Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]([CH2:47][CH2:48][O:49][CH3:50])=[C:45]=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:45]([NH:44][CH2:47][CH2:48][O:49][CH3:50])=[O:46])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COCCN=C=O
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (42.8 mg, 0.070 mmol) and triethylamine (0.029 mL, 0.211 mmol) in DCM (0.75 mL) was added 1-isocyanato-2-methoxyethane (11.0 μL, 0.105 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (26.3 mg, 60.5%) as a hygroscopic, yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=6.3 Hz, 6H), 1.83-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.61 (t, J=5.6 Hz, 2H), 2.82-2.93 (m, 2H), 3.14-3.21 (m, 2H), 3.23 (s, 3H), 3.24-3.31 (m, 2H), 3.31-3.37 (m, 2H), 3.60 (t, J=5.8 Hz, 2H), 4.08-4.17 (m, 1H), 4.29 (s, 2H), 4.49-4.56 (m, 1H), 5.61-5.70 (m, 1H), 6.66-6.73 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 505.0.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]([O:18][C:19](OC2C=CC=CC=2)=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34].C(O)(=O)C>O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]2[NH:34][C:19](=[O:20])[O:18][C:8]=2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCc1oc(=O)[nH]c1-c1ccc(Cl)cc1
Yield: 70.9 %

Procedure:
Ethyl 6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanoate (32.3 g), ammonium acetate(29.7 g) and acetic acid(150 ml) was stirred for 1 hour under reflux. Water was added to the reaction mixture to give ethyl 5-[4-(4-chlorophenyl)-2-oxo-4-oxazolin-5-yl]pentanoate(17.7 g, 71%). This was recrystallized from acetone-isopropyl ether to give colorless needls. mp 143-144° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:10]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:10][C:9]([C:2]1[CH:3]=[C:4]([C:9]([CH3:10])([CH3:8])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:1]=1[OH:7])([CH3:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: C=C(C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccccc1)c1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 140 °C

Procedure:
This intermediate is made by reacting a mixture of 705.8 grams (7.5 moles) of phenol with 1772.7 grams (15 moles) of alpha-methylstyrene in the presence of 25.7 grams (0.135 moles) of p-toluenesulfonic acid monohydrate catalyst. This mixture is heated under nitrogen at 140° C. for 2.5 hours. The reaction mixture is cooled to 110° C. and 1125 ml of toluene is added. After washing the resulting solution at 80° C. with 750 ml of an aqueous solution of 37.5 grams of sodium carbonate and 75 grams of sodium chloride the organic phase is washed thrice with 1000 ml of aqueous sodium chloride solution; then dried over anhydrous sodium sulfate; filtered and vacuum distilled. The above-named product is obtained as the main fraction boiling at 172°-175° C./0.15-0.18 mm Hg in a yield of 1229.8 grams (49.6% of theory). The product melts at 63°-65° C.
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:16]2[CH:15]=[C:14]([C:13]3[O:26][C:2]4[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=4[N:12]=3)[CH:19]=[CH:18][CH:17]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(-c3cccnc3)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2nc(-c3cccc(-c4cccnc4)c3)oc12
Yield: 15.7 %

Procedure:
Methyl 2-hydroxy-3-(3-(pyridin-3-yl)benzamido)benzoate (0.9 g, 2.5 mmol) and 4-methylbenzenesulfonic acid monohydrate (1 g, 5 mmol) were added to toluene (20 mL) and the mixture was stirred under reflux for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 10:1). 130 mg of methyl 2-(3-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxylate as a solid was obtained. Yield: 15%. LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.Cl.[CH3:22][N:23]([CH3:33])[C:24]1[CH:32]=[CH:31][C:27]([CH2:28][NH:29][NH2:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:29]([CH2:28][C:27]3[CH:31]=[CH:32][C:24]([N:23]([CH3:33])[CH3:22])=[CH:25][CH:26]=3)[N:30]=2)[CH:20]=1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reactant: CN(C)c1ccc(CNN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1ccc(Cn2nc(-c3cc(Cl)ccc3O)nc2-c2cc(Cl)ccc2O)cc1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 4 h with 2.2 g of 4-dimethylaminobenzylhydrazine hydrochloride and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(4-dimethylaminobenzyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 205-207 C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:45][C:44]3[CH:46]=[CH:47][C:41]([Cl:40])=[CH:42][CH:43]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: Nc1ccc(Cl)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(Cl)cc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 4-chloroaniline (56 mg, 0.44 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound as a yellow solid. LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: O(C)[Na].[C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:5].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([CH3:25])=[CH:22][C:23]=1N.O>CO>[CH3:26][C:20]1[C:21]([CH3:25])=[CH:22][C:23]2[NH:5][C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][C:18]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)NCC#N
Reactant: Cc1cc(N)c(N)cc1C
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2nc(CNC(=O)OC(C)(C)C)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.3 g of a 30% NaOCH3 solution were added to tert-butyl cyanomethylcarbamate (0.4 g; 25.6 mmol) in 10 ml of CH3OH, and the mixture was stirred at room temperature for 1 h. After addition of 5.15 g of 4,5-diamino-ortho-xylene bishydrochloride, the reaction mixture was stirred overnight and then added to 100 ml of H2O, and the solid obtained by filtration was dried at 30° C. in vacuo. 0.5 g; ESI-MS [M+H+]=276
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:28]2[CH2:30][CH2:29]2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH:28]1([C:27]2[CH:26]=[C:25]3[C:16]([N:17]4[C:22]([CH2:23][O:24]3)=[N:21][NH:20][C:19](=[O:31])[CH:18]4[CH3:32])=[CH:15][C:14]=2[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:29][CH2:30]1
Reactant: CC1C(=O)NN=C2COc3cc(C4CC4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(C4CCNCC4)cc3N21
Yield: 87 %

Procedure:
A solution of 4-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.030 g, 0.068 mmol) in DCM (6 mL) and trifluoroacetic acid (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 7-cyclopropyl-4-methyl-6-piperidin-4-yl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (0.0275 g, 87%). LC/MS (Table 1, Method 5) Rt=2.041 min.; MS m/z: 341 [M+H]+.
Reaction SMILES: C1COCC1.[CH:6]1([C:12]([C:14]2[C:15]([NH:21][CH2:22][CH3:23])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Cl[CH:25]([CH2:31][CH2:32][C:33]([O-:35])=O)[C:26]([O:28]CC)=[O:27].N1C(C)=CC=CC=1C>O>[CH:6]1([C:12]2[C:14]3[C:15](=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[N:21]([CH2:22][CH3:23])[C:33](=[O:35])[C:32]=2[CH2:31][CH2:25][C:26]([OH:28])=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)C(Cl)CCC(=O)[O-]
Reactant: CCNc1nc(C)ccc1C(=O)C1CCCCC1
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCn1c(=O)c(CCC(=O)O)c(C2CCCCC2)c2ccc(C)nc21
Temperature: 60 °C

Procedure:
To a 20 ml THF solution containing 2.34 g of 3-cyclohexanecarbonyl-2-ethylamino-6-methylpyridine were added 3 ml of monoethyl chloroglutarate and 2.8 ml of 2,6-lutidine, followed by stirring under heating at an oil bath temperature of 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, and the whole was extracted with ethyl acetate. The organic layer was washed with 3M hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and 1.00 g of sodium methoxide was added to a 20 ml ethanol solution of the resulting residue, followed by heating under reflux for 1 hour. Then, 20 ml of a 1M sodium hydroxide aqueous solution was added to the reaction solution, followed by heating under reflex for another 1 hour. After the mixture was cooled to room temperature, water was added thereto, and the mixture was neutralized with 1M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol-water to obtain 764 mg of 3-(4-cyclohexyl-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)propanoic acid as colorless crystals.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]>Cl>[F:12][C:13]1[CH:18]=[C:17]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:16]=[CH:15][C:14]=1[F:19]
Reactant: Fc1ccccc1F
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc(F)c(F)c1
Yield: 31.2 %

Procedure:
45 gm of succinic anhydride and 130.7 gm of aluminum chloride were added to 57 gm of difluorobenzene, and the mixture was heated under reflux for 4 hours. Upon the addition of 200 ml of 1% hydrochloric acid aqueous solution, the reaction mixture was extracted with chloroform, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using a chloroform-methanol (30:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 30 gm of the title compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:24])([F:23])[F:22])=[C:15]([CH3:25])[C:14]=1[CH3:26])=[CH:3]\[C:4]([OH:6])=O.C(N1C=CN=C1)([N:30]1[CH:34]=[CH:33]N=C1)=O.C(N)C>C1COCC1.CCCCCC>[CH2:34]([NH:30][C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:27])/[CH:11]=[CH:12]/[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][C:21]([F:22])([F:23])[F:24])=[C:15]([CH3:25])[C:14]=1[CH3:26])[CH3:33]
Reactant: CC(/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C)=C\C=C\C(C)=C\C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCNC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC(F)(F)F)c(C)c1C
Temperature: -10 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of 2.0 g (5.3 mmol) of (2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenoic acid in 60 ml of dry THF and 1.6 g of (10 mmol) of carbonyldiimidazole was heated to 35°-40° C. for 0.5 hour. The reaction mixture was cooled to -10° C. and excess gaseous ethyl amine was introduced. The resulting mixture was stirred for 1 hour at 23° C., diluted with 100 ml of hexane, and filtered through silica gel (200 g, 1:1 ethyl acetate-hexane as elutant). Further chromatographic purification (silicia gel, 5 to 10% ethyl acetate in methylene chloride) gave a yellow solid which, after recrystallization (ethyl acetate-hexane), yielded 1.4 g of N-ethyl(2E,4E,6E,8E)-3,7-dimethyl-9-[2,3,6-trimethyl-4-(trifluoromethoxy)phenyl]-nonatetraenamide; mp 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:3]=1[C:4]#[N:5].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:9]=[C:8]([O:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:3]=1[C:4]#[N:5]
Reactant: Oc1ccccc1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)cc(Oc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 101 %

Procedure:
A mixture of 2,6-dichloro-4-(4-phenoxyphenyl)nicotinonitrile (51 mg, 0.149 mmol, from Step 2 of Example 8), phenol (15.47 mg, 0.164 mmol) and cesium carbonate (97 mg, 0.299 mmol) in DMSO (1.5 mL) was stirred at room temperature for 15 h. The mixture was diluted with ethyl acetate (60 mL), washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0% to 20% ethyl acetate in hexanes, gave 2-chloro-6-phenoxy-4-(4-phenoxyphenyl)nicotinonitrile as a white solid (60 mg, 75% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.52-7.73 (2H, m), 7.37-7.52 (4H, m), 7.25-7.36 (1H, m), 7.20-7.24 (1H, m), 7.08-7.18 (4H, m), 6.87 (1H, s); MS (ES+) m/z: 399 (M+H); LC retention time: 4.283 min (analytical HPLC Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=O)[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].[CH3:31][N:32]([CH:34]=[O:35])C>C(OCC)(=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:9]2[CH:10]=[N:16][N:15]3[C:25](=[O:28])[N:12]([CH:13]([CH2:4][CH:5]([CH3:8])[CH3:6])[C:34]([NH:32][CH3:31])=[O:35])[N:11]=[C:14]3[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CNC(=O)C(CC(C)C)n1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Yield: 40 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (40 mg, 0.11 mmol), prepared as described in Example 1,2-bromo-N,4-dimethylpentanamide (25 mg) and K2CO3 (31 mg, 0.22 mmol) in DMF (2 ml), was heated at 85° C. for 1.5 hours. After this time, the reaction mixture was cooled to RT and diluted with ethyl acetate. The resultant solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified using reverse phase preparative HPLC to give the title compound, 2-(7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)-N,4-dimethylpentanamide (28 mg, 40%) as a yellow solid. MS M+H=484; 1H NMR (CDCl3) δ 8.23 (1H), 7.36-7.30 (6H), 7.12 (2H), 6.90 (1H), 5.13 (1H), 2.81 (3H), 2.22 (1H), 1.98 (1H), 1.42 (1H), 0.93 (6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14]C=O)=[CH:9][CH:8]=2)=[N:3]1.[OH-].[Na+].O>CO>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[N:3]1
Reactant: CC1(C)COC(c2ccc(COC=O)cc2)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)COC(c2ccc(CO)cc2)=N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
4-(4,4-Dimethyloxazolin-2-yl)-1-(formyloxymethyl)benzene (37 mg) was dissolved in methanol (0.4 ml), added with 1 N aqueous sodium hydroxide (0.18 ml) and stirred at room temperature for 20 minutes. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:2) to obtain 17.7 mg of the title compound. Yield: 54%.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[C:12]1([NH:18][NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO.C[O-].[Na+]>C(O)CCC>[C:20]1([N:19]2[C:1](=[O:9])[CH2:2][C:3](=[O:5])[N:18]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: c1ccc(NNc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CO
Product: O=C1CC(=O)N(c2ccccc2)N1c1ccccc1
Temperature: 100 °C
Yield: 68.7 %

Procedure:
Three point six five (3.65) grams (22.8 mmol) of diethyl malonate and 4.00 g (21.7 mmol) of 1,2-diphenylhydrazine were dissolved in 10 ml of n-butanol, then 4.61 g (23.9 mmol) of a 28% methanol solution of sodium methoxide was added thereto, and the reaction system was heated at 100° C. for 10 hours. Subsequently, the solvent was distilled off under reduced pressure, 10 ml of water was added thereto and stirred, and then the reaction solution was filtered. An activated carbon was added to the recovered filtrate and stirred for 30 minutes. After stirring, the solution was filtered again to recover the filtrate. Four (4) ml of hydrochloric acid was added to the filtrate, and the precipitated solid was recovered by filtration. Thus, 3.76 g (yield: 60%) of 1,2-diphenyl-3,5-pyrazolidinedione was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22].Cl>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:22]1[O:10][C:5]2[C:4]([O:11][CH3:12])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:23])[CH3:20]
Reactant: CC(=O)CCl
Reactant: COc1cc(Br)cc(C=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
10.0 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde was dissolved in 39 ml of N,N-dimethylformamide, and the resulting solution was mixed with 11.9 g of anhydrous potassium carbonate and stirred at room temperature. 5.0 g of chloroacetone was added dropwise to the above reaction solution at the same temperature, followed by additional 1 hour of stirring at an elevated temperature of 80° C. The resulting reaction solution was diluted with ethyl acetate and adjusted to pH 2 with concentrated hydrochloric acid, and the resulting organic layer was collected. The organic layer was dried to distill off the solvent, and the resulting residue was purified by silica gel column chromatography, thereby obtaining 4.0 g of 2-acetyl-5-bromo-7-methoxybenzofuran.
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=2)=[CH:6][N:5]=1.[Na].N>ClCCl.CO>[NH2:3][C:4]1[C:9]([C:10]2[O:11][C:12]3[C:18]([CH2:19][OH:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][C:7]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][N:29]([CH3:1])[CH2:28][CH2:27]3)[CH:25]=2)=[CH:6][N:5]=1
Reactant: C=O
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(CO)c2o1
Agent: N
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5cccc(CO)c5o4)c3)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
37% Aqueous formaldehyde (0.015 ml) at 0° C., was added to a stirred solution [2-[2-amino-5-[1-(4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazol-7-yl]methanol (46 mg) dissolved in dichloromethane (2 ml) and methanol (2 ml) over a period of 5 minutes. The resulting solution was stirred at 0° C. for 10 minutes. Sodium triacetoxyhydroborate (30.0 mg) was added at 0° C. to the mixture and stirred at 0° C. for 1 hour. A solution 7N of ammonia in methanol (20 ml) was added to the mixture and adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 4 to 8% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness and the product was recrystallized from acetonitrile to afford [2-[2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazol-7-yl]methanol (37.0 mg) as a solid. NMR Spectrum: (CDCl3) 2.05-2.29 (m, 6H), 2.36 (s, 3H), 2.98-3.08 (m, 2H), 4.12-4.23 (m, 1H), 5.09 (s, 2H), 6.88 (bs, 2H), 7.37 (dd, 1H), 7.43 (d, 1H), 7.66 (d, 1H), 7.67 (s, 1H), 7.74 (s, 1H), 8.30 (d, 1H), 8.32 (d, 1H); Mass spectrum: M+H+ 405;