Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.CCN(CC)CC.[NH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(Cl)Cl>[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:30][CH2:29]1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a stirring solution of 2-(4-Chloro-7-methylquinazolin-2-yl)-phenol (100 mg, 0.35 mmol), Et3N (72 μL, 0.52 mmol), and CH2Cl2 (300 μL) under N2, was added 4-aminopiperidine (54 μL, 0.52 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using 98% CH2Cl2/2% MeOH to obtain the desired amine as a white solid (11 mg, 0.31 mmol, 89% yield). LC/MS (10-99%) M/Z 349.3 retention time 2.22 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=2)[NH:12][N:11]=1.[CH:20]([O-])=[O:21].[Na+]>CN(C=O)C.CCOC(C)=O.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>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH:20]=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: Ic1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 90 °C
Yield: 37 %

Procedure:
3-(1H-benzimidazol-2-yl)-5-iodo-1H-indazole (500 mg, 1.39 mmol) was dissolved in DMF (5 mL), then Pd(PPh3)2Cl2 (24 mg, 0.034 mmol) and sodium formate (142 mg, 2.1 mmol) were added. The reaction mixture was put under vacuum and recharged with CO three times, then heated up to 90° C. for 4 hr. The mixture was diluted with EtOAc, washed with brine, dried and concentrated. The crude product was purified by flash chromatography to afford 3-(1H-benzimidazol-2-yl)-1H-indazole-5-carboxaldehyde (135 mg, 37%) as yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5]C=O)[CH3:4].[CH3:8][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:13])[C:10](=[O:12])C.Cl>CCOCC.C1C=CC=CC=1>[CH3:13][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[C:10](=[O:12])[CH2:4][CH:3]=[O:5]
Reactant: CCOC=O
Reactant: CC(=O)C(C)(C)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)(C(=O)CC=O)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 8.8 g. of 50% NaH oil dispersion in 150 ml. of dry benzene was treated at 25° C. with 13.6 g. of ethylformate in 20 ml. of dry benzene under N2. Over a period of a half hour, 14.9 g. of 3-methyl-3-phenyl-2-butanone in 80 ml. of dry benzene was added at 0° C. After stirring at 40° C. for 4 hours, the mixture was diluted with 250 ml. of ether, treated with ice and acidified with hydrochloric acid. The acidic solution ws extracted with ether and the ether extract was washed with brine, sodiuim bicarbonate solution, washed again with brine and dried. The solvent was evaporated and the residue was distilled under reduced pressure to afford 14.8 g. of the title product as an oil, B. P. 83°-84°/0.2 mm., λmaxfilm 3.5 (broad) 5.75, 5.90, 6.12, 6.30, 6.70, 6.80, 6.95, 7.31, 7.94, 8.18, 9,38, 12,60, 13.05 and 14.28 μ.
Reaction SMILES: [B:1]([Cl:4])(Cl)Cl.[OH:5][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>CCCCC>[Cl:4][B:1]1[O:12][C:9]([CH3:11])([CH3:10])[C:6]([CH3:8])([CH3:7])[O:5]1
Reactant: ClB(Cl)Cl
Reactant: CC(C)(O)C(C)(C)O
Solvent: CCCCC
Product: CC1(C)OB(Cl)OC1(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
About 82 mL of BCl3 is added dropwise over 30 minutes to a stirred solution of dry pinacol in pentane (1.3 L) at −30° C. The reaction mixture is stirred at 20° C. for 1 hour. A solid byproduct, B2[(OCMe2)2]3 is removed by filtration. The remaining solution is distilled to give about 90 grams of 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:9]=1)=[O:4]
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1cc(N)nn1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc(NCc2cccc(Cl)c2)nn1C

Procedure:
5-Amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (644, 1.3 g, 8.0 mmol) was combined with 3-chlorobenzaldehyde (645, 0.95 mL, 8.4 mmol) and acetonitrile (40 mL). Trifluoroacetic acid (3.2 mL, 42.0 mmol) was added followed by triethylsilane (6.7 mL, 42.0 mmol). The reaction was heated to reflux overnight and then concentrated. Ethyl acetate was added and the solution was washed with 1N potassium carbonate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated. The compound (646, 0.944 g, 42%) was crystallized from a mixture of ethyl acetate:hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6]Cl.[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:20]2[N:38](CC(=O)C3C=CC=CC=3)[CH2:39][NH:40][C:19]=2[CH2:18]1)=[O:16].C(#N)C>CCOCC>[CH3:13][O:14][C:15]([CH:17]1[N:22]([C:23](=[O:37])[CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:21][C:20]2[N:38]=[CH:39][N:40]([CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:19]=2[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Reactant: COc1ccc(CCl)cc1OC
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2ccc(OC)c(OC)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 1.5 g 3,4-dimethoxybenzyl chloride, 2.5 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 30 mL acetonitrile is heated at reflux 16 hr. The cooled solution is added dropwise to 400 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 40 mL methanol and treated with 8 g zinc dust and 40 mL acetic acid. The resulting suspension is sonicated 2 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 450 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99:1) as a crisp foam. NMR (CDCl3) 3.88 (s,3H,0Me); 3.80 (s,3H,0Me); 3.58 (s,3H,0Me).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=O.[NH2:17][C:18]1[C:19](Cl)=[N:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[NH:1][C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)=[CH:7][CH:8]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: Clc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
A mixture of 23.2 g (0.10 mole) of 2-amino-4'-chlorobenzophenone and 14.7 g (0.11 mole) of 3-amino-2-chloropyridine (96%) were heated for 1.5 hr at 180° C. under nitrogen atmosphere. The mixture was cooled to room temperature and methylene chloride added. After stirring for 30 min., solids were separated by filtration and triturated in hot 190 proof ethanol. The remaining insoluble material was collected by filtration and recrystallized from benzeneisooctane to give 2.7 g product, m.p. 203°-204.5° C. Drying conditions prior to analyses were: overnight at 97°-98° C./0.1 mm Hg.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17](O)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2

Procedure:
Reaction of 2-phenylquinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 17 (18. % yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.63 and 2.90 (2t, 2H), 3.49 and 4.04 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.39 and 4.92 (2s, 2H), 6.32 and 6.77 (2d, 1H), 6.70 and 6.91 (2d, 1H), 7.57-7.60 (m, 3H), 7.69-7.79 (m, 1H), 7.86-7.98 (2d, 1H), 8.06-8.18 (m, 2H), 8.50-8.56 (m, 2H), 8.68 and 8.72 (2s, 1H); MS (ESI) m/z 412 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][C:14](=[O:16])[NH:13][N:12]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH2:17]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[O:15][C:14](=[O:16])[N:13]([CH:24]3[CH2:25][CH2:26][N:21]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH2:23]3)[N:12]=2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: O=c1[nH]nc(-c2cc(Cl)cc3c2OCC3)o1
Reactant: CCCCN1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCN1CCC(n2nc(-c3cc(Cl)cc4c3OCC4)oc2=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
2.38 g (0.01 mol) of 5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,3,4-oxadiazol-2(3H)-one, in suspension in 80 ml of tetrahydrofuran, are introduced into a 250 ml three-necked round-bottomed flask, cooled to 0° C. and placed under magnetic stirring, 1.57 g (0.01 mol) of 1-butylpiperidin-4-ol, 3.41 g (0.013 mol) of triphenylphosphine and then 2.44 g (0.014 mol) of ethyl azodicarboxylate are added and the mixture is stirred at room temperature for 3 h and then at 40° C. for 3 h. The solvent is evaporated under reduced pressure and the residue is taken up in water and extracted five times with diethyl ether. The organic phase is dried over magnesium sulphate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, elution being carried out with an 80/20 mixture of ethyl acetate and heptane. 3 g of compound are obtained. Melting point: 133.8-134° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2.Cl.O.[CH3:27]O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]([O:14][C:15]2[CH:16]=[N:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:27])=[O:12])=[CH:7]2
Reactant: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cn1
Reactant: CO
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a solution of 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid (4.7 g) in a mixture of methanol (30 mL) and toluene (90 mL) was added dropwise 2M trimethylsilyldiazomethane diethyl ether solution (7.4 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, and 2M trimethylsilyldiazomethane diethyl ether solution (3.7 mL) was added dropwise to the mixture. After stirring at 0° C. for 30 min, 1M hydrochloric acid (2 mL) was added to the mixture to quench the reaction. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual yellow oil was solidified with ethyl acetate-diethyl ether. The resulting solid was washed with diethyl ether to give the title compound (3.6 g, 74%) as a pale orange solid. MS 363 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 184 mg (1.0 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) in 3 mL of dimethylformamide was treated with 55 mg of 60% sodium hydride (33 mg NaH, 1.4 mmol). The reaction mixture was stirred at room temperature for 30 minutes then treated with 169 mg (1.19 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled, poured into 50 mL of water and the resultant mixture was extracted with ethyl ether. The combined extracts were washed with water, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed on silica, eluting with hexane/ethyl acetate (10:1) to give 271 mg (0.89 mmol,88%) of the product. FAB-MS: calculated for C19H15NO2 305: found 306 (M+H). 1H NMR (200 MHz,CDCl3): δ 2.28 (s,3H), 6.82 (d,2H), 7.19 (d,3H), 7.2-7.5 (m,5H), 8.05 (d,2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:24])[CH:21](Cl)[CH3:22])=[N:17][CH:18]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:24])[CH:21]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH3:22])=[N:17][CH:18]=1
Reactant: C1CCNC1
Reactant: CC(Cl)C(=O)Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)Nc1ccc(Br)cn1)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.01 g (29.0 mmol) K2CO3 and 1.19 mL (14.5 mmol) pyrrolidine are added successively to a solution of 3.5 g (13.3 mmol) N-(5-bromo-pyridin-2-yl)-2-chloro-propionamide in 50 mL DMF. The reaction is stirred for 3 days at RT and combined with 150 mL water. The aqueous phase is extracted twice with EtOAc and the organic phase is dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: PE/EtOAc 4:6 after EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:3]=1[CH:4]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][CH2:22][C:23]#[N:24]>>[CH2:11]([O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:23]([NH2:24])[C:22]([CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH3:13])=[CH:4]2)[CH3:12]
Reactant: COc1ccccc1CCC#N
Reactant: CCOc1ccc(N)c(C=O)c1
Product: CCOc1ccc2nc(N)c(Cc3ccccc3OC)cc2c1

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-ethoxybenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:40][C:41]([F:53])([F:52])[C:42]1[CH:43]=[C:44]([C:48]([NH2:51])([CH3:50])[CH3:49])[CH:45]=[CH:46][CH:47]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[N:11]([CH2:13][C:14]([NH:51][C:48]([CH3:50])([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([C:41]([F:40])([F:52])[F:53])[CH:43]=3)[CH3:49])=[O:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(NC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
318 mg (1.26 mmol) of [4-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 233A are placed in 10 ml DMF and treated with 221 mg (1.64 mmol) of HOBt and 314 mg (1.64 mmol) of EDC hydrochloride. After 10 mins' stirring, 332 mg (1.64 mmol) of 1-methyl-1-[(3-trifluoromethyl)phenyl]ethylamine from Example 1A are added and the mixture is stirred overnight at room temperature. For the workup, the reaction mixture is stirred with 100 ml water. Next, the resulting precipitate is suction-filtered, washed with water and dried under high vacuum. Further purification is effected by preparative HPLC [Method 10]. 209 mg (38% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: COc1ccc2c(-c3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-cyano-phenylboronic acid to give 4-[6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 356(MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:11][CH2:12][CH3:13])[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C([O-])(=O)C.[Na+].CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>C(O)(=O)C>[CH2:11]([C:4]1[NH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([N:1]2[CH:21]=[CH:25][CH:24]=[CH:23]2)[N:3]=1)[CH2:12][CH3:13]
Reactant: COC1CCC(OC)O1
Reactant: CCCc1nc(N)c(C(=O)OC)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(-n2cccc2)c(C(=O)OC)[nH]1
Yield: 46.2 %

Procedure:
To stirred acetic acid (1.5 L) at 80° C. was added over a 5-minute period a mixture of methyl 4-amino-2-propylimidazol-5-carboxylate (Example 4, 145 g, 0.798 mol) and sodium acetate (388 g, 4.73 mol). The mixture was heated at reflux for 5 minutes and then 2,5-dimethoxy-tetrahydrofuran (117 g, 0.885 mol) added all at once. The resulting dark solution was refluxed for 20 minutes, then poured onto ice. The gummy mixture was extracted with dichloromethane, the combined organic layers washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue dissolved in dichloromethane (2 L). The dichloromethane solution was treated with silica gel (500 g) and the suspension filtered through a bed of silica gel (300 g) eluting with dichloromethane. The filtrate was evaporated to dryness under reduced pressure and the crude product recrystallized from ether/hexane (2:1) to provide 86 g (46% yield) methyl 2-propyl-4-(1H-pyrrol-1-yl)imidazol-5-carboxylate, mp 135°-138° C. MS (DEI) 234 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-(trifluoromethoxy)phenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: I[CH:2]([CH3:8])[CH2:3][C:4]([F:7])([F:6])[F:5].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[F:5][C:4]([F:7])([F:6])[CH2:3][CH:2]([S:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CC(I)CC(F)(F)F
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(CC(F)(F)F)Sc1ccccc1
Yield: 79 %

Procedure:
To a solution of 54.9 mmol 3-iodo-1,1,1-trifluorobutane in 50 ml N,N-dimethylformamide were added 49.9 mmol thiophenol and 74.9 mmol potassium carbonate. The mixture was ultrasonicated at room temperature for 90 min. The reaction mixture was then diluted with ether and was washed three times with water. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil (yield 79%). MS (m/e): 221.3 (M+, 15%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.[CH3:19][O:20][CH2:21]CCl>>[CH3:19][O:20][CH2:21][CH2:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)C
Reactant: COCCCl
Product: COCCc1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 45, 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2 g 8.4 mmol,) was reacted with 2chloroethyl methyl ether (0.76 mL, 10 mmol) to provide the desired product. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.1 %

Procedure:
To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06 mL) and acetic anhydride (5.13 g), and the mixture was stirred at room temperature for 21 hrs. Ethyl acetate (200 mL) was added to the reaction mixture, and the mixture was washed with water (100 mL), an aqueous copper sulfate solution (40 mL), water (60 mL) and saturated brine (60 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (8.34 g) as a colorless oil.