Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[ClH:7].[Cl:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[F:16][C:17]([F:46])([F:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:22].O>CN(C)C=O>[ClH:8].[ClH:7].[F:46][C:17]([F:16])([F:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:25][C@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:22]
Reactant: ClCc1ccccn1
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccn3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
Potassium carbonate (187 mg) and 2-(chloromethyl)pyridine hydrochloride (81 mg) were added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (200 mg) in N,N-dimethylformamide (4 ml) at room temperature with stirring. After 2 hours, the reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with water and then dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and toluene (1:3) and treated with 4N hydrogen chloride in ethyl acetate solution to afford (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-pyridylmethyl)piperazine dihydrochloride (123 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13](=[S:15])[NH2:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.Br[CH:28]([C:37](=O)[CH3:38])[C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[S:15][C:28]([C:29]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:30])=[C:37]([CH3:38])[N:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)C(Br)C(=O)N1CCOCC1
Reactant: NC(=S)c1cc2ccc(O)cc2oc1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3ccc(O)cc3oc2=O)sc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5.8 %

Procedure:
To a stirred suspension of 7-hydroxy-2-oxo-2H-chromene-3-carbothioic acid amide (354 mg, 1.6 mmol) in anhydrous N,N-dimethylformamide (7 mL), 1,8-diazabicyclo-[5.4.0]undec-7-ene (480 μL, 490 mg, 3.2 mmol) was added followed by a solution of 2-bromo-1-morpholin-4-yl-butane-1,3-dione (750 mg, 3.0 mmol) in anhydrous N,N dimethylformamide (15 mL) and the mixture was stirred at room temperature for 15 h. The reaction mixture was poured into water (100 mL) and extracted first with chloroform (3×30 mL) then after saturation with NaCl, with tetrahydrofuran (3×50 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in chloroform (16 mL), pyridinium p-toluenesulfonate (40.2 mg, 0.16 mmol) was added and the mixture was stirred at 60° C. for 4.5 h. The reaction mixture was washed with a mixture of brine (10 mL) and 5% NaHCO3 solution (5 mL) and then with brine (2×15 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica, eluting with a 9:1:0.1 mixture of chloroform, methanol and cc. NH4OH. The title compound (34.6 mg, 0.093 mmol, 5.8%) was obtained as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54]O.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:54][CH2:53][N:52]([CH3:56])[CH3:51])[CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)[N:21]=[N:20][C:19]=1[O:30][CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(O)cc2n1C(=O)OC(C)(C)C
Reactant: CN(C)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(OCCN(C)C)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
100 mg 6-hydroxy-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester and 175 mg triphenylphosphine are dissolved in 7 mL toluene and 2 mL THF. After dropwise addition of 84 μL 2-dimethylaminoethanol and 123 μL diethyl azodicarboxylate, the reaction mixture is stirred at room temperature for 5 hours. The solvent is removed in vacuo and the residue is dissolved in dichloromethane. The organic phase is washed with water and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are dried over MgSO4 and concentrated in vacuo. Purification by HPLC afforded 35 mg (43%) 6-(2-dimethylaminoethoxy)-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CO[Na].[C:23]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br)#[N:24]>CS(C)=O>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[C:23]#[N:24])=[CH:16][CH:17]=2)[C:9](=[O:19])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cccc(=O)n1Cc1ccc(O)cc1
Reactant: N#Cc1ccccc1CBr
Agent: CO[Na]
Solvent: CS(C)=O
Product: CCCCc1cccc(=O)n1Cc1ccc(OCc2ccccc2C#N)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 2.57 g of 6-butyl-1-p-hydroxybenzyl-1,2-dihydro-2-oxopyridine (obtainable from IIIa and p-hydroxybenzyl bromide), 0.5 g of CH3ONa and 40 ml of DMSO is stirred for 0.5 hour. A solution of 2.2 g of o-cyanobenzyl bromide in 15 ml of DMSO is added dropwise and the mixture is stirred for 16 hours at 20° and evaporated to give 6-butyl-1-(4-o-cyanobenzyloxybenzyl)-1,2-dihydro-2-oxopyridine after conventional working-up.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)(=[O:3])[CH3:2].[Cl:19]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]2[Cl:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(OC(C)=O)cc2c1Cl
Yield: 74.6 %

Procedure:
A solution of ethyl 5-acetoxyindole-2-carboxylate (500 mg) in dichloromethane (10 ml) was stirred at room temperature in the presence of N-chlorosuccinimide (297 mg) and potassium carbonate (279 mg) overnight. The resulting precipitate was collected by filtration, washed with cold dichloromethane followed by water and dried under vacuum overnight to give the desired product as a white powder (425 mg, 75%). NMR: δ 1.35 (t,3H), 2.25 (s,3H), 4.4 (q,2H), 7.1 (d,1H), 7.3 (s, 1H), 7.5 (d, 1H), 12.2 (s, 1H); m/z 281.9 (M+H+).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:31])[CH3:30]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: CC(=O)c1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2- methylpropanamide (5.20 mg, 0.0137 mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.50 mg, 22.0% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.75 (s, 3H), 2.53 (apparent sept, partially hidden, 2H, J=7.6 Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 498.81 (M+), 499.6 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:33])[CH2:22][C:23]4[CH:32]=[CH:31][C:26]5C(=O)OC[C:25]=5[CH:24]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.N1(C(=O)CC2C=CC(N3C=NN=N3)=CC=2)CCNCC1.[N:55]1[O:56][N:57]=C2C=C(CC(=O)C)C=CC=12>>[N:55]1[O:56][N:57]=[C:25]2[CH:24]=[C:23]([CH2:22][CH:21]([N:18]3[CH2:17][CH2:16][N:15]([C:13](=[O:14])[CH2:12][C:9]4[CH:10]=[CH:11][C:6]([N:1]5[CH:5]=[N:4][N:3]=[N:2]5)=[CH:7][CH:8]=4)[CH2:20][CH2:19]3)[CH3:33])[CH:32]=[CH:31][C:26]=12
Reactant: CC(=O)Cc1ccc2nonc2c1
Reactant: CC(Cc1ccc2c(c1)COC2=O)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1
Agent: Cl
Agent: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Product: CC(Cc1ccc2nonc2c1)N1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1

Procedure:
1-{4-[1-(2,1,3-Benzoxadiazol-5-yl)propan-2-yl]piperazin-1-yl}-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone was prepared in an analogous fashion to that described above for the synthesis of 5-[2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)propyl]-2-benzofuran-1(3H)-one starting from 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride and 1-(2,1,3-benzoxadiazol-5-yl)propan-2-one. LC/MS: [(M+1)]+=433.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:9])=[O:8].C=O.[C:12](=O)([O-])[O-:13].[K+].[K+]>>[OH:13][CH2:12][NH:9][C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)Cc1cccs1
Agent: C=O
Agent: [K+]
Product: O=C(Cc1cccs1)NCO
Temperature: 0 °C

Procedure:
A mixture of 2-thienylacetamide, formaldehyde solution (37%, 1 equivalent) and a catalytic amount of potassium carbonate is warmed on a steam bath until a homogeneous solution is obtained. The solution is cooled to 0° C. overnight and the resulting solid collected by filtration.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH2:22][O:23]CC2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][C:6]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:22][OH:23])[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:7][C:6]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=C(CCCC2CCCCC2)COCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(CC(CO)CCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of 1.54 g (2.30 mmol) of N-[2-t-butyl-5-(5-cyclohexyl-2-benzyloxymethyl-1-pentenyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 208) in 15 ml of ethanol was vigorously stirred in a stream of hydrogen in the presence of 1.54 g of 10% w/w palladium-on-charcoal at room temperature for 4 hours and 20 minutes and then at 40° C. for 2 hours. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure. The concentrate was purified by column chromatography through 75 g of silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent. Fractions containing the desired compound together with a small amount of impurities were combined and concentrated by distillation under reduced pressure. The concentrate was again purified by column chromatography under the same conditions as above, to give 1.19 g (yield 90%) of the title compound as a foam-like material.
Reaction SMILES: ClC(O[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=O.[CH3:14][CH2:15][N:16]([CH:20]([CH3:22])C)[CH:17]([CH3:19])C.[CH3:23][N:24]([CH:26]=[O:27])[CH3:25]>>[CH2:20]([N:16]1[CH2:15][CH2:14][CH:23]([N:24]2[C:25]3[C:9](=[CH:10][CH:5]=[CH:6][CH:7]=3)[CH2:8][NH:11][C:26]2=[O:27])[CH2:19][CH2:17]1)[C:22]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C1NCc2ccccc2N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a solution of 1-benzyl-4-((2-aminomethyl)phenylamino)piperidine (1.74 g, 5.90 mmol) from Step 3 in dry DMF (50 mL) was added 4-nitrophenyl chloroformate (1.25 g, 6.20 mmol) and DIEA (3.08 mL, 17.7 mmol). After the reaction had been stirred at ambient temperature for 24 h, the solvent was removed under reduced pressure. The residue was dissolved in DCM (100 mL) and washed with saturated aqueous NaHCO3 (4×50 mL), dried (MgSO4), and filtered. The solution was concetrated and the precipitate which formed was collected by filtration to give 1-(1-benzyl-4-piperidinyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid (50% yield).
Reaction SMILES: C([Si]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH:16]2[CH2:18][CH2:17]2)=[CH:11][C:10]=1[CH3:19])(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>C1COCC1>[CH:16]1([C:12]2[CH:11]=[C:10]([CH3:19])[C:9]([OH:8])=[C:14]([CH3:15])[CH:13]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(C2CC2)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C2CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a suspension of (4-bromo-2,6-dimethylphenoxy) tert-butyldimethylsilane (668 mg, 2.12 mmol) and tetrakis(triphenylphosphine)palladium (122 mg, 0.11 mmol) in THF (20 mL) was added cyclopropyl zinc chloride (28.0 mL, 11.2 mmol). The mixture was heated at 80° C. for 24 h and cooled to room temperature. The reaction was passed through a short pad of SiO2 to remove the catalyst and the solution was concentrated to oil. The resulting oil was diluted in EtOAc (100 mL), washed with brine (100 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=90:10) yielded 370 mg (63%) of tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane. To tert-butyl(4-cyclopropyl-2,6-dimethylphenoxy)dimethylsilane (320 mg, 1.16 mmol) in THF (10 mL) was added a solution of tetrabutylammonium fluoride (5.0 mL, 1 M in THF, 5.0 mmol) and acetic acid (0.40 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=85:15) yielded 175 mg (93%) of 4-cyclopropyl-2,6-dimethylphenol as a light yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]([C:16]#[N:17])=[C:8]([CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:36].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:23][CH:24]=2)[C:7]([C:16]([NH2:17])=[O:36])=[C:8]([CH:10]([OH:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.34 g of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide, 0.30 g of the title compound was obtained as a powder, melting at 157°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:29][C:26]1[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2ccc(Cl)nc2)c(Cl)c1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a mixture of 0.40 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.21 g of potassium carbonate and 20 ml of N,N-dimethylformamide was added dropwise a solution of 0.25 g of 6-chloro-3-(chloromethyl)pyridine dissolved in 5 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 7 hours, the reaction mixture was poured into ice-water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.44 g of 3,5-dichloro-4-(6-chloro-3-pyridylmethyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (77% yield), m.p. 93.3° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:22]([C:24]2[CH:25]=[N:26][C:27]3[N:28]([N:30]=[CH:31][C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH:29]=2)=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:22]([C:24]2[CH:25]=[N:26][C:27]3[N:28]([N:30]=[CH:31][C:32]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH:29]=2)=[O:23])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNC(=O)c2cnc3c(-c4cccc(Cl)c4)cnn3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1N1CCNCC1)c1cnc2c(-c3cccc(Cl)c3)cnn2c1
Yield: 89.8 %

Procedure:
A solution of N-{2-(4-t-butoxycarbonyl piperazino)phenyl}methyl 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-6-amide (300 mg) and trifluoroacetic acid (0.42 ml) in chloroform (6 ml) was heated at reflux over 6 hours. The reactant was cooled, and ice and a 2N aqueous sodium hydroxide solution (3 ml) were added, and thereafter extracted with chloroform. The organic layer was dried with magnesium sulfate, and thereafter the solvent was distilled under a reduced pressure. The residue was purified by an alumina column chromatography, and thereafter recrystallized from tetrahydrofuran-diisopropyl ether to yield N-(2-piperazinophenyl)methyl 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-6-amide (220 mg, 90%). mp: 185-188° C.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][C:21](C)([O-])[CH3:22].[K+].O>CN(C)C=O>[CH2:22]([S:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:21]=[CH2:20]
Reactant: N#Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1S
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCSc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Yield: 43.5 %

Procedure:
1.0 g (3.6 mmol) of 2-mercapto-4-(4-trifluoromethylphenyl)benzonitrile, 0.45 g (4.0 mmol) of potassium tert-butoxide and 0.5 g (4.1 mmol) of 3-propenyl bromide were stirred in 20 ml of N,N-dimethylformamide at room temperature for 1 hour. The resulting reaction mixture was poured into 20 ml of water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.5 g of 2-(2-propenylthio)-4-(4-trifluoromethylphenyl)benzonitrile (yield 43.0%) as yellow crystals (m.p. 89-90° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH2:37]Cl)[C:32]([NH2:34])=[O:33])[CH2:25][CH2:24]1>CN(C)C=O>[CH3:19][O:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N:31]([C:32]([NH:34][CH2:5][CH2:6][CH2:7][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[O:33])[CH2:35][CH:36]2[CH2:37][CH2:9][CH2:10][CH2:11][CH2:2][CH2:3][CH2:4]2)[CH2:25][CH2:24]1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: COCOC1CCN(CCN(CCCCl)C(N)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOC1CCN(CCN(CC2CCCCCCC2)C(=O)NCCCOc2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 0 °C

Procedure:
A solution of 1.6 g of 6-hydroxycarbostyril, 1.4 g of potasium carbonate and 4.2 g of N-cyclooctylmethyl-N-[2-(4-methoxymethoxy-1-piperidinyl)-ethyl-N-(3-chloropropyl)urea in 20 ml of dimethylformamide was stirred at 80° C. for 1 day. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 5% methanol/dichloromethane) to obtain 0.76 g of 6-[3-{N-[2-(4-methoxymethoxy-1-piperidinyl)ethyl]-N-cyclooctylmethylamino}carbonylaminopropoxy]carbostyril.
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].S(Cl)([Cl:19])=O.O>C(Cl)Cl.N1C=CC=CC=1>[Cl:19][CH2:2][C:3]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)Oc1cc(C)ccc1CCl

Procedure:
A solution of 2.20 g (0.0098 mole) of methyl 2-(2-hydroxymethyl-5-methylphenoxy)propionate in 10 mL of dry methylene chloride was added to a colorless solution of 1.28 g (0.0108 mole) of thionyl chloride and 5 drops of pyridine in 10 mL of dry methylene chloride during a 10 minute period. This mixture was heated at reflux for one hour and then poured into 50 mL of water. The phases were separated, and the aqueous phase was extracted three times with methylene chloride. These extracts were combined with the organic phase, which was then washed three times with a saturated aqueous solution of sodium bicarbonate and once with a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure, leaving a yellow oil as a residue. This oil was placed on a silica gel column and eluted with methylene chloride. After the product-containing fractions were combined and the solvent evaporated under reduced pressure, 2.06 g of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate was recovered as a colorless oil. The NMR spectrum was consistent with the proposed structure.