Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:16][C:17]([C:19]1[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=1[CH3:26])=O)C.C(OCCOCCO)C.CO.C[O-].[Na+]>COCCOCCOC.CCCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:17]([C:19]2[N:23]([CH3:24])[N:22]=[C:21]([CH3:25])[C:20]=2[CH3:26])=[O:16])[C:12]#[N:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CC#N)cc1
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: CO
Solvent: COCCOCCOC
Product: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Temperature: 92.5 °C
Yield: 93.6 %

Procedure:
In a 10 L-reaction flask equipped with a rectification column and a separating tank, 314 g (1.81 mol) of 4-tert-butylphenylacetonitrile, 300 g (1.65 mol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 3000 g of heptane, 225 g of diethylene glycol dimethyl ether, and 99 g of diethylene glycol monoethyl ether were added, the atmosphere was substituted with nitrogen, then azeotropic dehydration was carried out by heating at 90 to 95° C. for 1 hour. The temperature was maintained, 381 g (1.98 mol) of 28% sodium methoxide methanol solution was added dropwise over 10 hours, and the resulting mixture was further reacted for 10 hours. During this reaction, it is continued to remove alcohol separated in the phase under the heptane phase in the separating tank. After cooling to 30° C. or less, 3000 g of water was added to separate out heptane phase, and the resulting aqueous phase was washed with 600 g of heptane to separate out heptane phase. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 478 g (yield 94.0%) of 2-(4-tert-butylphenyl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile. To the aqueous phase, 206 g (1.98 mol) of 35% hydrochloric acid was gradually added dropwise to be neutralized. After stirring for 1 hour, separated crystal was filtered, washed with 300 g of water, and then dried to obtain 469 g (yield 92.0%) of 3-oxo-2-(4-tert-butyl phenyl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].[CH3:21][N:22]1[C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][N:24]=[C:23]1[CH:40]=[O:41].C(N(CC)CC)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:40]([C:23]1[N:22]([CH3:21])[C:26]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:9]=2[NH:10][C:11]2[C:12]([CH3:20])=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[C:7]#[N:8])=[CH:25][N:24]=1)=[O:41]
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(C=O)n1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(Nc2c(C#N)cncc2-c2cnc(C=O)n2C)ccc2[nH]ccc12
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (250 mg, 0.67 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole-2-carbaldehyde (see e.g., U.S. Pat. No. 6,521,618) (401 mg, 1.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (24 mg, 0.034 mmol), and triethylamine (74.9 mg, 0.74 mmol) in dioxane (6 mL) was heated at the reflux temperature for 22 h, cooled to room temperature, and concentrated in vacuo. The residue was suspended in CH2Cl2 and filtered and the solid was washed with CH2Cl2. The combined filtrate and washings were concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate/CH2Cl2, 20% to 90%; MeOH/ethyl acetate, 5%) to provide 103 mg (43%) of 5-(2-formyl-1-methyl-1H-imidazol-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 537 as a dark yellow solid. MS: 355.2 (M+H); melting range: 200-202° C.; and HRMS: 357.1458.
Reaction SMILES: [OH:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26]CC)=[O:25].[OH-].[K+]>CN(C=O)C.O.CO>[Cl:15][C:3]1[C:2]([O:1][CH2:23][C:24]([OH:26])=[O:25])=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[C:4]=1[Cl:14]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCCc2cc(O)c(Cl)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)COc1cc2c(c(Cl)c1Cl)C(=O)CCCC2

Procedure:
2-Hydroxy-3,4-dichloro-6,7,8,9-tetrahydro-5H- benzocyclohepten- 5-one (10 g., 0.04 mole), anhydrous potassium carbonate (7 g., 0.05 mole) and ethyl bromoacetate (8.35 g., 0.05 mole) in DMF (75 ml.) are stirred at 60° C. for 1 hour. Then potassium hydroxide (5 g.) dissolved in water (5 ml.) and methanol (100 ml.) is added. The mixture is refluxed for one hour. The methanol is distilled, the residue is poured into water, and the solution is filtered. Upon acidification with 12 N NCl, (3,4-dichloro-5-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten- 2-yloxy)acetic acid separates and is collected by filtration.
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:16](=[O:27])[C:15](O)=[C:14]2[C:29](=O)[CH2:30][O:31][CH3:32])=[CH:9][CH:8]=1>CCO.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]3[C:29]([CH2:30][O:31][CH3:32])=[N:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[C:15]=3[C:16](=[O:27])[N:17]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[CH:9][CH:8]=1
Reactant: COCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)C1c1ccc(Cl)cc1
Reactant: NNC1CC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(Cc1ccc(OC)cc1)C2=O
Temperature: 115 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
Cyclopropylhydrazine (2.71 g) (Step 17.2) was added to a solution of 5-(4-chlorophenyl)-3-hydroxy-4-(2-methoxyacetyl)-1-(4-methoxybenzyl)-1H-pyrrol-2(5H)-one (5 g, 12.4 mmol) (Step 130.2) in a mixture of EtOH and toluene (60 mL, 1:1, v/v). The reaction mixture was stirred 16 h at 115° C., concentrated, quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 20-50%) to afford the title compound (2.62 g) as a yellow solid. tR: 1.24 min (LC-MS 2); ESI-MS: 438.1 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([CH3:25])[CH:19]=1)=[O:10].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[C:20]([CH3:25])[CH:19]=1)=[O:10]
Reactant: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1Br
Reactant: OB(O)c1cccnc1
Product: Cc1cc(C(=O)NCCCCCC(=O)Nc2ccccc2N)ccc1-c1cccnc1
Yield: 63 %

Procedure:
The procedure of Example 81 was repeated except for using N-(5-(2-aminophenylcarbamoyl)pentyl)-4-bromo-3-methylbenzamide instead of N-(5-(2-aminophenylcarbomoyl)pentyl)-3-bromo-2-methylbenzamide, and 3-pyridinyl boronic acid instead of phenyl boronic acid to obtain the title compound (32 mg, 63%).
Reaction SMILES: CN(C)[CH:3]=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:12][O:13][C:14]1[CH:18]=[CH:17][O:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:3][O:4][C:18]=1[CH:17]=[O:16]
Reactant: COc1ccoc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccoc1C=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
A 3-L, one-necked, round-bottomed flask was equipped with a Teflon-coated magnetic stirbar. The system was flame-dried and flushed with argon. The flask was charged with a solution of N,N-dimethylformamide (31.9 mL, 413 mmol, 1.35 equiv) in dichloromethane (1.2 L). The solution was cooled to 0° C. in a dry ice-acetone bath, and then oxalyl chloride (32.5 mL, 367 mmol, 1.2 equiv) was added over 16 min. Vigorous bubbling occurred and a white solid precipitated. After stirring for 20 min, the reaction mixture was cooled to −40° C. by addition of dry ice to the cooling bath and a solution of 3-methoxyfuran (Meister, C.; Scharf, H.-D. Synthesis 1981, 737-739) (30 g, 306 mmol, 1 equiv) in dichloromethane (100 mL) was added via cannula. A dark-brown color formed during the addition. After stirring for 20 min, the cooling bath was removed and saturated aqueous sodium bicarbonate solution (1.5 L) was added. The biphasic mixture was stirred vigorously for 6 hours, and then was partitioned. The aqueous layer was further extracted with dichloromethane (2×800 mL). The organic layers were combined and the combined layers were dried over sodium sulfate. The solids were filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography on silica gel (100% diethyl ether) to furnish 3-methoxyfurfural 6 (21.2 g, 55%) as a light-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1.CCN(CC)CC.[CH:25](O)([CH3:27])[CH3:26]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:25]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[N:6][CH:7]=1)([CH3:27])=[CH2:26]
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cn1
Reactant: CC(C)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(C(=O)OCc2ccccc2)nc1
Temperature: 80 °C

Procedure:
A mixture of benzyl 5-bromopicolinate (2.92 g, 10 mmol), potassium isopropenyl trifluoroborate (3.05 g, 21 mmol), Pd(dppf)Cl2 (445 mg, 0.54 mmol), and Et3N (1.4 mL) in isopropyl alcohol (20 mL) was degassed with N2 and heated at 80° C. for 7 h. The mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with H2O, 5% citric acid, sat.NaHCO3 (aq.) and brine, then dried (MgSO4) and concentrated. The product benzyl 5-isopropenylpicolinate (1.27 g) was obtained by silica gel chromatography (elution with 0-16% EtOAc/Hex).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10]3[CH:13]=[CH:14][CH:15]=[N:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1.[C@H:18](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>[CH3-].C[Al+]C.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Cl-].[Ti+3].O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[CH2:18])[C:10]3[CH:13]=[CH:14][CH:15]=[N:16][C:9]=3[CH2:8][O:7][C:6]=2[CH:17]=1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: O=C1c2ccc(F)cc2OCc2ncccc21
Agent: [Ti+3]
Agent: C[Al+]C
Agent: [CH3-]
Solvent: C1CCOC1
Product: C=C1c2ccc(F)cc2OCc2ncccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Combine 8-fluoro-11H-10-oxa-1-aza-dibenzo[a,d]cyclohepten-5-one (567 mg, 2.47 mmol) and anhydrous tetrahydrofuran (25 mL). Chill the solution to 0° C. and add Tebbe reagent (0.5M/L solution in toluene, 5.4 mL, 2.72 mmol). Remove cooling and stir the admixture for 10 min. Quench the reaction by adding saturated aqueous Rochelle's salt solution (75 mL). Stir the biphasic mixture rapidly for 10 min, then separate the layers and extract the aqueous layer with ethyl acetate. Dry the combined organic layers with magnesium sulfate, filter and strip. Purify the crude product by flash chromatography (25% ethyl acetate/hexanes) to provide 416 mg(74%) of purified product. LCMS (APCI-pos): 228.1 (M+H). LCMS (APCI-neg): 226.9 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=1
Reactant: COc1cc(C(O)c2ccccc2)ccc1-c1cccc(C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COc1cc(C(=O)c2ccccc2)ccc1-c1cccc(C)c1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Alcohol 9 was dissolved in 8 mls of DCM, followed by the addition of PCC (4 eq, 2.63 mM) and celite the reaction mixture was stirred for 8 hours, after which it was diluted with ether, followed by washes with bicarb solution and brine. The organic layer was separated and dried under reduced pressure. The product was the subjected to flash chromatography using 20% EtOAc/hexanes as the solvent system to obtain the product as a white solid. Yield=90.5% (Rf=0.57; 20% EtOAc/Hexanes), 1H NMR, 500 MHz Varian, CDCl3, δ 7.86 (d, J=10.00 Hz, 1H), 7.84 (d, J=15.00 Hz, 1H), 7.58 (m, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.38 (d, J=10.00, 1H), 7.36 (d, J=9.5 Hz, 2H), 7.33 (t, J=15.5 Hz, 1H), 7.19 (d, J=7.5, 1H), 3.86\ (s, 3H), 2.41 (s, 3H) MS: m/z (ESI, pos.)=325.3 ([M+23])
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:4].[NH2:19][CH:20]([CH3:25])[CH2:21][C:22]([NH2:24])=[O:23]>C(#N)C>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH:20]([CH3:25])[CH2:21][C:22](=[O:23])[NH2:24])=[CH:10][CH:9]=1)=[O:4]
Reactant: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Reactant: CC(N)CC(N)=O
Solvent: CC#N
Product: COC(=O)NC=Cc1ccc(OCC(O)CNC(C)CC(N)=O)cc1
Reaction time: 20 h

Procedure:
7.5 g (0.03 mol) of 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxypropane are dissolved in 75 ml of acetonitrile and added dropwise to a boiling stirred solution of 3.34 g (0.029 mol) of β-aminobutyric acid amide in 75 ml of acetonitrile. The mixture is stirred for 20 hours under reflux, the solvent is removed by distillation under reduced pressure and the oil which remains is partitioned between 350 ml of 0.1 N hydrochloric acid and 300 ml of ethyl acetate. The hydrochloric acid extract is separated off, rendered alkaline with sodium carbonate and extracted four times with 100 ml of ethyl acetate at a time. The organic phases are dried over sodium sulphate and evaporated under reduced pressure. The resulting oil yields 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2-hydroxy-3-(2-carbamoyl-1-methyl-ethylamino)-propane, of melting point 109°-111° C., from acetone-ethyl acetate.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH:7][CH2:8][N+:9]([O-])=O)(=[O:3])[CH3:2].P(Cl)(Cl)Cl>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:4][CH2:5]/[CH:6]=[CH:7]/[C:8]#[N:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=CC[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC/C=C/C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-acetoxy-4-nitro-but-2-ene (4 g.) in 40 cc of methylenechloride and 40 cc of pyridine was added under ice cooling 4.4 cc of PCl3. The reaction was worked up after 1 hour stirring at room temperature. The crude product was purified by distillation and column chromatography. γ-Acetoxycrotononitrile was obtained as a colorless liquid.
Reaction SMILES: C(#N)C.[F:4][C:5]([F:21])([F:20])[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([S:16]([OH:19])(=[O:18])=[O:17])[CH:7]=1.[F:22]F>C(OCC)C>[F:22][N+:9]1[C:10]([C:12]([F:13])([F:15])[F:14])=[CH:11][C:6]([C:5]([F:4])([F:20])[F:21])=[CH:7][C:8]=1[S:16]([O-:19])(=[O:18])=[O:17]
Reactant: FF
Reactant: O=S(=O)(O)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Solvent: CC#N
Solvent: CCOCC
Product: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)[n+]1F

Procedure:
In a 25 ml flask, acetonitrile (6 ml) was added to 4,6-bistrifluoromethylpyridine-2-sulfonic acid (874 mg, 2.64 mmol) to prepare a homogeneous mixture. Then, the flask was dipped in a cooling bath kept at -40° C., and to the mixture, the fluorine gas diluted with the nitrogen gas to a concentration of 10% was introduced at a flow rate of 15 ml/min. The total amount of the fluorine gas was 211 ml. As the fluorination reaction proceeded, a precipitate was formed. After the reaction, only the nitrogen gas was introduced for 30 minutes. After the addition of ethyl ether to the mixture, the resulting precipitate was recovered by filtration to obtain N-fluoro-4,6-bistrifluoromethylpyridinium-2-sulfonate (787 mg). Yield, 95%. Melting point, 172°-174° C. (with decomposition).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4]1.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([NH:18][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4]1)[CH3:17]
Reactant: CC(c1ccccc1)N1CCC(CCl)C1
Reactant: CCN
Product: CCNCC1CCN(C(C)c2ccccc2)C1
Yield: 98 %

Procedure:
A solution of 4.0 g (15.4 mmol) [3R-(R*,R*)]-3-(chloromethyl)-1-(1-phenylethyl)pyrrolidine in 60 ml 70% ethylamine was heated in a pressure bottle on the steam bath overnight. The mixture was cooled, filtered, and evaporated to a thick syrup which was treated with 50 ml 2N sodium hydroxide and extracted with 3×30 ml dichloromethane. The combined organic layer was dried (MgSO4) and evaporated to afford 3.49 g (98%) of the title compound as a syrup, [α]D +45.6° C. (C, 1.04, methanol).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCN(CCCCCCCCCCOC3CCCCO3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: C(CCCCCN1CCNCC1)CCCCOC1CCCCO1
Reaction time: 8 h
Yield: 82 %

Procedure:
583 mg (1.40 mmole) quantity of 1-benzyl-4-[10-(2-tetrahydropyranyloxy)decyl]piperazine was dissolved in 20 ml of ethanol, and 200 mg of 10 % palladium-carbon was added thereto and the mixture was shaken at 3 atm. for 8 hours under hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to dryness, giving 375 mg (yield: 82 %) of N-[10-(2-tetrahydropyranyloxy)decyl]piperazine. Then, using N-t-butoxycarbonylphenylglycine and N-[10-(2-tetrahydropyranyloxy)decyl]piperazine was treated in the same procedure as in Reference Examples 1 and 3, giving 384 mg (yield: 75 %) of 1-(2-amino-2-phenylethyl)-4-[10-(2-tetrahydropyranyloxy)decyl]piperazine as a hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][CH2:12][OH:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: OCCCO
Product: Clc1cccc(C2OCCCO2)c1

Procedure:
The title compound was prepared as a colourless oil, bp 95°-102° C./0.2 mm, from 3-chlorobenzaldehyde (24 g) and 1,3-propanediol (20 g) by an analogous procedure to that described in Example X 1.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1>[C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:19](=[O:21])[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of 2-tert-butylaniline (5.0 g, 33.5 mmol) and triethylamine (11.2 g, 110.6 mmol) in THF (350 mL) was added acetyl chloride (2.89 g, 36.9 mmol). After being stirred at room temperature for 3 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting white solid was triturated with hexane/ethyl acetate to give the title compound (6.13 g) as a white crystalline powder.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:32](/[CH2:42][CH3:43])=[CH:33]/[CH2:34][CH2:35][C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:32](/[CH2:42][CH3:43])=[CH:33]/[CH2:34][CH2:35][C:36]([CH2:40][CH3:41])([OH:39])[CH2:37][CH3:38])[S:30][CH:31]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC/C(=C\CCC(O)(CC)CC)c1cc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC/C(=C\CCC(O)(CC)CC)c1cc(CCc2ccc(CO)c(CO)c2)cs1

Procedure:
In a manner similar to that of Example 6(l), by reaction of 1 g (1.55 mmol) of (E)-7-{4-[2-(3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl)ethyl]-2-thienyl}-3-ethylnon-6-en-3-ol with 3.7 mL (3.7 mmol) of 1.0 M tetrabutylammonium fluoride solution, the desired product is obtained in the form of white crystals (m.p.=85-86° C.; m=580 mg; Y=90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH3:10][C:11]1([CH3:20])[O:15][C@H:14]([CH2:16][CH:17]=O)[C:13](=[O:19])[O:12]1.C(O)(=O)C.[BH4-].[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:17][CH2:16][C@H:14]2[O:15][C:11]([CH3:20])([CH3:10])[O:12][C:13]2=[O:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1(C)OC(=O)[C@@H](CCNc2cc(F)cc(F)c2)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (4.0 g, 31.0 mmol), (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (4.9 g, 31.0 mmol) and acetic acid (1.7 ml, 31.0 mmol) in 1,2-dichloroethane (100 mL) under nitrogen at 0° C. was added sodium borohydride (1.17 g, 31.0 mmol mol) in portions over 10 minutes. The resulting mixture was stirred at RT for 2.5 hours. After cooling to 0° C. the reaction mixture was quenched by the careful addition of saturated aqueous NaHCO3 (100 mL) followed by DCM (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to provide the crude (R)-5-[2-(3,5-difluorophenylamino)ethyl]-2,2-dimethyl-1,3-dioxolan-4-one as a yellow oil (8.07 g, 29.7 mmol, 96% yield) which was used without any further purification in the next reaction step. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=272.3; tR=1.76 min.
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20]([C:22](=O)[CH3:23])[CH:21]=1>CO.C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:25])=[C:20](/[C:22](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:23])[CH:21]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1cccc(S(N)(=O)=O)c1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(N)(=O)=O)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 40.5 %

Procedure:
3-(hydrazinecarbonyl)benzenesulfonamide (50 mg, 0.232 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (39.6 mg, 0.232 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-3-(2-(1-(5-chloro-2-hydroxyphenyl)ethylidene)hydrazinecarbonyl)benzenesulfonamide (36 mg, 0.094 mmol, 40.4% yield) as a solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.34 (s, 1H), 8.15 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.73 (t, 1H, J=8.0 Hz), 7.64 (m, 1H), 7.51 (bs, 2H), 7.32 (dd, 1H, J=2.4 & 8.4 Hz), 6.92 (d, 1H, J=8.4 Hz), 2.49 (s, 3H). Mass [M+H]+:368.0