Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C@@H:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][OH:9])[CH3:2].C(N(C(C)C)CC)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C@H:7]([CH:8]=[O:9])[NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH3:2]
Reactant: CCOC(=O)CC[C@H](CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC[C@H](C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
Under an atmosphere of argon, to a mixed solution of (4R)-4-t-butoxycarbonylamino-5-hydroxypentanoic acid ethyl ester (1.62 g) and diisopropylethylamine (6.5 ml) in dimethylsulfoxide-ethyl acetate (1:1, 40 mL) was added sulfur trioxide pyridine complex (2.96 g) in ice bath and the mixture was stirred in ice bath for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with 0.5N hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (1.65 g) having the following physical data.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])[CH2:8][CH2:9][CH3:10].[C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br)#[N:28]>CN(C)C=O>[C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][CH2:10][CH2:9][CH2:8][C:7]([NH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:11])#[N:28]
Reactant: N#Cc1ccccc1CBr
Reactant: CCCC(=O)Nc1cc(C(=O)OCC)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCCCc2ccccc2C#N)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 117 %

Procedure:
Potassium carbonate (296 mg) was added to a solution of 200 mg of ethyl 3-butyrylamino-4-nitrobenzoate and 154 mg of 2-cyanobenzyl bromide in N,N-dimethylformamide, and the mixture was stirred at 20° C. for 3 hours. The reaction mixture was extracted with ethyl acetate and with water. The organic layer was washed with water and with a sodium chloride aqueous solution, and was then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 330 mg of yellow oil of ethyl 3-[N-(2-cyanobenzyl)butyrylamino]-4-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([S:22][CH3:23])[N:10]=1)=[O:8].[CH3:28]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:5][N:6]([CH3:28])[C:7]([C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][N:12]=[C:11]([S:22][CH3:23])[N:10]=1)=[O:8]
Reactant: CSc1ncc(-c2ccccc2C)c(C(=O)NCc2cc(Cl)cc(Cl)c2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: ClCCl
Product: CSc1ncc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 0.6 g (1.43 mmol) methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid 3,5-dichloro-benzylamide in 10 ml N,N-dimethylformamide 0.073 g (1.85 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction stirred for 1 h. After the addition of 0.14 ml methyl iodide at 0°, the reaction mixture was stirred for 3 hrs at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated and the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) to give 0.57 g (92%) 2-methylsulfanyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide as a colorless oil, MS (ISP): 432.2, 434.2 (M+H+).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C([O-])(=O)C.[Na+].Cl[CH2:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23].O>CS(C)=O.C(OCC)(=O)C>[CH3:26][C:21]([CH3:27])([CH2:20][CH2:19][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(C)(C)CCCl
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)(C)CCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a stirred solution of 83.2 grams (0.51 mole) of N-hydroxyphthalimide in 500 ml of dimethyl sulfoxide was added 41.8 grams (0.51 mole) of sodium acetate. Upon completion of addition the reaction mixture was stirred for one hour at ambient temperature. After this time 84.2 grams (0.51 mole) of methyl 4-chloro-2,2-dimethylbutanoate was added dropwise. The reaction mixture was then heated to 100° C. where it stirred for 16 hours. The reaction mixture was cooled and 300 ml of water and 1000 ml of ethyl acetate were added. The mixture was shaken and the organic layer separated. The organic layer was washed with three 200 ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 1:3 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to a residual oil. The oil was dissolved in 500 ml of diethyl ether and washed with two 100 ml portions of aqueous 1N sodium hydroxide. The ether layer was concentrated under reduced pressure to give 90.3 grams of methyl 2,2-dimethyl-4-(phthalimidooxy)butanoate as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[K+].C(=O)(O)[O-].[K+].[C:14]1([C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:23][CH2:24]Br)[C:21]#[N:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:26]1([C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([CH2:23][CH2:24][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:21]#[N:22])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: N#CC(CCN1CCCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 75.3 %

Procedure:
To a warmed mixture of 1.96 parts piperidine, 1.91 parts potassium iodide and 25 parts deionized water under a nitrogen atmosphere is added 3.46 parts potassium bicarbonate and 7.51 parts of 2,2-diphenyl-4-bromobutyronitrile. The mixture is heated to reflux and maintained thereat for 4.5 hours. After cooling to room temperature, the reaction mixture is extracted three times with 14 part portions of ethyl ether. The ether extracts are combined, and extracted six times with 25 parts by volume portions of dilute acetic acid solution. The acid extracts are combined, basified to about pH 10 - 12 with 50% sodium hydroxide solution, and again extracted with ethyl ether. The ether extracts are combined and dried over anhydrous potassium carbonate. Removal of the solvent affords 2,2-diphenyl-4-piperidinobutyronitrile, identical to the product of Example 22, in a 75.3% yield.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([C:21]([O:25][N:26]1N=NC2C=CC=C[C:27]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNOC.C([O-])(O)=O.[Na+]>CN(C=O)C.CC(OC)(C)C.CCN(CC)CC>[CH3:21][O:25][N:26]([CH3:27])[C:9](=[O:10])[CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of 3,3-diphenylpropionic acid ((CAS RN: [606-83-7]), 1.5 g) in DMF (17 mL) was added TBTU (3.0 g) and Et3N (2.8 mL) at 0° C. The reaction mixture was stirred at rt for 10 min and again was cooled down to 0° C. N,O-dimethylhydroxylamine hydrochloride (0.78 g) was added and the mixture was stirred at rt for 2 days. A saturated solution of NaHCO3 and TBME were added, the phases were separated and the inorganic one was extracted with TBME. The combined organic layers were washed with 1M KHSO4 followed by brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to yield the title compound as a light brown oil (1.5 g, 84%), MS (ESI+): m/z=270.2 ([M+H]+).
Reaction SMILES: [CH2:1]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:2]1=[O:3].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.N1C2C(=CC=CC=2)C=C1.[BH3-]C#N.[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.O>[O:3]=[C:2]1[CH2:1][N:11]2[C@H:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@H:14]3[C:9]3[C:10]2=[C:5]([CH:6]=[CH:7][CH:8]=3)[NH:4]1
Reactant: O=C1CNc2ccccc2N1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Temperature: 0 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
The procedure described in Example 4, Steps E through G, was utilized to prepare ethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,40′:4,5]-pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate from the corresponding amine, 1,3,4-trihydroquinoxalin-2-one, and ethyl 4-oxopiperidinecarboxylate. This indole (5.74 g, 19.2 mmol) was dissolved in TFA (100 mL). The reaction was cooled to 0° C. NaCNBH3 (3.96 g, 63.0 mmol) was added in small portions over 30 min, keeping the temperature less than 5° C. The reaction was stirred at r.t. for 4 hr. Ice was added to the reaction flask, and the reaction was basified with 50% NaOH until pH=12. Water (80 mL) was added to dissolve the precipitate. The reaction was extracted with CHCl3 (3×200 mL). The combined organic layers were washed with brine, dried, and concentrated to afford ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (4.41 g, 77%). 1H NMR (CDCl3, 300 MHz) δ 8.45 bs, 1H), 6.86 (d, J=7.4 Hz, 1H), 6.74 (dd, J=7.7 Hz, 7.7 Hz, 1H), 6.63 (d, J=7.3 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.89-3.993 (m, 2H), 3.41-3.47 (m, 2H), 3.33-3.41 (m, 2H), 3.12-3.31 (m, 1H), 2.69-2.75 (m, 2H), 1.90-1.92 (m, 2H), 1.28 (t, J=7.3 Hz, 3H) ppm. MS-APcI: 302 [MH]+
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([O:14]COC)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2>Cl.O1CCOCC1>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([OH:14])=[C:3]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COCOc1c(-c2ccccc2)c(C)cc2cc(OC)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
6-methoxy-1-(methoxymethoxy)-3-methyl-2-phenylnaphthalene (15) (500 mg, 1.62 mmol, 1 equiv) was dissolved in 4 N HCl in dioxane (5 mL) and the mixture was stirred at RT for 1 h. The reaction was then concentrated to dryness to provide 7 (428 mg, 100%) as a tan oil. 1H NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 8.04 (m, 1H), 7.38 (m, 3H), 7.21 (m, 4H), 7.03 (m, 1H), 3.84 (s, 3H), 2.06 (m, 3H). LRMS m/z 265.1 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C@@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][OH:12])#[N:2].N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>ClCCl.C1(C)C=CC=CC=1>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C@@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:23]1=[O:24])#[N:2]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](CO)NCCCCCCC#N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1COC(=O)N1CCCCCCC#N
Reaction time: 1 h

Procedure:
To a solution of amine 2-1 (620 mg) and pyridine (0.48 mL) in dichloromethane (10 mL) at 0° C. was added a solution of phosgene in toluene (1.72 mL, 1.9 M) and the mixture was stirred at the temperature for 1 h. The mixture was diluted with dichloromethane and washed with 1 N HCl and brine, and dried over Na2SO4. Filtration and concentration of the filtrate gave the crude product which was purified by chromatography. Eluting with 60% ethyl acetate in hexanes afforded the desired product 2-2 (560 mg). 1H NMR (400 MHz, acetone-d6): δ 4.61 (dd, 1H), 4.52 (t, 1H), 4.35 (dd, 1H), 3.80 (s, 3H), 3.48 (m, 1H), 3.15 (m, 1H), 2.47 (t, 2H), 1.75–1.35 (m, 8H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6].CCN(CC)CC.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>C(Cl)Cl>[C:18]([CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6])(=[O:21])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: O=C1C=C(CCO)C(=O)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)CCC1=CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxyethyl maleimide (5 g, 35.4 mmol) and Et3N (4.25 g, 43.0 mmol) was dissolved in 75 mL of methylene chloride and cooled to 0° C. Acryloyl chloride (3.20 g, 35.4 mmol) in 25 mL of methylene chloride was added dropwise over 30 minutes. The solution was stirred at room temperature for 30 minutes followed by refluxing for 1 hour. The triethylamine hydrochloride was removed by filtration and the yellow solution was concentrated. The yellow crystals were purified by sublimation yielding white crystals, m.p. 77-78° C. (5.00 g, 72.3%). 1H-NMR (CDCl3, δ, ppm): 3.81-3.87 (2H, —NCH2—, t) 4.22-4.33 (2H, —OCH2—, t), 5.81-5.85 (2H, CH2═CH, cis), 6.00-6.13 (1H, CH2═CH—,q), 6.34-6.42 (1H CH2═CH, trans), 6.73 (2H, —OC—CH═CH—CO—, s). 13C—NMR (CDCl3, δ, ppm): 170.4 (2C, C═O, maleimide), 165.8 (1C, C═O, ester), 134.2 (2C, —CH═CH—), 131.45 (1C, —CH═), 127.9 (1C, CH2═), 61.5 (1C, β-CH2—), 36.8 (1C, α-CH2—).
Reaction SMILES: FC(F)(F)S([C:6]1[C:7](=[O:27])[N:8]([CH3:26])[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)(=O)=O.[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:11]=[C:6]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7](=[O:27])[N:8]([CH3:26])[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2cc(S(=O)(=O)C(F)(F)F)c(=O)n(C)c2-c2ccncc2)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cc(-c3ccccc3)c(=O)n(C)c2-c2ccncc2)cc1
Yield: 58.6 %

Procedure:
A mixture of 3-trifluoromethanesulfonyl-5-(4-methoxyphenyl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one (0.055 g), benzeneboronic acid (0.25 g) and aqueous sodium carbonate (2M; 2 cm3) in dimethoxyethane (5 cm3) was degassed and purged with nitrogen at room temperature. Tetrakis(triphenylphosphine)palladium (0) (0.1 g) was added and the mixture was refluxed under nitrogen for 2 hours. The mixture was diluted with water (10 cm3) and extracted with ethyl acetate (3×10 cm3). The extracts were dried (sodium sulphate), filtered and concentrated. Preparative thin layer chromatography, eluting with 95:5 dichloromethane-methanol, gave 5-(4-methoxyphenyl)-6-(4-pyridyl)-3-phenyl-1-methyl-1H-pyridin-2-one (0.028 g; 61%) as a pale pink foam. Recrystallised to give a beige powder m.p. 183-185° C. (EtOAc-hexane). δH (360 MHz; CDCl3) 3.39 (3 H, s, NCH3), 3.73 (3 H, s, OCH3), 6.69 (2 H, d, J 9, methoxyphenyl H-2), 6.90 (2 H, d, J 9, methoxyphenyl H-3), 7.13 (2 H, d, J 6, pyridyl H-3), 7.35-7.44 (3 H, m, 3 of Ph), 7.59 (1 H, s, pyridone H-4), 7.77 (2 H, d, J 8, 2 of Ph) and 8.60 (2 H, d, J 6, pyridyl H-2); m/z (ESP+) 369 (MH+; 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH2:24])[CH2:18][CH2:17][CH2:16]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[N:15]12[CH2:22][CH2:21][CH2:20][C:19]1([CH2:23][NH:24][C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH2:18][CH2:17][CH2:16]2
Reactant: NCC12CCCN1CCC2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC12CCCN1CCC2
Temperature: 17.5 °C
Reaction time: 20 h
Yield: 92.2 %

Procedure:
In 60.0 ml of dimethylformamide (DMF) was dissolved 7.90 g (36.8 mmol) of 4-chloro-3-nitroquinoline, and 5.66 g (40.5 mmol) of (1-azabicyclo[3.3.0]octan-5-yl)methylamine was added to the solution under cooling with ice. After stirring at 15 to 20° C. for 20 hours, the reaction mixture was poured into 400 ml of ice-water and rendered basic with sodium carbonate. The thus formed precipitate was collected by filtration, washed with water, and dried in a desiccator under reduced pressure to obtain 10.6 g (yield: 92.2%) of the titled compound as a yellow powder.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Cl.[C:17]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].C(N(CC)CC)C>CN1CCCC1=O.C(OCC)C>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]([N:24]2[CH2:25][CH2:26][CH:21]([NH:20][C:17](=[O:19])[CH3:18])[CH2:22][CH2:23]2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(=O)NC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(OC)c1cc(N2CCC(NC(C)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
12 Grams of 2-nitro-5-chlorobenzaldehyde dimethyl acetal, 16.3 g of 4-acetylaminopiperidine hydrochloride, 13.7 g of sodium carbonate and 13 ml of triethylamine in 150 ml of N-methylpyrrolidone solution were mixed together and reacted by heating at 120° C. for 12 hours with stirring under nitrogen gas stream. After the reaction was completed, the solvent was removed by evaporation and thus obtained residue was added with water and extracted with dichloromethane, then the extract was washed with water and with an aqueous solution saturated with sodium chloride, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the residue thus obtained was added with diethyl ether, then the crystals formed were collected by filtration to yield 11.2 g of 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde dimethylacetal.
Reaction SMILES: [CH:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Br[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>[Zn]>[OH:13][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCCCCCCC=O
Agent: [Zn]
Product: CCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Yield: 80.7 %

Procedure:
The reaction of dodecanal (0.92 g) and tert-butyl bromoacetate (1.56 g) was carried out under the presence of zinc (0.59 g) according to similar manner to that of Preparation 1-(1) to afford an oil of tert-butyl 3-hydroxytetradecanoate (1.21 g).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: Brc1cnc2cnccn12
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cnc2cnccn12
Temperature: 50 °C
Yield: 91.7 %

Procedure:
A mixture of 3-bromoimidazo[1,2-a]pyrazine (0.15 g, 0.76 mmol; prepared according to J. Bradac, et al. J. Org. Chem. (1977), 42, 4197-4201), 0.09 g (0.91 mmol) of ethynyltrimethylsilane, 0.044 g (0.038 mmol) of Pd(PPh3)4, 0.014 g (0.076 mmol) of Cul, and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.15 g of product: 216 m/z (M+H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([CH3:39])([CH3:38])[C:11]([NH:13][C:14]1[C:15]([C:34]([O:36][CH3:37])=[O:35])=[C:16]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:17]=[CH:18][CH:19]=1)=[O:12]>C(#N)C>[Br:1][C:17]1[C:16]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[C:15]([C:34]([O:36][CH3:37])=[O:35])[C:14]([NH:13][C:11](=[O:12])[C:10]([CH3:39])([CH3:38])[CH3:9])=[CH:19][CH:18]=1
Reactant: COC(=O)c1c(CCC2CCCN2C(=O)OC(C)(C)C)cccc1NC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1CCC1CCCN1C(=O)OC(C)(C)C
Yield: 78.7 %

Procedure:
N-Bromosuccinimide (1.24 g) was added to a solution of tert butyl 2-{2-[3-(2,2-dimethyl-propionylamino)-2-methoxycarbonylphenyl]-ethyl}-pyrrolidine-1-carboxylate (Intermediate 37, 2.74 g) in acetonitrile (40 mL) and the resultant mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-25% to give tert butyl 2-{2-[6-bromo-3-(2,2-dimethylpropionylamino)-2-methoxycarbonylphenyl]-ethyl}-pyrrolidine-1-carboxylate (2.55 g) as a colourless gum.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2CCN(C3C=C(C=CN=3)C(OC)=O)C2=O)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:27]=1[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][N:43]=2)[C:37](OC)=[O:38])[C:30]1=[O:44].FC1C=CC(CN)=CC=1>>[F:25][C:26]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:27]=1[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([CH:41]=[CH:42][N:43]=2)[C:37]([NH:7][CH2:6][C:5]2[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=2)=[O:38])[C:30]1=[O:44]
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3F)C2=O)c1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1ccnc(N2CCN(Cc3ccc(F)cc3F)C2=O)c1
Yield: 55 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate with methyl 2-(3-(2,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate to react with 4-fluorobenzylamine, 2-(3-(2,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(4-fluorobenzyl)isonicotinamide was obtained as a colorless solid in 55% yield: mp 171-173° C.; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.36 (dd, J=5.1, 0.6 Hz, 1H), 7.56-7.27 (m, 4H), 7.07-6.97 (m, 2H), 6.92-6.74 (m, 3H), 4.58 (d, J=6.0 Hz, 2H), 4.48 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H); MS (ES+) m/z 441.1 (M+1).