Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][CH2:20][OH:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1.C[OH:23].O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([OH:23])=[O:21])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])=[N:7][C:6]=2[CH:17]=1
Reactant: OCCCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reactant: CO
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CCc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reaction time: 0.75 h
Yield: 72.6 %

Procedure:
10.3 ml (41 mmol of O) of Kiliani solution was added at −10° to −5° C. within 20 minutes to a solution of 6.44 g (20 mmol) of 5-chloro-2-(2-chlorophenyl)-7-(3-hydroxy-propyl)-benzoxazole in 130 mg of acetone. After 45 minutes, 5 ml of methanol and 130 ml of water were added. The acetone was removed in vacuo, the solid suspended, collected, and washed with 1 N sulfuric acid and water. The residue was taken up in 35 ml of 1 N NaOH and 50 ml of water, and extracted with ether. The water phase was acidified with 5 N HCl to pH 3. Filtration and washing gave the title compound (4.88 g, 72.6%), mp 152-4° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[C:20]([F:19])([F:32])[F:31])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(F)cc1C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)cc4C(F)(F)F)cc3CC[C@@H]12
Yield: 37.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-trifluoromethyl-4-fluorophenylboronic acid (162 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 96 mg (38%) of the title compound as an amorphous foam. mp 70°. FDMS: m/e=391. α[D]589 =+55.81 (c=0.60, chloroform).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=[C:20]3[NH:28][CH:29]=[CH:30][C:19]=23)[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][N:21]=[C:20]3[NH:28][CH:29]=[CH:30][C:19]=23)[CH2:16][CH2:17]1)=[O:11]
Reactant: COC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
(R)-Methyl 4-(4-(2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.025 g, 0.046 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour and then concentrated. The resulting residue was dissolved in minimal DCM and added to a stirring solution of 1M HCl in ether. The resulting solid (R)-methyl 4-(4-(2-amino-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.015 g, 74% yield) was collected and dried as the dihydrochloride salt. MS ESI (+) m/z 442 detected.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:22][CH:21]=1>O1CCCC1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]([CH3:30])[C:27]([N:3]2[C@H:2]([CH3:1])[C@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[O:28])=[CH:24][CH:25]=1
Reactant: CC(C(=O)Cl)c1ccc(Br)cc1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone (0.348 g, 1.96 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. n-Butyllithium (1.6M in hexanes; 1.64 mL, 2.62 mmol) was added, and the reaction was stirred for 1 hour at −78° C. 2-(4-Bromo-phenyl)-propionyl chloride (0.540 g, 2.18 mmol) in tetrahydrofuran (10 mL) was added, and the reaction was stirred for 30 minutes. The mixture was concentrated, and the residue was partitioned between EtOAc and water. The organic layer was separated, dried, and concentrated, and the crude material was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give two diastereomers as separated products. Diastereomer A was the first product to come off the column, while Diastereomer B was the second product to come off the column.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[O:16][C:14]1[C:8]2[CH2:9][C:10]([CH3:12])([CH3:13])[O:11][C:7]=2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:15]=1
Reactant: COC(=O)c1cc(Oc2cc(F)cc(F)c2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2c(Oc3cc(F)cc(F)c3)cc(C(=O)O)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 4-(3,5-difluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (113a) (0.4 g, 0.0012 mol) in MeOH (5 mL) was added NaOH (0.5 g, 0.012 mol) in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/10) showed the starting material was still present. The mixture was refluxed for another 3 hrs. After TLC indicated the reaction was complete. The solvents were removed in vacuo. The residue was dissolved in water and acidified with conc. HCl to pH 1. The aqueous phase was extracted with EtOAc (2×15 mL). The organic phase was dried over Na2SO4 and concentrated to give an off-white solid (0.308 g, 80% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:13]=[C:14]=[S:15])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].[Na:16].[N:17]1C=CC=CC=1.O>>[C:10]([C:8]1[CH:7]=[C:6]([NH:13][C:14]([NH2:17])=[S:15])[CH:5]=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1)([OH:12])=[O:11].[Na:16]
Reactant: O=C(O)c1cc(N=C=S)cc(C(=O)O)c1
Reactant: c1ccncc1
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1cc(C(=O)O)cc(C(=O)O)c1
Temperature: 53 °C

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred suspension of BHAlyslys2lys4lys8lys16DBL32 (300 mg; 0.02 mmol) in dry dichloromethane (3 ml) and the resulting solution stirred at room temperature under nitrogen for two hours and then concentrated. The residue was dissolved in water and the solution passed through a column of Amberlite IRA 401 (OH) and the filtrate concentrated to give a viscous oil (186 mg). The oil was dissolved in a 1:1 mixture of pyridine/water (8 ml) and sodium 3,5-dicarboxyphenyl isothiocyanate (450 mg; 2 mmol) added. The resulting solution was heated at 53° C. for 13 hours under nitrogen. The solution was then concentrated to give a white solid residue. The crude product was purified by gel filtration (Sephadex LH20; water) to give BHAlyslys2lys4lys8lys16lys32 with 64 sodium 3,6-dicarboxyphenylurea groups as a white fluffy solid.
Reaction SMILES: C([O:4][C@H:5]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:25])[CH2:16][C:17]([F:24])([F:23])[CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])[CH2:6]1)(=O)C.C(Cl)(Cl)(Cl)Cl.CC1C=C(C)N=C(C)C=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[OH-].[K+].CO>C1(C)C(C)=CC=CC=1.CC(C)=O.C1COCC1.C1C=CC=CC=1.C(OCC)(=O)C>[F:23][C:17]([F:24])([CH2:16][C@H:15]([C@@H:14]1[C@:26]2([CH3:34])[C@H:11]([C:10]3[C@H:29]([CH2:28][CH2:27]2)[C@:30]2([CH3:33])[C:7]([CH2:6][CH:5]([OH:4])[CH2:32][CH2:31]2)=[CH:8][CH:9]=3)[CH2:12][CH2:13]1)[CH3:25])[CH2:18][C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CC(F)(F)CC(C)(C)O)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1C
Product: C[C@H](CC(F)(F)CC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4CC(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 21.7 %

Procedure:
To a solution of the acetate (14) (19 mg, 0.0396 mmol) in carbontetrachloride (2 ml) N-bromosuccinimide (10 mg, 0.0571 mmol) was added and this mixture was refluxed under argon atmosphere for 20 min. After cooling to 0° C., the resulting precipitate was filtered off. The filtrate was concentrated below 40° C. to leave the residue. This residue in xylene (2 ml) was added dropwise to a refluxing solution of S-collidine (0.5) and xylene (1.5 ml) and refluxing was continued for 20 min. The usual work-up (ethyl acetate for extraction) gave the crude diene. This diene in acetone (10 ml) was treated with a catalytic amount of TsOH at room temperature under argon atmosphere in the dark for 14 hr. The usual work-up (ethyl acetate for extraction) gave the crude 5,7-diene acetate. This acetate in THF (5 ml) was treated with 5% KOH-MeOH (1.0 ml) at room temperature under argon atmosphere in the dark for 30 min. The usual work-up (ethyl acetate for extraction) gave a crude product, which was submitted to preparative TLC (benzene-ethyl acetate 2:1, developed twice). The band of Rf value 0.47 was scraped off and eluted with ethyl acetate. Removal of the solvent provided the 5,7-diene (15) (3.75 mg, 21.7%). UV λmax mm: 294, 282, 272.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:24][C:23]2[CH:26]=[C:27]([C:30]3[CH:35]=[N:34][CH:33]=[N:32][CH:31]=3)[CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Reactant: COc1ccc(-c2cncnc2)cc1C=O
Product: COC(=O)C1CCC(NCc2cc(-c3cncnc3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Ex. 89, Step A) and the known 2-methoxy-5-(pyrimidin-5-yl)benzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92). 1H NMR (400 MHz, CD3OD): δ 9.07 (s, 1H), 8.99 (s, 2H), 7.61 (dd, 1H, J=9,2 Hz), 7.45 (d, 1H, J=2 Hz), 7.22 (dd, 2H, J=9,5 Hz), 7.07 (t, 2H, J=9 Hz), 7.02 (d, 1H, J=9 Hz), 3.76 (d, 1H, J=13 Hz), 3.59 (s, 3H), 3.56 (s, 3H), 3.55-3.49 (m, 1H), 3.53 (d, 1H, J=13 Hz), 3.45-3.36 (m, 1H), 3.26 (td, 1H, J=6,2 Hz), 2.36-2.26 (m, 1H), 2.12-2.01 (m, 1H), 1.99-1.88 (m, 2H). Mass spectrum (NH3 /CI): 436 (M+1).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1C)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.C1C[O:23][CH2:22][CH2:21]1>>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:21][CH2:22][OH:23])=[CH:10][CH:9]=1
Reactant: CC(=O)Oc1ccc(O)cc1C
Reactant: C1CCOC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: OCCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Methyl-4-hydroxyphenyl acetate (23.0 g, 139.0 mmol) was dissolved in THF (400 ml). After cooling to 0° C., lithium aluminum hydride (LAH; 7.9 g, 209.0 mmol) was added over 1 hr, stirred for 2 hrs at 0° C. and additionally for 8 hrs at room temperature. 1N aqueous HCl (300 ml) was added at 0° C. and the reaction mixture was extracted with ethylacetate (200 ml×3). The combined organic layer was washed with water (200 ml×2) and sat. NaCl (200 ml) and dried over MgSO4. The dried organic layer was evaporated and the residue was purified by fresh column chromatography on silica gel (hexane/ethylacetate=3/1, v/v) to obtain white solid of the desired product, 4-hydroxyphenethyl alcohol (16.3 g, 118.0 mmol, yield 85%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:24][CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([O:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:38])[C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(OC)CCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OC)CCCC1
Reaction time: 1.5 h

Procedure:
To a solution of 2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinoline (0.30 g, 0.88 mmol) in dichloromethane at rt was added m-CPBA (278 mg, 0.88 mmol). The solution was stirred for 1.5 h and concentrated ammonium hydroxide (5.73 mL) was added and the mixture was cooled in an ice bath. To the mixture was added TsCl (176 mg, 0.924 mmol). The mixture was stirred 3 h at rt. Water (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organics were washed twice with brine, dried over Na2SO4, filtered, and concentrated to a yellow oil. The crude product was purified by flash chromatography (silica gel, gradient elution with 1-10% CMA/CHCl3). The purified product was crystallized from acetonitrile to provide 2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine as off white crystals (0.122 g, 39%) after vacuum drying at 80° C., mp 148.0-150.0° C.
Reaction SMILES: Cl(O)(=O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@H:22]3[O:31][C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]3[CH2:32][CH2:33][N:34]3[C:42](=[O:43])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:44])=[CH:16][CH:15]=2)[CH:10]=[C:11]([F:13])[CH:12]=1>C(#N)C.C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH2:32][CH2:33][N:34]4[C:35](=[O:44])[C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:42]4=[O:43])[C@H:24]([OH:28])[C@H:25]([OH:26])[O:31]3)=[CH:16][CH:15]=2)[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: CC1(C)O[C@@H]2O[C@H](CCc3ccc(-c4cc(F)cc(F)c4)cc3)[C@H](CCN3C(=O)c4ccccc4C3=O)[C@@H]2O1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC[C@@H]1[C@H](O)[C@H](O)O[C@@H]1CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 55 °C

Procedure:
Perchloric acid (0.3 mL) was added to a solution of the compound obtained from step b above (0.2 g) in acetonitrile (6 mL) and water (2 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using sodium bicarbonate solution. The solvents were evaporated under reduced pressure. The residue thus obtained was taken up in ethyl acetate and water. The organic layer was separated and washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.15 g).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14](Cl)=[N:13][N:12]=[N:11]1>O>[CH:7]1[CH:6]=[C:5]([N:10]2[NH:11][N:12]=[N:13][C:14]2=[O:1])[C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: [OH-]
Reactant: Clc1ccccc1-n1nnnc1Cl
Agent: [Na+]
Solvent: O
Product: O=c1nn[nH]n1-c1ccccc1Cl
Temperature: 110 °C
Yield: 95.8 %

Procedure:
A solution of sodium hydroxide (13 g, about 45% by weight) in water, 1-(2-chloro-phenyl)-5-chlorotetrazole (12.9 g) in water (6.5 ml) were mixed and the mixture was heated to 110° C. The reaction was initiated and the temperature increased to 115° C. After 3 minutes from the initiation of the reaction, the temperature was lowered to room temperature and then water (20 ml) was added. The insoluble matter was extracted with toluene (10 ml) and the aqueous solution was adjusted to a pH of 1. The solid matter was collected by filtration followed by washing with water and drying to obtain a pale tan solid 1-(2-chlorophenyl)-5(4H)-tetrazolinone (11.3 g) (yield: 96%). melting point: 123°-125° C.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.O1CCCC1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:18][CH:17]=1>C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:22]([CH2:23][CH3:24])([OH:25])[C:19]1[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: Clc1cccc(Br)c1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(O)cc1)c1cccc(Cl)c1

Procedure:
To a Grignard reactant prepared from 14.6 g. of magnesium turnings and 115 g. of 3-chloro-bromobenzene in 350 ml. of dry tetrahydrofurane a solution of 30.1 g. of 4'-hydroxy-propiophenone in 540 ml. of dry tetrahydrofurane is added dropwise, with stirring under slight reflux. The reaction mixture is slightly boiled for 30 additional minutes, cooled and decomposed by pouring onto a mixture of ice and glacial acetic acid. After separation the organic phase is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Crystallization of the solid residue from a mixture of n-hexane and ethyl acetate yields 42.6 g. of the named compound, melting at 132° to 134° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[N:22]=[C:15]2[C:16]([CH2:20][OH:21])=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[N:22]=[C:15]2[C:16]([CH:20]=[O:21])=[CH:17][CH:18]=[CH:19][N:14]2[N:13]=1
Reactant: Cc1nc2c(CO)cccn2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(C=O)cccn2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83613.3 %

Procedure:
Under nitrogen atmosphere, to a solution of oxalyl chloride (16.0 mL, 180 mmol) in dichloromethane (200 mL) was added dimethyl sulfoxide (30.0 mL, 0.420 mol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (2-methyl[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol (23.0 g, 0.141 mmol) in dichloromethane (82 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (99.0 mL, 0.710 mol) at −78° C., and the mixture was stirred for 1 hr and warmed to room temperature. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (methanol/ethyl acetate=1/10) to give the title compound (19.0 g, yield 84%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cccc(OC)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (4.6 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (10.0 g), copper acetate (12.0 g) and pyridine (10.6 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.9 g, 48%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[N:6]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:5](=[O:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CCc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 46.9 %

Procedure:
2-Methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one (1 g, 4 mmol) and 1-(2-bromo-ethyl)-4-nitro-benzene (919 mg, 4 mmol) and potassium carbonate (669 mg, 4.8 mmol) are dissolved in 12 mL acetone and the reaction mixture is heated at 70° C. for 5 min in the microwave oven (Biotage Initiator) and again heated for 5 min at 120° C. The mixture is cooled to room temperature, filtered and the filtrate evaporated to yield the crude product which is subjected to flash chromatography. ISCO Companion CombiFlash, 80 g silica gel, cyclohexane/ethyl acetate, followed by a second purification step, 40 g silica gel, acetone/cylohexane to yield 2-methyl-3-[2-(4-nitro-phenyl)-ethyl]-5,5-diphenyl-3,5-dihydro-imidazol-4-one (750 mg, 45%). LC/MS at 254 nm; [M+H] 400; Rt 3.391 min.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=O.CN>O1CCCC1>[CH3:20][NH:22][C:17](=[O:19])[CH2:16][N:15]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(-c2nc3cccnc3n2CC(=O)O)s1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(C)s2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A solution of 2-(5-methyl-2-thienyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for 33/4 hours with a stream of nitrogen bubbling through it. A solution of methylamine (36 ml of a 3.03M solution in tetrahydrofuran, 0.1098 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol, and filtered while hot. Addition of isopropyl ether caused solid to precipitate. The solid was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at room temperature overnight to give 3.12 g (60%) of title compound, mp 213°-216° C.