. All the liquid migrated into the silica gel, and the column was placed still for 24 hours. Next, the column was eluated with n-hexane. After evaporating the solvent from the eluate collected from the elution, 230 mg (0.91 mmole) of a purified title product was obtained with a yield of 91%.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[C:19]([CH:20]=O)[C:18]([OH:23])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(Br)ccc1O
Product: O=c1cc(N2CCN(Cc3cc(Br)ccc3O)CC2)nc[nH]1

Procedure:
6-[4-(5-Bromo-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromosalicylaldehyde. Mass spectrum (ES) MH+=365.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([S:12]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]#[N:18])(=[O:14])=[O:13])[CH:6]=[CH:5]3)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#Cc1ccccc1S(=O)(=O)c1ccc2cc(Br)ccc2c1
Product: N#Cc1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared from 2-[(6-bromo-2-naphthyl)sulfonyl]benzonitrile (Step 3) and 4-fluorobenzeneboronic acid according to the method of Example 2 Step 1. 1H NMR (500 MHz, CDCl3) δ 8.80 (1H, s), 8.42 (1H, d, J=7.9 Hz), 8.11 (1H, d, J=8.6 Hz), 8.00 (2H, t, J=9.0 Hz), 7.93 (1H, dd, J=1.7, 8.7 Hz), 7.85-7.79 (3H, m), 7.70-7.64 (3H, m), 7.19 (2H, t, J=8.6 Hz).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:10])[O:7][CH2:8][CH3:9])C.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]=1[Cl:18].C(O)(=O)C>C1COCC1>[CH2:8]([O:7][C:6]([CH:21]1[CH2:20][CH:19]([C:14]2[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:29])=[O:10])[CH3:9]
Reactant: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Temperature: 0 °C
Yield: 80 %

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 1.69 g, 42 mmol) in THF (80 ml) under N2 was added dropwise diethylcarbonate (4.85 ml, 40 mmol) at room temperature, followed by 4-(3′,4′-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalone 1 (5.82 g, 20 mmol) in THF (20 ml). The mixture was refluxed for 48 hours, then cooled to 0° C. Acetic acid (10 ml) was added dropwise, and the mixture was extracted with Et2O. The Et2O extracts were washed with saturated NaHCO3 solution, brine, dried over MgSO4, and evaporated. The residue was purified by chromatography, CombiFlash silica gel column (hexane:CH2Cl2=50:50) to give Compound 9 as a clear oil (5.81 g, 80%). 1H NMR (CDCl3) δ 1.30 (t, J=7.2 Hz, 3H), 2.77 (dd, J=16 Hz, 9.6 Hz, 1H), 2.91 (dd, J=15.6 Hz, 6.4 Hz, 1H), 4.10 (dd, J=12 Hz, 6.4 Hz, 1H), 4.19-4.30 (m, 2H), 6.87 (d, J=6.8 Hz, 1H), 7.00 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.27-7.36 (m, 5H), 7.89 (dd, J=8.4 Hz, 2.0 Hz, 1H), 12.50 (s, 1H). 13C NMR (CDCl3) δ 14.5, 29.1, 43.4, 61.0, 95.6, 125.0, 127.6, 127.9, 128.1, 130.2, 130.6, 130.7, 131.0, 131.3, 132.8, 140.4, 143.9, 164.8, 172.6.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.Cl.[CH2:5]1[CH2:9]O[CH2:7][CH2:6]1>>[CH:6]([C:5]1[CH:9]=[CH:7][C:6]([CH2:2][CH2:1][OH:3])=[CH:5][CH:9]=1)=[CH2:7]
Reactant: C1CCOC1
Reactant: C1CO1
Agent: Cl
Product: C=Cc1ccc(CCO)cc1
Temperature: 0 °C

Procedure:
To a VP-MgCl solution as prepared in Example 12 of this section was added a solution of 4.84 g ethylene oxide (0.11 mol) in 50 ml THF. The solution was added via additional funnel over one hour, maintaining the reaction mixture at 0° C. Keep stir at 0° C. for one more hour after the addition was finished. The reaction was then stirred for an additional 1 h at 0° C. 60 ml of 2 M aqueous hydrochloric acid (HCl) solution was added via the addition funnel, maintaining the temperature below 20° C. The reaction was filtered and extracted two times with 100 mL of diethyl ether. The organic phases were combined, dried over MgSO4 and filtered. The diethyl ether was removed by vacuum evaporation at room temperature. 11.2 g white waxy solid, 75.7%). 1H NMR (DMSO-d6): δ 7.20-δ 7.40 (m, 4H, aromatic), δ 6.72 (m, 1H, vinyl), δ 5.75 (d, 1H, vinyl), δ 5.23 (d, 1H, vinyl), δ 4.70 (t, 1H, OH), δ 3.65 (t, 2H, CH2—O), δ 2.72 (t, 2H, CH2—C).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C:26]2=[N:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C@:26]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[F:8])[NH:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Fc1ccccc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Toluene (100 ml) and THF (10 ml) were added to 2-bromofluorobenzene (3.11 g). The reaction solution was cooled to −78° C., and n-butyllithium (2.63 M, 6.15 ml) was added dropwise. After stirring at the same temperature for one hour, a mixed solution of (3aR,5R)-5-benzyloxymethyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole (2.00 g) in toluene (20 ml) and THF (2 ml) and a boron trifluoride-diethyl ether complex (2.03 ml) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to the reaction solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (2.29 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](#[N:22])[CH3:21]>>[CH2:1]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[CH:13][CH:14]=2)/[C:9]/1=[CH:21]/[C:20]#[N:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: COc1ccc2c(c1)C(=O)C(Cc1ccccc1)C2
Product: COc1ccc2c(c1)/C(=C/C#N)C(Cc1ccccc1)C2

Procedure:
Starting with 2-benzyl-6-methoxy-1-indanone and acetonitrile, the title compound was synthesized in otherwise the same manner as Reference Example 1 (yield 76%). This compound was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:29])[N:7]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.[O-:34][C:35]#[N:36].[K+]>O>[C:23]1([C:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:7]3[C:6](=[O:29])[C:5]4[C:10](=[CH:11][C:2]([NH:1][C:35]([NH2:36])=[O:34])=[CH:3][CH:4]=4)[NH:9][C:8]3=[O:12])[CH2:18][CH:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)[nH]c2c1
Reaction time: 3 h
Yield: 27.7 %

Procedure:
To a mixture of 7-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.39 g), acetic acid (5 ml) and water (10 ml) was added a solution of potassium cyanate 0.16 g) in water (2 ml) and the resulting mixture was stirred for additional 3 hours. The reaction mixture was poured into water and precipitated solid was filtered, washed in turn with water and ethanol and dried to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-ureido-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[OH:10].[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:6][C:5]1[C:7]([Cl:9])=[CH:8][C:2]([Cl:1])=[C:3]([OH:10])[CH:4]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Oc1cc(O)c(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
4,6-dichlororesorcinol (3.80 g, 21 mmol), allyl bromide (1.82 mL, 21 mmol) and potassium carbonate (2.24 g, 21 mmol) were combined in DMF and stirred at room temperature for 18 hours. The DMF was removed in vacuo and the residue acidified with 2M hydrochloric acid (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic solution was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate 9:1 to 4:1 to afford the title compound as a yellow oil in 27% yield, 1.24 g.