Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.OC(C(F)(F)F)=O.[CH3:30][C:31]1[N:36]=[C:35]([CH2:37][C:38](O)=[O:39])[CH:34]=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[CH3:22][N:14]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([NH2:21])[C:20]=2[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([C:38](=[O:39])[CH2:37][C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=2)[CH2:4][CH2:5]3)=[CH:13]1
Reactant: Cc1cccc(CC(=O)O)n1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C)c5ncnc(N)c45)ccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (6-methyl-2-pyridinyl)acetic acid TFA salt (118 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), and DIEA (0.387 mL, 2.217 mmol) in N,N-Dimethylformamide (DMF) (3 mL) were stirred overnight at room temperature. At this time, LCMS analysis indicated complete conversion, so water (15 mL) was added to the reaction mixture, and the resulting mixture stirred for 30 minutes at room temperature, forming an emulsion-like mixture. The mixture was extracted with ethyl acetate: methanol (ca. 1% methanol, 3×30 mL) and the combined organics were dried over sodium sulfate, filtered and concentrated. The residue was adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc, 12-g column) to afford 7-methyl-5-{1-[(6-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (167.3 mg, 0.420 mmol, 95% yield) as an off-white solid. LC-MS (ES) m/z=399 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.46 (s, 3H), 3.23 (t, J=8.34 Hz, 2H), 3.75 (s, 3H), 4.00 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 6.01-6.41 (m, 2H), 7.17 (t, J=7.33 Hz, 2H), 7.23 (d, J=8.34 Hz, 1H), 7.27-7.34 (m, 2H), 7.68 (t, J=7.58 Hz, 1H), 8.12 (d, J=8.08 Hz, 1H), 8.18 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCCCC1C=CC=CC=1.[Mg].[CH3:23][Si:24]([CH3:33])([CH3:32])[C:25]1[O:29][CH:28]=[C:27]([CH:30]=[O:31])[CH:26]=1.S(=O)(=O)(O)O>C(OCC)C>[OH:31][CH:30]([C:27]1[CH:26]=[C:25]([Si:24]([CH3:33])([CH3:32])[CH3:23])[O:29][CH:28]=1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Br[Mg]CCCc1ccccc1
Agent: BrCCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(C(O)CCCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-phenylpropylmagnesium bromide (3.3 ml of an 0.313M solution in ethyl ether, 1.03 mmol, generated from 1-bromo-3-phenylpropane and magnesium) at 0° under argon, was added dropwise 5-trimethylsilyl-3-furaldehyde (0.145 g., 0.862 mmol) in 5 ml ethyl ether. This solution was allowed to warm to room temperature, stirred for one hour, and then poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: C[C@H]1CCCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: C[C@@H]1CCCN1C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-2-methylpyrrolidine (1.2 equiv) to give 171 (14.8 mg, M+1 381.1)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[I:17])[C:5]([NH2:18])=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:19][CH3:20])[C:5]2[NH:18][C:21](=[O:22])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[I:17])[C:6]=2[C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(F)c(F)c(Nc2ccc(F)cc2I)c1N
Solvent: ClCCl
Product: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(F)cc1I
Reaction time: 16 h

Procedure:
To the stirred solution of 5,6-difluoro-N1-(4-fluoro-2-iodophenyl)-3-methoxybenzene-1,2-diamine (0.17 gm, 0.43 mmol) in CH2Cl2 (2 ml), 1,1′-Carbonyldiimidazole (0.085 gm, 0.53 mmol) was added. This reaction mixture was kept stifling at room temperature for 16 hours when product precipitated out. The white solid was filtered and used further without any purification. (0.089 gm); m/z=419 [M−1]−.
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.[BH4-].[Na+].Cl>CS(C)=O>[OH:11][CH:4]1[CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[C:2](=[O:1])[N:3]1[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: O=C(O)Cc1ccc(N2C(=O)C3CCCCC3C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(N2C(=O)C3CCCCC3C2O)cc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
00.2 mole of the 4-(1,3-dioxo-hexahydro-2-isoindolinyl)phenylacetic acid thus obtained was dissolved in 20 ml of dimethyl sulphoxide. The resulting mixture was reduced with 1.14 g (0.03 mole) of sodium borohydride, as described in step (b) of Example 1, and was then poured into ice-water. The mixture was acidified with dilute hydrochloric acid, to precipitate crystals. These crystals were collected by filtration, dried and recrystallized from a mixture of ethanol and petroleum ether, giving 5.0 g (86.2%) of 4-(3-hydroxy-1-oxo-hexahydro-2-isoindolinyl)phenylacetic acid, decomposing at 145° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[N:6][CH:5]=1.Cl>[OH-].[Na+].CO>[OH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:12])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(CO)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CO)nc1
Temperature: 25 °C

Procedure:
A solution of 6-hydroxymethyl-nicotinic acid methyl ester (0.400 g, 2.38 mmol) in 1.0 N NaOH (25.0 mL) and methanol (10.0 mL) was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and the pH was adjusted to 7.0 with 1.0 N HCl. The reaction mixture was concentrated in vacuo and the resulting salt was slurried in DMF and filtered to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=4)=[CH:19][CH:20]=3)[CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:46]5[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]5)[CH:26]=4)=[CH:19][CH:20]=3)[CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc3ccc(Oc4ccnc(NC(=O)CCl)c4)cc3c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)Nc2cc(Oc3ccc4ccc(C(=O)Nc5cccc(C(C)(C)C)c5)cc4c3)ccn2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of N-(3-tert-butylphenyl)-7-({2-[(chloroacetyl)amino]pyridin-4-yl}oxy)-2-naphthamide (65.0 mg, 0.133 mmol) and potassium carbonate (36.8 mg, 0.266 mmol) in DMF (2 mL) was added 1-methylpiperazine (0.177 mL, 0.160 mmol). The reaction mixture was allowed to stir at 60° C. for 2 h. and then concentrated. EtOAc and water were added and the organic and aqueous solutions were separated. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-[(2-{[(4-methylpiperazin-1-yl)acetyl]-amino}pyridin-4-yl)oxy]-2-naphthamide I-264 ( ) (33 mg, 37%).
Reaction SMILES: [C:1]1([P@@:7]2(=[O:13])[CH2:11][CH2:10][CH2:9][C:8]2=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl>[C:1]1([P:7]2(=[O:13])[CH2:11][CH2:10][CH2:9][C:8]2=[CH2:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C1CCC[P@]1(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C1CCCP1(=O)c1ccccc1

Procedure:
Phenyl-2-methylenephospholane-1-oxide (3.0 g, chemical purity ca. 80%) was separated by repeated injections on a CHIRALPAK® AD 20 μm column (250×50 mm; mobile phase 100% acetonitrile, flow rate 120 ml/min) to afford 0.9 g of (S)-1-phenyl-2-methylenephospholane-1-oxide (ee 100%, chemical purity 95%; [α]D=−99.6 (c=1.03, CHCl3) and 1.0 g of (R)-1-phenyl-2-methylenephospholane-1-oxide (ee 99.4%, chemical purity 99.5%; [α]D=+106.8 (c=1.00, CCHCl3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]([O:26][CH:27]([O:38][CH2:39][CH3:40])[N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][C:29]1=[O:37])[CH3:25].[H-].[Na+]>C1COCC1>[CH2:39]([O:38][CH:27]([O:26][CH2:24][CH3:25])[N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:29]1=[O:37])[CH3:40]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: CCOC(OCC)N1C(=O)Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2ccccc21
Reaction time: 0.75 h
Yield: 79.2 %

Procedure:
4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (338 mg, 1 mmol) was dissolved in THF (20 ml) at 40° C., and 1-diethoxymethyloxindole (705 mg, 3 mmol), (prepared according to Synthesis 1975, 168), and sodium hydride (138 mg, 5.8 mmol, pre-washed with petroleum ether) were added successively to the solution at ambient temperature. After stirring for 45 minutes, the volatiles were removed by evaporation and the residue dissolved in methylene chloride. The solution was washed with an aqueous saturated sodium chloride solution, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column flash chromatography using methylene chloride/ethyl acetate (1/1) followed by an increasingly polar mixture of methylene chloride and methanol (2 to 4%) as eluent. The purified product was triturated with ether. collected by filtration, washed with a 1/1 mixture of ether/petroleum ether and dried under vacuum to give 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (425 mg, 84%) as a yellow-orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:9]=[C:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:19].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:9]=[C:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:19])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(C=C2Cc3ccccc3C2=O)cc1OCCCCl
Product: COc1ccc(C=C2Cc3ccccc3C2=O)cc1OCCCn1ccnc1

Procedure:
2-[3-(3-IMIDAZOL-1 YL PROPOXY)-4-METHOXYBENZYLIDENE)INDAN-1-ONE (6) (DPJ-RG-1090) was prepared by fusing compound 5 with imidazole following the method described for 2
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].COCOC.C[O-].[Na+].Cl>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC#N
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCOC
Solvent: Cc1ccccc1
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 94.7 %

Procedure:
In a 50 mL-volume glass flask equipped with a stirrer and a thermometer were placed under argon atmosphere 1.75 g (6.01 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carbaldehyde, 2.5 mL (47.5 mmol) of acetonitrile, 13.5 mL of methylal (dielectric constant at 20° C.: 2.7), and 0.56 g (10.3 mmol) of sodium methoxide. The content was reacted at 41° C. for 9 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 30 mL of toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with two portions of saturated aqueous sodium chloride solution (10 mL), the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.79 g (yield: 96%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.C(O)(C)(C)C.[CH3:19][C:20]1([CH3:27])[CH2:25][C:24](=O)[CH2:23][CH2:22][O:21]1.CC(C)([O-])C.[K+]>C(COC)OC.C(OCC)C>[CH3:19][C:20]1([CH3:27])[CH2:25][CH:24]([C:10]#[N:11])[CH2:23][CH2:22][O:21]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(C)CC(=O)CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CC1(C)CC(C#N)CCO1
Temperature: -20 °C
Yield: 84.4 %

Procedure:
p-Toluenesulfonylmethyl isocyanide (693 mg) and tert-butanol (438 μl) were added to a solution of 2,2-dimethyltetrahydro-4H-pyran-4-one (350 mg) in dimethoxyethane (10 ml) with stirring. Potassium tert-butoxide (766 mg) were added in three portions under cooling at −20° C. The mixture was heated to room temperature and then stirred for 18 hours. Diethyl ether was added and the mixture was filtered through Celite. Thereafter, the solvent was evaporated under reduced pressure to give the title compound (321 mg).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl.ClCCl.CO>C(O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=3)[CH2:28][CH2:29]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(CC2CCN(CCCN(C(=O)C3CCN(C(C)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(C(=O)O)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
To a solution of the compound obtained in Example 233 (200 mg, 0.37 mmol) in ethanol (2 mL) was added aqueous solution of 1N-sodium hydroxide (0.56 mL, 0.56 mmol), and the mixture was stirred at 80° C. for 3 hours. To the mixture was added, dropwise aqueous solution of 1N-hydrochloric acid (0.56 mL, 0.56 mmol) under ice cooling, and the mixture was concentrated under reduced pressure. The concentrate was subjected to flash column chromatography (silica gel 20 g, dichloromethane/methanol=20/1 to 2/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added diisoprpyl ether, and the resulting precipitates were collected by filtration to give the titled compound (120 mg, 0.21 mmol, Yield 56%) as white amorphous substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2].C([O-])([O-])=[O:38].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:23][CH2:22]3)[CH2:17][CH2:18]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)=[O:38]
Reactant: N#Cc1cc(N2CCN(CC[C@H]3CC[C@H](NS(=O)(=O)c4cccnc4)CC3)CC2)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(N2CCN(CC[C@H]3CC[C@H](NS(=O)(=O)c4cccnc4)CC3)CC2)cc(C(F)(F)F)c1

Procedure:
0.37 g (0.7 mmol) of trans-N-(4-{2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyridine-3-sulfonamide was dissolved in 2 ml dimethylsulfoxide, 80 mg K2CO3 was added and 0.15 ml of 30% H2O2 was dropped in while keeping the temperature at 20° C. After stirring for 2 h 20 ml of water was added, the precipitate filtered, washed with water giving the title compound, melting point:191° C. (0.2 g; 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1.C(C1NC=CN=1)(C1[NH:33]C=CN=1)=O.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21]([NH2:33])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c2C1
Agent: N
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(N)=O)c2C1
Temperature: 70 °C

Procedure:
A suspension of 4-[2-(5-Chloro-2-fluoro-phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid (25 mg, 60.56 μmol) and carbonyl-diimidazole (20 mg, 121.11 μmol) in dry DMF (3 mL) was heated at 70° C. for 1 h and then cooled to r.t. A stream of NH3 gas was passed through the solution for 30 min., giving clean conversion to the amide product. Evaporation of the solution, followed by HPLC purification gave, after lyophilization, the pure amide of formula (62) as the TFA salt (20 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)=[O:3].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2[C-](N(C)C)C=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2]>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccccc2)cc1
Yield: 87.6 %

Procedure:
According to General Procedure A, a mixture of 4-chloroacetophenone (65 μL, 0.50 mmol), phenylboronic acid (91 mg, 0.75 mmol), CsF (228 mg, 1.50 mmol), Pd(OAc)2 (2 mg, 0.01 mmol) and ligand 12f (8 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to reflux, cooled and filtered. After evaporation of the solvent, recrystallization from hexane containing a small amount of EtOAc gave 51b (86 mg, 88%) as colorless crystals. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, 2H, J=8.4 Hz), 7.69 (d, 2H, J=8.4 Hz), 7.63 (d, 2H, J=7.2 Hz), 7.50-7.40 (m, 3H), 2.64 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 197.7, 145.8, 139.8, 135.8, 128.93, 128.89, 128.2, 127.24, 127.20, 26.6.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12]([OH:14])=O)[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>C(Cl)Cl>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:14])[NH:32][C:31]1[CH:33]=[CH:34][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: CC(C)OC(=O)C(C(=O)O)=C1SCS1
Reactant: Nc1ccc(Cl)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)C(C(=O)Nc1ccc(Cl)cc1)=C1SCS1
Reaction time: 1 h

Procedure:
A solution of isopropyl 2-(1,3-dithietan-2-ylidene)-2-carboxyacetate (10 g) in methylene chloride (100 ml) was cooled to -10° C. and thereto phosphorous pentachloride (8.9 g) was added portionwise and then stirred for 1 hr. To the reaction mixture pyridine (13.8 ml) and 4-chloroaniline (5.45 g) were added and stirred for 2 hrs. The mixture was washed with dil-HCl, 10% aqueous sodium hydroxide solution and water and then evaporated. The residue was purified with ethyl acetate to afford the titled compound as a white solid. (8.9 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:28]CC3C=CC=CC=3)=[CH:5][C:4]=2[N:3]=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C(N)=NC=2C=1)C1C=CC=CC=1>>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25][CH2:26][CH3:27])[N:14]([CH2:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:28])=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Agent: CCCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Yield: 40.3 %

Procedure:
The general method described in Example 5 was followed using N-[2-(4-amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (1.00 g, 2.01 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine. The crude product was recrystallized from methanol (20 mL). The crystals were collected in three crops and washed with methanol and ethyl acetate. The crops were combined and purified by column chromatography on silica gel (eluting with 89.1:9.9:1 chloroform:methanol:ammonium hydroxide) to provide 330 mg of N-[2-(4-amino-2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a white powder, mp 255-256° C. 1H NMR (300 MHz, DMSO-d6, 350K) δ 9.18 (br s, 1H), 8.09 (d, J=8.9 Hz, 1H), 7.00 (br s, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.77 (dd, J=8.9, 2.5 Hz, 1H), 6.11 (s, 2H), 4.84 (s, 2H), 4.81 (s, 2H), 3.56 (q, J=7.0 Hz, 2H), 2.97 (s, 3H), 1.29 (s, 6H), 1.15 (t, J=7.0 Hz, 3H);
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([C:24](=[O:28])[C:25]([NH2:27])=[O:26])=[C:10]([CH3:23])[N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:5].[OH-].[Na+]>CO>[NH2:27][C:25](=[O:26])[C:24]([C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[O:6][CH:4]([CH3:5])[C:3]([OH:29])=[O:2])[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[CH3:23])=[O:28]
Reactant: COC(=O)C(C)Oc1cccc2c1c(C(=O)C(N)=O)c(C)n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OC(C)C(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of 521 mg (1.3 mmol) of dl-2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoic acid methyl ester and 10 mL of 1N NaOH in 30 mL of methanol was heated to maintain reflux for 0.17 hours, cooled to room temperature and stirred for 0.5 hour. The mixture was concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic to pH 2-3 with 1N HCl and extracted with EtOAc. The EtOAc solution was concentrated at reduced pressure and the residue stirred with a EtOAc-ether mixture. The insoluble material was filtered to give 246 mg (50% yield) of dl-2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoic acid, mp, 201-204° C.