Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][OH:11])[C:5]#[N:6].Cl.[NH2:13][OH:14].C(=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][OH:11])/[C:5](=[N:13]/[OH:14])/[NH2:6]
Reactant: N#Cc1ccc(CO)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N/C(=N\O)c1ccc(CO)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
To a mixture of 3-fluoro-4-(hydroxymethyl)benzonitrile (3.51 g, 23.2 mmol) and hydroxylamine hydrochloride (3.23 g, 46.4 mmol) in methanol (100 mL) under nitrogen was added sodium bicarbonate (7.80 g, 93 mmol). The reaction mixture was stirred at room temperature for 5 min. and then immersed in an oil bath and heated at reflux for 2 h. HPLC analysis indicated that the starting material had been consumed. The heterogeneous mixture was filtered, the solid was washed with methanol, and the filtrate was concentrated under reduced pressure. The white solid residue was diluted with ethyl acetate (400 mL) but remained heterogeneous. The mixture was sonicated for 5 min and filtered under reduced pressure. The filtrated was washed with water (60 mL), and washed with a 10% aqueous solution of lithium chloride (60 mL), and washed with brine (60 mL). The combined aqueous layers were extracted with ethyl acetate (100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded (Z)-3-fluoro-N′-hydroxy-4-(hydroxymethyl)benzimidamide (3.85 g, 20.9 mmol, 90% yield) as a white solid. The compound had an HPLC time=0.263 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=184.9. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.54 (d, 2H), 5.28 (t, J=5.83 Hz, 1H), 5.86 (s, 2H), 7.40 (dd, J=11.65, 1.39 Hz, 1H), 7.44 (t, J=7.91 Hz, 1H), 7.51 (dd, J=8.05, 1.66 Hz, 1H), and 9.72 (s, 1H).
Reaction SMILES: Br[CH:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)[CH:3]=O.[CH:16]1([NH:22][C:23]([NH2:25])=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([NH:22][C:23]2[S:24][C:2]([C:5]3[CH:14]=[C:13]4[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]4)=[CH:7][CH:6]=3)=[CH:3][N:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC(=S)NC1CCCCC1
Reactant: O=CC(Br)c1ccc2c(=O)[nH]cnc2c1
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(-c3cnc(NC4CCCCC4)s3)ccc12

Procedure:
A solution of bromo-(4-oxo-3,4-dihydro-quinazolin-7-yl)acetaldehyde and N-cyclohexylthiourea in dimethylformamide is heated at 70° C. until completion of the reaction (5-12 hours). The mixture is quenched with 10% dimethylamine in ethanol and the solvent is removed under reduced pressured. The crude is purified by chromatography on silica gel to isolate the desired compound.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.[CH3:15][NH2:16]>O>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]1[C:2]([NH:16][CH3:15])=[N:3][S:4][N:5]=1
Reactant: Clc1cccc(Cl)c1-c1nsnc1Cl
Reactant: CN
Solvent: O
Product: CNc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 120 °C
Reaction time: 12 h

Procedure:
In a stainless steel vessel, 5.31 g of 3-chloro-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 100 ml of 40% aqueous methylamine solution were placed. After sealing the vessel, the solution was stirred at 120° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed three times with water and three times with saturated aqueous sodium chloride solution. The resultant was then dried over anhydrous sodium sulfate and then the resultant was concentrated, followed by purification by silica gel column chromatography to obtain 2.55 g of 3-(2,6-dichlorophenyl)-4-methylamino-1,2,5-thiadiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[F:20])[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 93 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-fluorophenyl)piperazine were rented by the same way with the example 106 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 3.18 (s, 4H), 3.78 (s, 4H), 4.14 (s, 3H), 6.94-7.11 (m, 4H), 7.35-7.45 (m, 2H), 7.74-7.77 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[N:18]([C:19]3[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([C:24]([OH:26])=[O:25])[CH:27]=3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC1CCCCC1=O)c1ccc(Br)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(Br)cc3)cc3c2CCCC3)ccc1O
Yield: 19.2 %

Procedure:
A mixture of 44.3 g. (0.15 mole) of 2-(p-bromophenacyl)cyclohexanone, 23.0 g. (0.15 mole) of 5-aminosalicylic acid, and 115 ml. of glacial acetic acid was heated under reflux for 2 hours, cooled and filtered. The filter cake was washed with water, dried and recrystallized from acetic acid to provide 11.9 g (19%) of tan crystals, m.p. 231°-232°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>CN1C(=O)CCC1.ClCCl.[Cu]I>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:3]=[C:2]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=1
Reactant: CN(C)CCOc1cc(Br)cc([N+](=O)[O-])c1
Reactant: c1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN(C)CCOc1cc(-n2cncn2)cc([N+](=O)[O-])c1
Yield: 57 %

Procedure:
Intermediate 16A (200 mg, 0.69 mmol), copper(I) iodide (65.9 mg, 0.35 mmol), potassium carbonate (287 mg, 2.1 mmol) and 1H-1,2,4-triazole (143 mg, 2.075 mmol) in NMP (2 mL) were heated at 120° C. for 6 hours. The reaction mixture was diluted with dichloromethane, and filtered through a plug of silica gel and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by reverse phase HPLC to obtain Intermediate 16B (109 mg, 56.8% yield) as a yellow solid. HPLC: Rt=0.74 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min, detection at 254 nm). MS (ES): m/z=278.08 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: CN1CCNCC1
Product: COc1ccc(-c2cc(CCCN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 62 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 62.0%).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:10]([CH2:11][CH3:12])=[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)[C:8]([CH2:26][CH3:27])=[N:7]1)C.[OH-].[Na+]>O1CCCC1.CO.O>[CH2:26]([C:8]1[C:9]([CH2:13][C:14]2[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH3:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[C:10]([CH2:11][CH3:12])[N:6]([CH2:5][C:4]([OH:28])=[O:3])[N:7]=1)[CH3:27]
Reactant: CCOC(=O)Cn1nc(CC)c(Cc2cc(C)c(OC)c3c2CCC3)c1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nn(CC(=O)O)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Reaction time: 1.75 h
Yield: 75.5 %

Procedure:
To a stirred solution of [3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic acid ethyl ester of step-III (9.0 gm, 0.0234 mole) in Tetrahydrofuran (40 ml) and Methanol (20 ml), a solution of Sodium hydroxide (1.87 gm, 0.0468 mole) in water (75 ml) was added at 20-30° C. and stirred for 1.5-2 hours. The reaction mixture was poured into water (50 ml) and extracted with Ethyl acetate (2×200 ml). The residual aqueous layer was acidified with dilute Hydrochloric acid. The separated solid was filtered, washed well with water (50 ml) and dried under vacuum at 60-65° C. to yield desired product as off white solid. (6.3 gm).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([OH:35])([C:12]3[S:13][C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([NH:24][C:25]5[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[N:18]=4)=[CH:15][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([O:38]C)=[O:37].[OH-].[K+]>C1COCC1.CO>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([OH:35])([C:12]3[S:13][C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([NH:24][C:25]5[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=[CH:27][N:26]=5)[N:18]=4)=[CH:15][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([OH:38])=[O:37]
Reactant: COC(=O)c1ccc2c(c1Br)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4c3ccc(C(=O)O)c4Br)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of methyl 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (50 mg, 0.081 mmol) in THF (1.6 mL) was added aqueous potassium hydroxide (172 μl, 1.61 mmol), and the mixture was stirred for 16 h at rt, after which time the reaction mixture was diluted with MeOH (2 mL), filtered, and purified by reverse phase HPLC using a C18 column and a mixture of MeCN and water modified with 0.1% TFA. The product-containing fractions were partitioned between pH 4 buffer (20 mL) and EtOAc (20 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (1×20 mL)), then the combined organic phases were washed with brine (20 mL), dried, and concentrated to yield 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (25 mg, 52%) as a white solid. MS ESI calcd for C26H20BrF3N4O3S [M+H]+ 605, found 605. 1H NMR (600 MHz, dmso) δ 10.17 (s, 1H), 8.62 (s, 1H), 8.46 (d, J=5.0, 1H), 8.20 (s, 1H), 7.35-7.29 (m, 3H), 7.19 (s, 1H), 7.08 (s, 1H), 6.68 (s, 1H), 2.79 (s, 3H), 2.32-2.2.24 (m, 4H), 2.06 (br s, 1H), 1.96 (br s, 2H) ppm.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH2:5][N:4]([CH3:17])[CH2:3]1.O.[OH-].[Na+].[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:1][CH:2]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[C:8]3[O:14][CH2:13][O:12][C:9]=3[CH:10]=2)[CH2:5][N:4]([CH3:17])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: COc1c2c(cc3c1OCO3)C(O)CN(C)C2
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1c2c(cc3c1OCO3)C(OC(C)=O)CN(C)C2
Reaction time: 1 h
Yield: 99 %

Procedure:
4.74 g (20 mmol) of 4-hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (6) was dissolved in 70 ml of methylene chloride, to which 1.71 ml of acetyl chloride was added dropwise at room temperature. This solution was stirred at 20°-30° C. for one hour, added with 30 ml of water and then further added with 25% aqueous solution of sodium hydroxide to make the water layer basic. After separating the layers, the water layer was extracted with 20 ml of methylene chloride. The methylene chloride layers were joined together and washed with 30 ml of water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5.53 g of 4-acetoxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (9) as a crystal (yield: 99%). This was then recrystallized from ethanol/n-hexane. Melting point: 109°-110° C.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)=[CH:5]OCC.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[C:3](=[O:20])[C:26]3[C:25](=[CH:24][CH:23]=[C:22]([CH3:21])[N:27]=3)[NH:28][CH:5]=2)=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: Cc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1C
Yield: 56.9 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.50 g (1.88 mmol) of 3-ethoxy-2-(4-methoxy-3-methyl-benzoyl)-acrylic acid methyl ester, 0.20 g (1.88 mmol) of 6-Methyl-pyridin-3-ylamine, and 10 mL of diphenyl ether to yield 0.33 g of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.O>[Cl:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:12]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:9][C:10]([CH:13]=[O:14])=[CH:11]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
By a similar reaction as in Reference Example 65 and using 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridine-3-sulfonyl chloride (1.30 g), the title compound was obtained as a pale-red solid (yield 1.14 g, 66%). More specifically, 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 mL), sodium hydride (60% in oil, 226 mg) was added and the mixture was stirred at room temperature for 15 min. 15-Crown-5 (1.1 mL) was added and the mixture was further stirred at the same temperature for 15 min. 6-Chloropyridine-3-sulfonyl chloride (1.30 g) was added. The reaction mixture was stirred at room temperature for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:2) to give the title compound as a pale-red solid (yield 1.14 g, 66%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:3]1=2.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C(Cl)Cl>[CH2:19]([NH:21][C:22]([NH:11][CH:10]1[C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:7][CH2:8][CH2:9]1)=[O:23])[CH3:20]
Reactant: CCN=C=O
Reactant: NC1CCCc2ccsc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)NC1CCCc2ccsc21

Procedure:
Equivalent amounts of 4,5,6,7-tetrahydrobenzo[b]thiophen-7-amine hydrochloride, triethylamine, and ethyl isocyanate in methylene chloride are stirred at room temperature for an hour and then heated to reflux for half an hour. The product is collected, washed well with water, and dried to afford the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[CH:12][CH:11]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2CCC(=O)CC2)cc1

Procedure:
1-(4-Methoxybenzyl)-4-piperidone is prepared from 4-piperidone and 4-methoxybenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [N:1]1([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>C(Cl)Cl.[Cl-].[Na+].O>[C:36]([O:39][CH2:40][C:41]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Reaction time: 1.25 h

Procedure:
2-[4-(Piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 330 mg 0.88 mmol) was stirred in DCM (6 ml) at room temperature. Triethylamine was added (153 mg 1.51 mmol) followed by dropwise addition of acetoxyacetylchloride (143 mg 1.05 mmol). After stirring for 1.25 hours, DCM (10 ml) and brine (5 ml) were added. The reaction was stirred vigorously for 10 minutes then the organic layers were separated, dried and evaporated under reduced pressure to give the title compound as a yellow foam. Quantitative yield. The solid was triturated with ether and re-evaporated. NMR: 1.40 (d, 6H), 2.08 (s, 3H), 2.48 (s, 3H), 3.05 (b d, 4H), 3.54 (b d, 4H), 4.81 (s, 2H), 5.70 (septuplet, 1H), 6.92 (d, 2H), 6.95 (d, 1H), 7.40 (s, 1H), 7.48 (d, 2H), 8.31 (d, 1H), 9.18 (s, 1H); m/z 478.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[N-:22]=[N+:23]=[N-].[Na+]>Cl.O.O>[N:1]([C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc([N+](=O)[O-])ccc1CO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=Nc1cc([N+](=O)[O-])ccc1CO
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
To a suspension of 2-amino-4-nitrobenzyl alcohol [(0.5 g) Bio. Org. Med. Chem (1995) 3, 2, 129] in concentrated hydrochloric acid/H2O (15 ml of 1:1 v:v) at −50 to 0° was added a solution of sodium nitrite (0.24 g) in water (2.5 ml) dropwise so the temperature did not rise above 0°. The mixture was stirred for 10 min, and added dropwise to a cooled (0°) solution of sodium acetate (3.0 g) and sodium azide (0.2 g) in water (10 ml). The resulting solid was filtered, washed with water and dried on the sinter to give the title compound as a pale brown powder (0.45 g, 78%). δH (d6 DMSO): 4.51 (2H, s), 5.52 (1H, br), 7.72 (1H, d, J 8.4 Hz), 7.99 (1H, d, J 2.2 Hz) and 8.04 (1H, dd, J 2.2, 8.4 Hz) .
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+].C(Cl)[Cl:32]>>[Cl:32][C:20]1[C:19]([O:22][CH3:23])=[CH:18][C:17]([O:24][CH3:25])=[C:16]([CH2:15][CH2:14][C:6]2([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH:21]=1
Reactant: ClCCl
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 6-[2-(2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (from Step 5, above) (4.50 g, 13 mmol) in CH2Cl2 (20 mL) was cooled to −5° C. and treated with a solution of SO2Cl2 (1.94 g, 14.3 mmol) in CH2Cl2 (10 mL) dropwise under nitrogen. The reaction mixture was stirred for an additional 15 minutes at −5° C., then allowed to warm gradually to room temperature. After a total reaction time of 2 h, an aqueous solution of NaHCO3 (5 wt %) was added to achieve a pH of 8 in the aqueous phase. The volatiles were removed in vacuo. The residue was treated with water and extracted with ethyl acetate (3×25 mL). The combined ethyl acetate extract was acidified to a pH 2 using 2 N HCl, then washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated to a yellowish solid. Recrystallization from ether afforded the title product as a white solid (2.18 g, 44%). 1H NMR (CDCl3) δ1.74 (m, 8H), 2.32 (m, 1H), 2.58 (m, 2H), 2.78 (s, 2H), 3.43 (s, 2H), 3.82 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 7.07 (s, 1H). HRMS calcd for C20H25O5Cl (M+H+): 381.1469, found 381.1475.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:13]([C:14](=[O:16])[CH3:15])=[C:9]3[CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C(O[CH:30](OC(C)(C)C)[N:31]([CH3:33])[CH3:32])(C)(C)C>O>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:13]([C:14](=[O:16])/[CH:15]=[CH:30]/[N:31]([CH3:33])[CH3:32])=[C:9]3[CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn3c(NC4CC4)cccc3c2C(C)=O)cc1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: O
Product: COc1ccc(-c2nn3c(NC4CC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A solution of 1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (1.22 g, 3.8 mmol) in N,N-dimethylformamide di-tert-butyl acetal (8 mL, 33 mmol) was heated under reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes-ethyl acetate to ethyl acetate) provided (2E)-1-[7-(cyclopropylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (1.19 g, 83%) as a gold foam. 1H NMR (CDCl3): δ 7.73 (d, 1 H), 7.62 (d, 2 H), 7.34 (t, 1 H), 6.97 (d, 2 H), 6.37 (d, 1 H), 6.29 (s, 1 H), 5.13 (d, 1 H), 3.85 (s, 3 H), 2.95 (broad, 3 H), 2.65 (m, 1 H), 2.50 (broad, 3 H), 0.86 (m, 2 H), 0.72 (m, 2 H); MS m/z 377 (M+1).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27]>CCOCC>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:27]
Reactant: COC1CCCCC1=O
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COC1CCCCC1(O)c1cccnc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 2.5M n-butyllithium in hexane (13.2 ml, 33 mmol) at -78° C. was added diethyl ether (15 ml) followed by a solution of 3-bromopyridine (4.7 g, 30 mmol) in ether (90 ml) over a period of 10 minutes. After 1 hour at -78° C. a solution of (±)-2-methoxycyclohexanone (3.84 g, 30 mmol) in ether (20 ml) was added dropwise during 10 minutes. After 2 hours at -78° C. and 30 minutes at 0° C. the reaction mixture was warmed to 20° C. and then poured onto ice (150 g). The mixture was extracted with ether (2×50 ml) and then the combined organic extracts were extracted with 1N hydrochloric acid (50 ml). This aqueous extract was washed with ether (20 ml) and then treated with 2M sodium hydroxide solution (25 ml) and extracted with ether (3×100 ml). The organic extracts were combined, washed with brine then dried over anhydrous sodium sulphate Concentration in vacuo afforded (±)-2-methoxy-1-(pyrid-3-yl)cyclohexanol (5.0 g, 24 mmol) as a 4:1 mixture of cis and trans isomers;