Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C)(C)C[C:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7](C(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)(C)C)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[Na+].[Na+].O.I[C:45]1[CH:50]=[CH:49][N:48]([CH3:51])[C:47](=[O:52])[CH:46]=1>C1(C)C=CC=CC=1.CCO.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>[CH3:51][N:48]1[CH:49]=[CH:50][CH:45]([CH:6]2[CH2:5][CH:4]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:9][C:8](=[O:10])[NH:7]2)[CH2:46][C:47]1=[O:52]
Reactant: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)O1
Reactant: Cn1ccc(I)cc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1C=CC(C2CC(c3ccccc3)OC(=O)N2)CC1=O
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 60.8 %

Procedure:
To a solution of 6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)-1,3-oxazinan-2-one (30 mg, 60.9 μmol) in toluene (3 mL) was added a solution of sodium carbonate (64.5 mg, 609 μmol) in EtOH (2 mL)/water (1 mL), 4-iodo-1-methylpyridin-2(1H)-one (14.5 mg, 609 μmol) and Pd(PPh3)4 (7.5 mg, 6 μmol) successively under nitrogen. The mixture was stirred at 100° C. for 2.5 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in water, extracted with EtOAc (5 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by HPLC to afford 6-(2_hydroxy-2-methylpropyl)-3-(2-(4-(1-methyl-2-oxo-dihydropyridin-4-yl)-6-phenyl-1,3-oxazinan-2-one (10.6 mg, 37%). 1H NMR (CDCl3) δ 7.40-7.19 (m, 8H), 7.09-7.06 (m, 2H), 6.73 (s, 1H), 6.38-6.36 (d, 1H), 3.51 (s, 3H), 3.27-3.24 (m, 1H), 2.85-2.76 (m, 1H), 2.34-2.21 (m, 2H), 2.16 (s, 2H), 1.65-1.53 (d, 3H), 1.45 (s, 3H), 1.08 (s, 3H), 0.96 (s, 3H); LC-MS Method 2 tR=1.05 min, m/z=475.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[SH:18]CCC(O)=O.[H-].[Na+].Cl>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][SH:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: O=C(O)CCS
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CS)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
To a dimethylformamide (160 ml) solution of 2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)oxirane (8.0 g) and methyl ester of 3-mercaptopropionic acid was added, under ice-cooling, 60% sodium hydride (4.0 g). The mixture was stirred for 15 minutes, to which was added dropwise a 1N aqueous solution of hydrochloric acid (101 ml) to adjust the pH to 7, followed by distilling off dimethylformamide and water. To the residue was added water (20 ml), which was extracted with ethyl acetate (50 ml×3). The extract was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, followed by distilling off the solvent. The residue was subjected to a silica gel chromatography (6.0×9.0 cm), followed by elution with ethyl acetate-hexane (3:1). The object fraction was concentrated, to which was added diethyl ether to afford 2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (6.44 g) as colorless needles, m.p. 112°-113° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14](Br)[CH2:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.O1CCCC1.C([Li])(C)(C)C.CCCCC.[B:42](OC(C)C)([O:47]C(C)C)[O:43]C(C)C>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12](=[CH:11][CH:10]=1)[CH:13]=[C:14]([B:42]([OH:47])[OH:43])[CH2:15][CH2:16]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrC1=Cc2ccc(OCc3ccccc3)cc2CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: OB(O)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Reaction time: 0.17 h

Procedure:
7-Benzyloxy-3-bromo-1,2-dihydro-naphthalene (21.75 g, 0.06900 mol) was azeotroped with toluene (100 mL, 0.9 mol) and dried on the high vacuum for 30 min. This was dissolved in tetrahydrofuran (200 mL, 2 mol), cooled with a dry ice-isopropanol bath under an atmosphere of nitrogen. 1.70 M tert-Butyllithium in pentane (89.3 mL, 0.152 mol) was added slowly, stirred for 10 min. Triisopropyl borate (79.1 mL, 0.345 mol) was added and the mixture was stirred for 1 hour with cooling then brought to r.t. The reaction was quenched with ice-water. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered, concentrated and dried on the high vacuum to give a crude intermediate, 6-(benzyloxy)-3,4-dihydronaphthalen-2-ylboronic acid.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[C:12]([C:15]1[C:16](=[S:26])[S:17][S:18][C:19]=1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)([OH:14])=[O:13].[O-]CC.[Na+].[CH2:31](I)[CH2:32][CH2:33][CH3:34]>C(O)C.C(OCC)(=O)C>[CH2:31]([O:13][C:12]([C:15]1[C:16](=[S:26])[S:17][S:18][C:19]=1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:14])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCI
Reactant: O=C(O)c1c(-c2cnccn2)ssc1=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1c(-c2cnccn2)ssc1=S
Temperature: 50 °C
Yield: 25.6 %

Procedure:
Anhydrous hexamethylphosphotriamide (5 cc) and 4-carboxy-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (1.28 g) (prepared as described in Example 32) are added to a solution of dry sodium ethoxide (0.34 g) in anhydrous ethanol (5 cc). The suspension obtained is heated to a temperature of about 50° C., the resulting solution is cooled to a temperature of about 20° C. and then butyl iodide (1.7 g) is added. The reaction mixture is then maintained at a temperature of about 50° C. for 7 hours. An insoluble material is filtered off and the filtrate is evaporated to dryness under reduced pressure (20 mm Hg). The oil obtained is treated with ethyl acetate (2 cc) and the product which crystallises is filtered off and washed with diethyl ether (2 cc). After drying, 4-butoxycarbonyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (0.4 g), melting at 127° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[C@H:6]([O:7][N+]([O-])=O)[CH2:5][C:4](=[O:11])[C:3]=1[CH2:12][C:13]#[CH:14].C(=O)([O-])[O-].[Ca+2]>O>[OH:7][C@H:6]1[CH2:5][C:4](=[O:11])[C:3]([CH2:12][C:13]#[CH:14])=[C:2]1[CH3:1]
Reactant: C#CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: C#CCC1=C(C)[C@@H](O)CC1=O
Reaction time: 5 h
Yield: 85.3 %

Procedure:
A mixture of 1.95 g of crude (R)-3-methyl-4-nitroxy-2-(2-propynyl)-2-cyclopenten-1-one prepared in Example 1, 1.00 g of calcium carbonate and 30 ml of water was stirred at a temperature of 80°-85° C. for 5 hours. Then the reaction mixture was cooled and filtered through celite. Thereafter, the water layer was saturated with sodium chloride and extracted with methyl isobutyl ketone. The organic layer was separated, washed with an aqueous saturated sodium chloride solution dried over anhydrous magnesium sulfate and, then, concentrated. Thus, 1.28 g of (S)-4-hydroxy-3-methyl-2-(2-propynyl)-2-cyclopenten-1-one (chemical purity: 90.1%, [α]D23 : +15.0° (C=1.06, in chloroform), (R)-isomer/(S)-isomer=11.6/88.4) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCO
Reactant: Cc1occc(=O)c1OCc1ccccc1
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 1-amino-4-hydroxybutane under substantially similar conditions to those described under Example 11 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(4'-hydroxybutyl)-2-methylpyrid-4-one as white crystals, m.p. 126°-128° C.; νmax (nujol) 1630, 3350 cm-1 ; δ(d6DMSO) 1.5 (m, 4H), 2.45 (s, 3H) 3.35 (t, 2H), 4.30 (t, 2H), 7.25 (d 1H), 8.2 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:13]2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCCC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1.64 g of ethyl 4-{1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidyl}butyrate (prepared as described in Example 34) were added to 15 ml of ethanol, and then 10 ml of a 10% w/v aqueous solution of sodium hydroxide were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was diluted with water. The pH was then adjusted to a value of 4 by the addition of aqueous hydrochloric acid, and then the mixture was extracted with ethyl acetate. The crystals obtained from the extract were recrystallized from ethanol to afford 1.46 g (95% yield) of the title compound, melting at 145°-147° C.
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[OH-].[K+]>CO.CCCCCC.CCCCCCC>[Cl:1][CH:2]1[O:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4](=[O:5])[C:3]1([CH3:17])[CH3:16]
Reactant: CC(C)(C(=O)N(O)Cc1ccccc1Cl)C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCCCCCC
Product: CC1(C)C(=O)N(Cc2ccccc2Cl)OC1Cl
Yield: 24.8 %

Procedure:
These compounds were prepared in the manner of Example 16, using 7.7 grams (0.025 mole) of 3,3-dichloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide (prepared in Example 10) and 1.6 grams (0.025 mole) of 85% pure potassium hydroxide in 70 ml of methanol. Thin layer chromatographic analysis of the reaction mixture on silica gel using 20% ethyl acetate in hexane as an eluent indicated that the reaction mixture was a two-component mixture. The crude reaction mixture was subjected to column chromatography on silica gel using 15% ethyl acetate in heptane. Initial fractions from the chromatography were combined to give 1.7 grams of 5-chloro-2-(2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([F:11])[CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A mixture of 2-fluoro-4-hydroxy-benzonitrile (15.0 g, 109 mmol), 3-fluorobenzyl bromide (22.7 g, 120 mmol) and potassium carbonate (18.1 g, 131 mmol) in dry acetone (250 mL) was heated under reflux for 4 h. After cooling to room temperature the mixture was filtered and the filtrate was evaporated to leave an off-white solid which was washed with hexane to afford the title compound (26.8 g, 100%) as a white solid. MS: m/e=245.2 (M+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[OH:14].[N:15]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1.C(OCC)(=O)C>[N:15]1([C:20]([O:14][C:5]2[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([F:10])=[CH:9][C:4]=2[F:3])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Oc1cc([N+](=O)[O-])c(F)cc1F)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a stirred, cold (0° C.) mixture of 1.74 g of sodium hydride (0.072 mole, 2.9 g of a 60% oil suspension) and 7.0 g (0.039 mole) of 2,4-difluoro-5-nitrophenol in 100 mL of tetrahydrofuran was added 6.4 g (0.048 mole) of 1-pyrrolidinecarbonyl chloride. The reaction mixture was allowed to warm to room temperature and was stirred for four hours. The mixture was diluted with ethyl acetate and was washed with an aqueous 10% hydrochloric acid solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and filtrate evaporated under reduced pressure leaving a semi-solid residue. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate:n-heptane (50:50) to yield 7.2 g of (2,4-difluoro-5-nitrophenyl) 1-pyrrolidinecarboxylate. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[I-:11].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][I:11]
Reactant: [I-]
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(CI)c(Cl)c1
Yield: 100.2 %

Procedure:
2,4-Dichlorobenzyl chloride (23.45 g) and potassium iodide (47.88 g) are stirred in acetone (100 ml) at room temperature for 24 hours. After concentrated, this is extracted with t-butyl methyl ether (300 ml) and water (100 ml). The extract is washed with water, dried and concentrated to obtain 2,4-dichlorobenzyl iodide (34.49 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[Sn](CCCC)(CCCC)CCCC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]>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.[Cu]I.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[N+:43]([O-:45])=[O:44])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccc(OC)cc2n1S(=O)(=O)c1ccccc1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3ccc(OC)cc3n2S(=O)(=O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
The title compound was synthesized by referring to Tetrahedron, 1994, 50 (6), 1899. A mixture of 1-benzenesulfonyl-6-methoxy-2-tributylstannyl-1H-indole (12.1 g), 4-bromo-3-nitroanisole (4.6 g), tetrakis(triphenylphosphine)palladium(0) (1.1 g), copper(I) iodide (760 mg) and toluene (90 ml) was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature, NH silica gel (20 g) was added thereto, the solution was concentrated in vacuo, and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.9 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([N:30]1[CH2:39][CH2:38][C:37]2[C:36](=[O:40])[NH:35][CH:34]=[N:33][C:32]=2[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:23]([N:30]1[CH2:39][CH2:38][C:37]2[C:36](=[O:40])[N:35]([C:2]3[CH:3]=[C:4]([CH:8]4[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]5[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=5)[NH:9]4)[CH:5]=[CH:6][CH:7]=3)[CH:34]=[N:33][C:32]=2[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Reactant: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-n2cnc3c(c2=O)CCN(Cc2ccccc2)C3)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1.0 mmol), 7-benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (300 mg, 1.3 mmol), copper(I) iodide (80 mg, 0.4 mmol), N,N-dimethylglycine hydrochloride (117 mg, 0.8 mmol) and potassium carbonate (769 mg, 5.6 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(7-benzyl-4-oxo-5,6,7,8-tetrahydro-4H-pyrido[3,4-d]pyrimidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (320 mg, 61%) as a white solid: LC/MS m/e calcd for C32H32N4O3 (M+H)+: 521.64, observed: 521.2.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].N(C(C)(CC)C#N)=NC(C)(CC)C#N.[C:30]([O:33][CH2:34][CH3:35])(=O)C>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:7][CH2:8][CH3:9].[C:10]([O:15][CH2:35][CH:34]1[O:33][CH2:30]1)(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)[O-]
Reactant: CCOC(C)=O
Agent: C=CC(=O)OCCCC
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC1CO1
Temperature: 60 °C

Procedure:
The following were added to a 946 mL bottle: 72.0 g of butyl acrylate (Dow Chemical Co., Midland, Mich.), 48.0 g of glydicyl methacrylate (Sartomer Co. Inc., Easton, Pa.), 0.18 g of 2,2′-azobis (2-methylbutanenitrile) (DuPont, Wilmington, Del.), 140 g of ethyl acetate, and 140 g of toluene. The solution was purged with nitrogen for two minutes at a rate of one liter per minute. The bottle was sealed and placed in a water bath that was maintained at 60° C., for 24 hours. The reaction mixture was 29.5 wt % solids, had a measured inherent viscosity of 0.78 dL/g and a Brookfield viscosity of 0.7 Pascal-seconds.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].Br[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([O:5][C:6]1[C:7](=[O:18])[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]=2[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(O)c2c(O)cccc2oc1=O
Reactant: CCOC(=O)CCBr
Product: CCCCOc1c(O)c2c(OCCC(=O)OCC)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-butoxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-butoxy-4-hydroxy-5-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[N+:6]([C:13]1[CH:14]=[CH:15][C:10]([CH3:16])=[CH:11][CH:12]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
nitrating toluene in a first nitration stage with an aqueous mixture of sulfuric acid and nitric acid to form a mononitrotoluene containing organic phase and a first aqueous spent acid phase containing nitric acid,
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C1COCC1>[C:22]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: OCCOCCOCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOCCOCc1ccccc1
Temperature: 0 °C
Yield: 84 %

Procedure:
To a 1 L three-neck round bottom flask equipped with mechanical stirrer were charged diethylene glycol monobenzyl ether (98.0 g, 0.5 mol), anhydrous triethylamine (120 mL, 0.85 mol), and anhydrous THF (300 mL). The solution was cooled in an ice/salt bath under dry air blanket for 15 minutes. Acryloyl chloride (55 mL, 0.68 mol) was added into the vigorously stirred cold solution through an addition funnel over 90 minutes and the addition rate was adjusted to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was stirred in the ice/salt bath for additional two hours followed by quenching with the addition of 2M HCl (400 mL). The mixture was extracted with ethyl acetate (300 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (4/1, v/v) as eluent to give the final product as a colorless oil (105.0 g, 0.42 mol, yield: 84%).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3F)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][N:21]=2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O.[OH-].[Na+]>C1COCC1>[OH:25][CH2:24][C:23]1[CH:28]=[CH:29][C:20]([NH:19][C@@H:16]2[CH2:17][CH2:18][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15]2)=[N:21][CH:22]=1
Reactant: COC(=O)c1ccc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(CO)cn2)C1
Temperature: 10 °C
Yield: 34.6 %

Procedure:
Lithium aluminium hydride (1.02 g) was added to a solution of methyl 6-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]amino}nicotinate (5.76 g) in THF (80 ml) with stirring at 5-15° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at 5-20° C. for 3 hours. The reaction mixture was cooled at 5° C. and H2O (1 ml), 15% NaOH solution (1 ml) and H2O (3 ml) was added and the resultant mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was filtrated and the filtrate was dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-{[5-(hydroxymethyl)-2-pyridinyl]amino}-1-pyrrolidinecarboxylate (1.82 g).