Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1(O)[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.B.[O:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl.[OH-:16].[Na+].O1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[C:7]([O:16][C@@H:13]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:11]=2)[C@H:14]2[O:10][CH2:7][CH2:2][NH:3][CH2:4]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OC1(Br)C=CC=CN1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: B
Agent: Cl
Agent: [Na+]
Product: Brc1ncccc1O[C@@H](c1ccccc1)[C@@H]1CNCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(S)-2-[(S)-(2-Bromo-pyridin-3-yloxy)-phenyl-methyl]-morpholine was synthesized from the corresponding amide (6-[Phenyl-(pyridin-3-yloxy)-methyl]-morpholin-3-one) using the following procedure: To a solution of compound 1 (0.4 g, 1.1 mmol) in anhydrous tetrahydrofuran (10 mL) under a nitrogen atmosphere was added a commercial solution of borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 3.4 mL, 3.4 mmol) via syringe. The reaction mixture was stirred at room temperature for 20 h. TLC analysis showed no reaction had occurred. A further amount of borane-tetrahydrofuran complex (3.0 mL, 3.0 mmol) was added and the reaction mixture was heated at reflux for 2.5 h. TLC analysis showed no starting material. The reaction mixture was brought to room temperature, treated with 1N HCl, stirred for 30 minutes, basified by the addition of 2N sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered, and solvent was removed under reduced pressure. Two chromatographies of the reaction product on silica gel (eluent—3:1 ethyl acetate/methanol for first chromatography, 10:1 dichloromethane/methanol for the second) gave 0.063 g (16%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.36 (m, 5H), 7.00 (m, 2H), 5.16 (d, 1H), 3.96 (m, 2H), 3.68 (m, 1H), 2.82 (m, 2H), 2.64 (m, 2H), 1.80 (br s, 1H). (MS) m/z 350.92 [Cl6H17BrN2O2+H+] HPLC—91.49% CHN—C22H21FN2O2 Calc'd: C, 55.03%; H, 4.91%; N, 8.02%. Found: C, 55.01%; H, 4.97%; N, 8.60%.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]2=[O:28])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:61][C@@H:62]([CH2:92]O)[CH2:63][N:64]1[CH:68]=[CH:67][C:66]([NH:69]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:65]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]2=[O:28])[C:9]([NH:69][C:66]2[CH:67]=[CH:68][N:64]([CH2:63][C:62]([OH:61])([CH3:92])[CH3:30])[N:65]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CC(C)Oc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (150 mg, 0.39 mmol) in dichloromethane (7 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (221 mg, 1.15 mmol) and N,N-diisopropylethylamine (250 mg, 1.93 mmol) at room temperature, under nitrogen. After 15 min, 1-hydroxybenzotriazole (177 mg, 1.20 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 60 mg, 0.39 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (70 mg, 34%) as a light yellow sticky solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.79-1.07 (m, 3H), 1.13 (br. s., 3H), 1.14 (br. s., 3H), 1.16-1.34 (m, 8H), 1.55-1.95 (m, 8H), 3.63 (br. s., 1H), 3.92 (s, 2H), 4.04 (d, J=18.1 Hz, 1H), 4.18 (d, J=18.1 Hz, 1H), 4.43-4.55 (m, 1H), 4.86 (s, 1H), 4.88 (dd, J=9.3, 1H), 6.67 (d, J=2.0 Hz, 1H), 6.93 (t, J=7.8 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 7.28 (d, J=2.0 Hz, 1H), 8.54 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH2:12])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([O-:19])=[O:18].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][NH:12][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:25][CH:24]=2)(=[O:27])=[O:28])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15]
Reactant: CCOc1cc(CN)c(Br)cc1C(=O)NC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(Br)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
After dissolving the N1-methyl-4-(aminomethyl)-5-bromo-2-ethoxybenzamide (6.77 g) in pyridine (50 ml), 4-nitrobenzenesulfonyl chloride (5.3 g) was added and the mixture was stirred at room temperature overnight. Water and ethyl acetate were then added for separation. The organic layer was washed with 1 N hydrochloric acid and brine and the precipitated crystals were filtered out (5.57 g). The organic layer of the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was washed with ethyl acetate and filtered. A total of 8.31 g of the title compound was obtained as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH2:32][CH2:33][C:34]([NH:23][S:20]([C:5]2[CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:8]([O:9][CH3:10])=[C:3]([CH:1]=[O:2])[CH:4]=2)(=[O:22])=[O:21])=[O:35])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=C(Cl)CCc1ccc(Cl)c(Cl)c1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc([N+](=O)[O-])c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccc(Cl)c(Cl)c2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide and 3-(3,4-dichlorophenyl)-propanoyl chloride, gave N-[3-(3,4-dichlorophenyl)-propanoyl]-5-formyl-6-methoxy-3′-nitro-biphenyl-3-sulfonamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]#[N:9])=[C:5](C)[CH:4]=1.[Cl:11]C1C=CSC=1C#N.[Cl:19]C1C=CSC=1C(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[ClH:11].[NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]#[N:9])=[C:5]([Cl:19])[CH:4]=1
Reactant: Cc1cc(CN)sc1C#N
Reactant: N#Cc1sccc1Cl
Reactant: NC(=O)c1sccc1Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cl
Product: N#Cc1sc(CN)cc1Cl

Procedure:
This compound was prepared analogously to 5-aminomethyl-3-methylthiophene-2-carbonitrile, the 3-chloro-2-cyanothiophene used having been prepared by dehydrating 3-chlorothiophene-2-carboxamide (substances commercially available) with trifluoroacetic anhydride.
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:20]2[CH:21]=[CH:22][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCC(C(=O)c2ccc(C(C)(C)C)cc2)CC1

Procedure:
19.1 g of 1acetylisonipecotoyl chloride, Example 1(b) are added portionwise to a stirring suspension of 13 g of t-butylbenzene and 27 g of aluminum chloride in 175 ml of dichloroethane. The reaction mixture is refluxed for 1 hour, cooled, and poured onto ice. The organic layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined, dried, and the solvent is removed under reduced pressure leaving the oil, 1-acetyl-4-(4-t-butylbenzoyl)piperidine.
Reaction SMILES: [C:1](=[O:15])([O:13][CH3:14])[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([CH:11]=O)[CH:4]=1.C1(P(=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][C:1]([O:13][CH3:14])=[O:15])=[CH:4][C:5]=1[CH:11]=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Oc1ccc(OC)c(C=O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OC(=O)OC)ccc1OC
Temperature: 80 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a solution of 3-formyl-4-methoxyphenyl methyl carbonate (10.0 g) in toluene (10 mL) was added ethyl (triphenylphosphoranylidene)acetate (21.5 g), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12.0 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=[O:17])[CH2:5]1.[OH-].[Li+].O>C1COCC1.CO>[C:12]([O:11][C:9]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Yield: 98 %

Procedure:
A solution of (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (18 g, 66.91 mmol) and lithium hydroxide (3.37 g, 80.3 mmol) in THF (50 mL), methanol (50 mL), and water (50 mL) was stirred at RT for 2 h. The reaction mixture was adjusted to ph 6 and extracted with 10:1 DCM:methanol. The organic phase was dried over sodium sulfate and concentrated to provide the title intermediate (17 g, 84% yield) as a colorless oil). 1H NMR (400 MHz, CDCl3): δ(ppm) 1.398-1.451 (d, 9H, J=21.2 Hz), 1.625-1.754 (m, 1H), 2.226-2.652 (m, 3H), 3.251-3.458 (m, 1H), 3.316 (s, 3H), 3.316-3.462 (m, 2H), 3.556-3.750 (m, 2H), 4.405-4.445 (m, 1H), 7.652 (s, 1H).
Reaction SMILES: [OH-].[K+].[C:3]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)([CH3:6])([CH3:5])[CH3:4].O.C(O)(C)C>C(O)(C)C.O.CC(C)=O>[C:3]([CH:7]1[CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC(C)(C)C1CCC(O)CC1

Procedure:
1 mg (2×10-5 moles) of [Ir(3,4,7,8 Me4 phen)COD]Cl oxidized with air in 50 ml of isopropanol-H2O (1%) were treated with 0.56 ml of an aqueous solution of KOH (100 mg in 50 ml of H2O) and successively heated at reflux for 1 hour. 5 g of 4-terbutyl-cyclohexanone were then added and it was heated at reflux for 30 minutes. The gaschromatographic analysis revealed a conversion of 100% and a trans/cis ratio=22.1 (95.5% of trans isomer). By addition of water and vacuum removal of the isopropanol and of the acetone which had formed, the reaction product 4-terbutyl-cyclohexanol was isolated. Ratios: [KOH]/[cat.]=1; [substratum]/[cat.]=1630. This example points out the possibility of obtaining, with a ratio KOH/cat.=1, the reduction of 4-terbutyl-cyclohexanone with a high stereoselectivity. In fact, when repeating the test under the same operative conditions as employed before, higher amounts of KOH were used, precisely 5.6 ml and 11.2 ml of aqueous solution, corresponding to a KOH/cat. ratio equal to 5 and 10, respectively. Equal conversions of 100% were obtained, while the trans/cis ratios decreased to 4.5 and 4, respectively.
Reaction SMILES: [CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19]C)[CH:17]=3)[N:12]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25](Cl)=[CH:24][CH:23]=3)[C:11]=2[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[Cl:41]CCl>>[CH:1]1([N:7]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:41])[C:11]=2[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCl
Reactant: COc1ccc2c(c1)c(CC(=O)N(c1nccs1)C1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: BrB(Br)Br
Product: Cc1c(CC(=O)N(c2nccs2)C2CCCCC2)c2cc(O)ccc2n1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2 g (3.83 mmol) of N-Cyclohexyl-N-thiazol-2-yl-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide in 20 mL of anhydrous dichloromethane under nitrogen at −78° C. was added dropwise 1.1 mL (11.5 mmol) of boron tribromide over 15 minutes. The reaction was allowed to warm to room temperature and stirred for 20 hr before quenching with water (5 mL). The layers were separated and the organic layer dried (Na2SO4), filtered and evaporated. The residue was chromatographed on silica to give the title compound. 1H NMR (DMSO) δ 9.24 (1H, s), 7.79 (2H, bs), 7.70 (4H, m), 6.87 (1H, d), 6.81 (1H, d), 6.59 (1H, dd), 4.43 (1H, bs), 3.40 2.08 (1H, m), 1.77 (4H, m), 1.61 (1H, m), 1.32 (4H, m). 5H concealed by DMSO and water signals.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH:18]=[CH:19][CH:20]=1>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH:18]=[CH:19][CH:20]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2cccc(OC)c2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2cccc(OC)c2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(3-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.65 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.34 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH:11]([OH:14])[CH2:12]Cl)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:1][C:2]1[N:3]([CH2:10][CH:11]2[CH2:12][O:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1cn(CC(O)CCl)c(Cl)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=[N+]([O-])c1cn(CC2CO2)c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
2-Chloro-1-(3-chloro-2-hydroxypropyl)-4-nitroimidazole prepared in Example 1 (2.04 g, 8.5 mmol) was dissolved in methylene chloride (20 ml), and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (2.04 ml, 13.67 mmol) was added to the solution. The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with 3N hydrochloric acid (20 ml) and a saturated saline solution (20 ml) in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford 2-chloro-4-nitro-1-(oxiran-2-ylmethyl)imidazole (190 mg, yield 11%) as a colorless oil.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([C:18]1[N:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:21]=[C:20]([C:27]([NH2:29])=O)[CH:19]=1)[CH2:15][CH2:16][CH3:17].C(N(CC)CC)C>ClCCl>[CH2:14]([C:18]1[N:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:21]=[C:20]([C:27]#[N:29])[CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1cc(C(N)=O)nn1C(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCc1cc(C#N)nn1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A solution of trifluoroacetic anhydride (13.5 mL, 95.4 mmol) in dichloromethane (84 mL) was added over 15 minutes to a 0° C. solution of 5-butyl-1-tert-butyl-1H-pyrazole-3-carboxamide (18.7 g, 86.7 mmol) and triethylamine (36.3 mL, 260 mmol) in dichloromethane (167 mL). The reaction was allowed to stir for 10 minutes before the ice bath was removed. The reaction was stirred at ambient temperature for 1 hour and then 2 M aqueous sodium carbonate was added. The mixture was transferred to a separatory funnel and was extracted with dichloromethane three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on a HORIZON HPFC system (silica gel, eluted with 20% ethyl acetate in hexanes). The appropriate fractions were combined, dried over magnesium sulfate, and concentrated under reduced pressure to yield 11.00 g of 5-butyl-1-tert-butyl-1H-pyrazole-3-carbonitrile as an orange oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[C:17]([O:25]CC)=[CH:18][C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[C:17](=[O:25])[CH:18]=[C:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=CC(=O)C(=O)OC)c1ncnc2c1ncn2Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)C(O)=CC(=O)c1ncnc2c1ncn2Cc1ccccc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Methyl 4-(9-benzyl-9H-purin-6-yl)-4-ethoxy-2-oxo-but-3-enoate (9) (100 mg, 0.20 mmole) obtained in above step was stirred at room in CH2Cl2 (20 mL) and treated with FeCl3.6H2O (0.125 g, 0.40 mmole). The reaction mixture was stirred at 40° C. for 5 h. Chloroform was distilled off and the resulting residue was treated with 1 N HCl (50 mL) for 1 h and then extracted with EtOAc (4×20 mL). The extract was dried over anhydrous sodium sulfate and the EtOAc distilled off to give a brownish residue which was purified by ion exchange chromatography (diethylamino sephadex anion exchange resin, CH3CN:H2O, (1:1) eluent). Yield 5.2 mg. Mp 166-167° C. 1H NMR (CDCl3) δ 3.99 (s, 3H, CH3), 5.54 (s, 2H, benzylic CH2), 7.35-7.41 (m, 5H, aromatic), 7.9 (s, 1H, olefinic CH), 8.3 (s, 1H, purine C8—H), 9.19 (s, 1H, purine C2—H). 13C NMR (CDCl3) δ 47.7, 53.4, 101.4, 128.0, 128.0, 128.9, 129.3, 131.8, 134.5, 147.4, 152.3, 154.3, 162.1, 172.8, and 185.7. FAB-HRMS: [M+H]+ Calcd. for C17H15N4O4 339.1093. Found 339.1083.
Reaction SMILES: [N:1]1([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([N:14](CCO)[CH2:15][CH3:16])[CH3:13]>>[N:1]1([CH2:6][C:7]([O:9][CH2:10][CH2:11][N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCCC1
Reactant: CCN(CC)CCO
Product: CCN(CC)CCOC(=O)CN1CCCC1

Procedure:
Using the method of Example 5, ethyl 1-pyrrolidineacetate was reacted with 2-(N,N-diethylamino)ethanol to provide 2-(N,N-diethylamino)ethyl 1-pyrrolidineacetate, b.p. 92° C. at 250 μmHg.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].I[C:16]1([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[C:20]1([S:19][C:16]2([O:1][C:2]3[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=3[CH:4]=[O:5])[CH2:18][CH2:17]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: IC1(Sc2ccccc2)CC1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
Silver carbonate (1.2 g, 4.34 mmol) was added to a solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (0.5 g, 2.43 mmol) and (1-iodocycloprop-1-yl)phenylsulfide (Cohen T. and Matz J. R., J. Am. Chem. Soc. 1980, 102, 6902) (1.2 g, 4.34 mmol) in toluene (30 mL) and the mixture was stirred at 40° C. overnight. The mixture was cooled, diluted with ethyl acetate and filtered, washing well with ethyl acetate. The mixture was washed with aqueous sodium hydroxide, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (95:5), to give the title compound as a yellow oil (191 mg, 27%). 1H NMR (360 MHz, CDCl3) δ 1.51-1.56 (2H, m), 1.44-1.48 (2H, m), 7.25-7.35 (7H, m), 7.69 (1H, d, J 2.0 Hz), and 10.26 (1H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C-:22]#[N:23].[Na+].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>CN(C)C=O.O.C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:22]#[N:23])=[C:17]([C:18]#[N:19])[C:20]#[N:21])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: [C-]#N
Reactant: CCn1c2ccccc2c2cc(C=C(C#N)C#N)ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Pb+4]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)C#N)ccc21
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
10.2 g (37.5 mmol) of N-ethyl-3-(2,2-dicyanoethenyl)carbazole and 100 ml of N,N-dimethylformamide as solvent were placed in a 500 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution of 1.84 g (37.5 mmol) of sodium cyanide and 4.3 ml of water, which was stirred for 10 minutes. Further, 16.6 g of lead tetraacetate was added. The resultant product was subjected to the reaction for 30 minutes. After the reaction was completed, 200 ml of chloroform was added. To the resultant aqueous solution was added 100 ml of water. The resultant liquid was washed in a separatory funnel. To the washed liquid was added sodium sulfate, which was left to stand for 30 minutes and dehydrated. The dehydrated solution was concentrated in an evaporator and dried under vacuum to obtain a red solid, which was recrystallized in the presence of benzene to obtain 1.5 g of a red crystal.