Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:24](=[O:41])[N:25]([C:32]2[O:40][C:36]3=[CH:37][CH:38]=[CH:39][C:35]3=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CCO.C1COCC1.O>[O:40]1[C:36]2=[CH:37][CH:38]=[CH:39][C:35]2=[CH:34][CH:33]=[C:32]1[N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([CH:11]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)=[CH:16][CH:17]=1)[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[CH:5][CH:6]=1)=[O:41]
Reactant: COC(=O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a stirred solution of 4-[2-(4-benzofuran-2-yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid methylester (6) (0.42 g, 0.75 mmol) in EtOH/THF/H2O (4:2:1) (20 mL) at rt, was added aq. 40% NaOH (2.5 ml), The reaction mixture was stirred overnight. After completion of the reaction, the solvent was removed under reduced pressure and the crude was acidified with 4N HCl (pH=2). The resulting mixture was extracted with ethyl acetate, the organic layer was dried over MgSO4 and concentrated. The resulting compound was dried under vacuum to afford 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid as a solid (0.35 g): 1H NMR (300 MHz, CD3OD): 10.23 (s, 1H), 7.78 (d, J=8.7 Hz, 4H), 7.55-7.66 (m, 4H), 7.20-7.40 (m, 9H), 6.10 (bt, 1H), 4.03 (t, J=7.2 Hz, 1H), 3.45 (dd, J=5.0, 9.0 Hz, 1H), 3.03 (dd, J=5.7, 12.9 Hz, 1H), 2.20-2.40 (m, 2H), 2.10-2.15 (m, 2H), 1.65-1.75 (m, 2H), 1.50-1.60 (m, 2H); LC-MS m/z=541 [C37H34NO3+H]+.
Reaction SMILES: O[CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1.S(Cl)([Cl:47])=O>C(Cl)Cl>[Cl:47][CH2:2][C:3]1[C:8]2[C:9]([O:31][CH3:32])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:6]=[C:5]([NH:33][C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])=[O:35])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(CO)c12
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)nc(CCl)c12
Temperature: 50 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
A solution of (R)-1-(4-(hydroxymethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (800 mg, 1.371 mmol, see Example 109) and thionyl chloride (0.110 ml, 1.508 mmol) in DCM (15 ml) was allowed to stir at 50° C. for 18 h. Removed the solvent by reduced pressure and the residue was purified on silical gel 0-100% EtOAc/Hexane and yielded (R)-1-(4-(chloromethyl)-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (402 mg, 0.668 mmol, 49% yield). MS: [M+H]+ m/z 602.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[CH2:14]([NH:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)=[O:29])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCCCNc1cc(Oc2ccc(N)cc2)ccn1
Solvent: C1CCOC1
Product: CCCCNc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1

Procedure:
4-(4-Aminophenoxy)-2-butylaminopyridine (54 mg), p-fluorophenyl isocyanate (34.5 mg) and tetrahydrofuran (5 ml) were stirred at room temperature for 2.5 hours. After adding NH type silica gel to the reaction solution, the solvent was distilled off under reduced pressure, and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (hexane:ethyl acetate=1:1, followed by ethyl acetate) The solvent was distilled off under reduced pressure and the residue was solidified with ethyl acetate-hexane to obtain 15 mg of the target substance as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[K+].OO.O.CC[O:29]C(C)=O>CCO.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]([NH2:19])=[O:29])[N:17]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: CCOC(C)=O
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)c1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
To a solution of 0.56 g (6.83 mmol) of sodium acetate in 10 mL of water was added 1.29 g (4.78 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone. The resulting solution was warmed for 30 minutes and then cooled in an ice/water bath. A solution of 4-(fluorophenoxy)benzaldehyde (789 mg, 3.65 mmol) in MeOH was added, followed by 10 mL of a concentrated aqueous NH4OH solution. Additional MeOH was added until a homogenous solution formed. After stirring at room temperature overnight, the reaction was diluted with water. The precipitate that formed was collected, washed with water and dried. Column chromatography (gradient from 8/2 to 2/3 hexane/EtOAc) afforded 0.6 g of a solid. A mixture of 0.5 g of the solid and 80 mL of a concentrated aqueous NH4OH solution was diluted with MeOH until a solution formed. The reaction was heated in a sealed tube for 1.5 days. After cooling to room temperature, the mixture was added to a water/EtOAc mixture. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated to dryness. Column chromatography (1:1 hexane/EtOAc) gave 2-[4-(4-fluorophenoxy)phenyl]-1H-imidazole-4-carbonitrile as a solid. 1H NMR (DMSO-d6): δ 13.37 (br s, 1H), 8.23 (s, 1H), 7.95 (d, 2H, J=8.7 Hz), 7.27 (t, 2H, J=8.9 Hz), 7.15 (dd, 2H, J=9.3, 4.5 Hz), 7.08 (d, 2H, J=8.7 Hz). To a solution of the nitrile in EtOH was added 1 g of KOH dissolved in 5 ml of water and 1.5 mL of a 30% aq. H2O2 solution. After heating at reflux for 3 hours, the reaction was added to water/EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The residue was subjected to flash chromatography (100% EtOAc) affording the title compound as a white solid, TLC Rf0.34 (5% MeOH/EtOAc). 1H NMR (CDCl3): δ 12.90 (br s, 1H), 8.08 (br s, 1H), 7.97 (d, 2H, J=9.0 Hz), 7.70 (s, 1H), 7.63 (br s, 1H), 7.26 (t, 2H, J=8.7 Hz), 7.15-7.10 (m, 2H), 7.07 (d, 2H, J=8.7 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][C@@H:24]([O:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=4)[CH2:23][C@H:22]3[CH2:37][O:38][C:39]3[CH:48]=[CH:47][C:42]([C:43]([O:45]C)=[O:44])=[CH:41][CH:40]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][C@@H:24]([O:26][C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=4)[CH2:23][C@H:22]3[CH2:37][O:38][C:39]3[CH:48]=[CH:47][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](Oc4ccc5ccccc5c4)C[C@H]3COc3ccc(C(=O)O)cc3)cc2o1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 4-((2S,4S)-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-4-(2-naphthyloxy)-2-pyrrolidinylmethoxy)benzoate (312 mg, 0.486 mmol) in THF (20 ml) was added 0.25N NaOH (20 ml). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was then concentrated under reduced pressure. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure, whereby the title compound (253 mg, 83%) was obtained as a pale pink solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+].[C:25](Cl)([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.[Pd]>[CH2:28]([O:27][C:25](=[O:26])[NH:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:12]2[CH2:17][CH2:16][Si:15]([CH3:19])([CH3:18])[CH2:14][CH2:13]2)=[C:4]([F:11])[CH:5]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si]1(C)CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si]1(C)CCN(c2c(F)cc(NC(=O)OCc3ccccc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
To a solution of 9a (1.32 g, 4.61 mmol) in THF, Pd/C is added for hydrogenation under a pressure of 35 psi in a par hydrogenator. The reaction mixture is filtered through celite. To the filtrate, saturated NaHCO3 (1.16 g, 13.84 mmol), CBzCl (1.17 g, 6.93 mmol) are added and stirred at 25° C. for 5 h. The solvent is removed, 10 mL water is then added and the aqueous layer is extracted with EtOAc. The crude mixture is then subjected to column chromatography on silica gel using hexane-DCM mixtures to afford the product 10a as a viscous liquid (1.25 g) in 69% yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CC(C)=O>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:3]2([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(Cc2ccc(C)cc2)CCCC1=O
Yield: 82.4 %

Procedure:
Under vigorously agitation, 39.0 g of ethyl 2-oxocyclopentane carboxylate was added to 105.6 g (purity of 98%) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 34.35 ml (purity of 98%) of p-methylbenzyl bromide. Upon the completion of the addition, the reaction mixture was heated for reflux for 4 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 53.57 g of colorless liquid as a distillate cut of 144-146° C./100 Pa was collected. Yield: 82.4%. MS: m/e 260(M+′), 242, 232(M+′—CH2CH2), 215(M+′—OCH2CH3), 187(M+′—CO2CH2CH3), 171, 155(M+″—C8H9) 127, 105(base), 77.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[C:18]([O:20]C)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.[Cl-].[Na+].O>[C:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[C:18]([OH:20])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2ccccc2n1CCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2ccccc2n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.3 %

Procedure:
Methyl 1-(2-phenylethyl)-1H-indole-2-carboxylate (318 mg) was dissolved in methanol (5 ml), 2M aqueous sodium hydroxide solution (1.14 ml) was added, and the mixture was stirred at room temperature for 17 hr. The aqueous layer was adjusted to pH 7 with 1M hydrochloric acid, saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1-(2-phenylethyl)-1H-indole-2-carboxylic acid (300 mg). The obtained 1-(2-phenylethyl)-1H-indole-2-carboxylic acid (300 mg), 1-tert-butyl 3-methyl (3R,5S)-5-[(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (185 mg) and diisopropylethylamine (431 μl) were dissolved in methylene chloride (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (168 mg) was added, and the mixture was stirred at room temperature for 15 hr. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (83 mg).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21](I)[CH3:22]>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([CH2:21][CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCI
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Product: CCN(c1ccc(OC)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine and ethyl iodide by a procedure similar to example 36 (58% yield). 1H NMR (CDCl3): 7.69-7.72 (m, 1H), 7.53 (ddd, J=8.1, 6.9 and 1.5 Hz, 1H), 7.09-7.14 (m, 2H), 6.94-6.70 (m, 3H), 6.83-6.87 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.87 (s, 1H), 1.30 (t, J=6.9 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]1[C:11]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1cccc2sc(-c3ccccc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1cccc2sc(-c3ccccc3)nc12

Procedure:
43 g of the compound from Example II were dissolved in 1 l of absolute methanol, 5 g of potassium carbonate were added and after 10 minutes at room temperature the mixture was concentrated. The residue was taken up using methylene chloride, and the solution was washed, dried and concentrated. 90% of theory of the title compound was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7](=[O:18])[N:8]([CH:10]([C:14]([O:16]C)=[O:15])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7](=[O:18])[N:8]([CH:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(C(=O)OC)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nn(C(C(=O)O)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The hydrolysis of 5-n-butyl-2-[1-(carbomethoxy)isobutyl]-2,4-dihydro-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 38) using methanolic sodium hydroxide in THF was carried out as described in Example 7. The material obtained after work-up (71%) was homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) m/e 475 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]3[S:13][CH:14]=[C:15]([C:16](O)=[O:17])[C:9]2=3)=[CH:5][CH:4]=1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2([NH2:35])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N(CC)(CCC)CCC.[Li+].[OH-]>CN(C=O)C.O.C1COCC1.CO.CC(O)=O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]3[S:13][CH:14]=[C:15]([C:16]([NH:35][C:32]4([C:29]5[CH:30]=[CH:31][C:26]([C:25]([OH:24])=[O:36])=[CH:27][CH:28]=5)[CH2:34][CH2:33]4)=[O:17])[C:9]2=3)=[CH:5][CH:4]=1
Reactant: O=C(O)c1csc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: CCCN(CC)CCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C2(NC(=O)c3csc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.8 %

Procedure:
A mixture of 0.33 g of 4-(4-Trifluoromethyl-benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid, 0.23 g of 4-(1-amino-cyclopropyl)-benzoic acid methyl ester, 0.5 g of HATU and 0.25 ml of Pr2NEt in 8 ml of DMF was stirred at room temperature for 16 h. The reaction was then diluted with 30 ml of water and extracted with 100 ml of EtOAc. The organic layer was washed with 50 ml of water and 50 ml of brine and dried over Na2SO4. The extract was filtered, and concentrated to give the crude methyl ester which was dissolved in 20 ml of 1:1 THF/MeOH and treated with 10 ml of 0.5 N aqueous LiOH solution. After stirring for 15 h at room temperature, 1 ml of AcOH was added and the reaction mixture was extracted with 75 ml of EtOAc. The organic layer was washed with 50 ml of brine, dried over Na2SO4. The extract was filtered and concentrated to give 0.22 g of the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32]O)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:29][CH2:28][N:30]([CH2:34][CH3:35])[CH2:31][CH3:32])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Reactant: CCN(CC)CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCN(CC)CCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C

Procedure:
To 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1.7 g), was added thionyl chloride (10 ml) and the mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature, excess thionyl chloride removed under reduced pressure to give an off white solid, to which was added dry tetrahydrofuran (20 ml). The solution was cooled to 0° C. and N,N-diethylethanolamine (2.1 ml) added dropwise. The reaction was left to warm to room temperature over 1 hour, poured into 10% sodium carbonate (100 ml) and extracted with ethyl acetate (3×100 ml). The organic layers were combined and washed with water (2×100 ml), brine (2×50 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product purified by column chromatography to give 2-diethylaminoethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (1.1 g). δ (360 MHz, DMSO-d6), 0.99 (1H, t, CH2CH3), 2.54 (4H, q, CH2CH3), 2.81 (2H, t, CH2N), 4.41 (2H, m, CO2CH2), 5.50 (2H, s, OCH2), 7.41 (3H, m, o,p-ArH). 7.60 (2H, d, m-ArH), 7.71 (1H, s, 3-H), 7.86 (1H, d, 6-H) and 8.12 (1H, d, 8-H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:8]2[C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=2)[CH:19]=1)#[N:17]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: N#Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C=C(n2cc(C#N)c3ccccc32)c2cc(C#N)ccc2O1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
The reaction mixture containing 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (1.5 g, 7.5 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), 3-cyanoindole (1.46 g, 9.75 mmol) and finely ground potassium carbonate (2.6 g, 18.75 mmol) in dimethylformamide (5.0 mL) was heated at 100° C. for three hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with water, 1N hydrochloric acid, sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to yield a colorless solid. This material was purified by flash chromatography (20% ethyl acetate in hexanes) to yield 4-(3-cyano-1H-indol-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.45 g) as a colorless solid, m.p. 192°-193° C. (dichloromethaneisopropyl ether): 1H NMR (CDCl3) δ 7.72 (m, 1 H), 7.6 (s, 1 H), 7.40 (dd, J=8.2 and 1.8 Hz, 1 H), 7.25 (m, 2 H), 7.1 (m, 1 H), 6.90 (d, J=8.7 Hz, 1 H), 6.70 (d, J=2.3 Hz, 1 H), 5.88 (s, 1 H), 1.55 (s, 6 H); 13C NMR (CDCl3) 156.8, 135.6, 135.3, 134.9, 134.4, 129.9, 129.5, 127.3, 126.6, 124.8, 123.0, 120.1, 119.0, 118.2, 114.8, 111.3, 104.5, 88.7, 78.6, 27.9 ppm.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:10](=[N:26][N:27]([CH2:30][CH3:31])[C:28]=3[CH3:29])[C:11]([N:19](C([O-])=O)C([O-])=O)=[N:12][C:13]=2[C:14]=1C(C)(C)C)(C)(C)C.C(C1C=CC2C3C(=NN(CCC)C=3C)C(N(C([O-])=O)C([O-])=O)=NC=2C=1C(C)(C)C)(C)(C)C.[C:64]1(=[O:70])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.C1(=O)CCC1>>[NH2:19][C:11]1[C:10]2=[N:26][N:27]([CH2:30][CH3:31])[C:28]([CH2:29][C:64]3([OH:70])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)=[C:9]2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C1CCCCC1
Reactant: CCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: CCCn1nc2c(N(C(=O)[O-])C(=O)[O-])nc3c(C(C)(C)C)c(C(C)(C)C)ccc3c2c1C
Agent: O=C1CCC1
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCCCC1

Procedure:
1-[(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclohexanol was prepared according to the method of Example 1 Part F using di(tert-butyl)2-ethyl-1-methyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate in lieu of di(tert-butyl)1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicabonate and cyclohexanone in lieu of cyclobutanone. The crude product was recrystallized from acetonitrile to provide 0.560 g of 1-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]cyclohexanol as a white powder, mp 211.5-213° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5].C(N(CC)CC)C.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22]([NH:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5])=[O:23]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(=O)C=Cc1ccccc1F
Yield: 97.8 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-serinate hydrochloride (2.5 g), triethylamine (2.4 mL), 2-fluorocinnamic acid (2.8 g), WSC.HCl (3.2 g), and methylene chloride (100 mL), to give the captioned compound (4.2 g, 98%) as an oily product.