Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.CO>C(O)C>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([CH:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Solvent: CO
Solvent: CCO
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A stirred mixture of 7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.0 g, 2.5 mmol) and cyclopropane carbonyl chloride (1 mL) was heated to reflux for 7 min. To the cooled mixture was added methanol (3 mL) at 0° C. and the mixture was stirred for 30 min. To the suspension was added ethanol (5 mL). The suspension was filtered and washed with ethanol to give cyclopropyl-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as an off-white solid (1.0 g, 86% yield); mp, 115-117° C.; 1H NMR (CDCl3) δ 0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz, 1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ 8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S+0.9 H2O: C, 58.98; H, 6.15; N, 5.73; H2O, 3.32. Found: C, 58.62; H, 5.99; N, 5.53; H2O, 3.15.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[N:16]1([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([N:16]2[CH2:21][CH2:20][N:19]([C:10](=[O:12])[CH2:9][CH2:8][C:6]3[CH:7]=[C:2]([Br:1])[C:3]([Cl:15])=[CH:4][C:5]=3[O:13][CH3:14])[CH2:18][CH2:17]2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1cc(Cl)c(Br)cc1CCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(Br)cc1CCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred solution of 3-(5-bromo-4-chloro-2-methoxyphenyl)propanoic acid (350 mg, 1.2 mmol) in DMF (30 mL) at RT, tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (317 mg, 1.3 mmol), BOP (731 mg, 1.4 mmol) and DIEA (461 mg, 3.6 mmol) were added and the mixture was stirred at RT for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (285 mg, 46% yield).
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](Cl)=[O:32]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:31](=[O:32])[CH:30]=[C:29]([CH3:34])[CH3:28])[CH2:24][CH2:23]2)[N:9]=1
Reactant: CC(C)=CC(=O)Cl
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(C(=O)C=C(C)C)CC3)nc(N)c2cc1OC
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.7 g of 3,3-dimethylacryloyl chloride, after which the mixture was stirred at room temperature for 15 hours. The resulting crystals were collected by filtration, washed with water and recrystallized from dimethylformamide to give 1.24 g of the desired product in the form of colourless powdery crystals melting at 278°-280° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([Si:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(O)ccc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(Br)c(C=O)c1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 2-bromo-5-hydroxybenzaldehyde (4.66 g, 23.2 mmol), tert-butyldiphenylchlorosilane (7.73 mL, 30.6 mmol), and imidazole (2.37 g, 34.8 mmol) in DMF (50 mL) was stirred at 25° C. for 12 hours and 60° C. for 12 hours. The solvent was removed in vacuo and the residue partitioned between methylene chloride (100 mL) and saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (10% ethyl acetate/hexane) to provide the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].FC(F)(F)C(O)=O.[CH2:20]([N:27]([CH2:33]OC)[CH2:28][Si](C)(C)C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl.C(OCC)(=O)C>[CH2:20]([N:27]1[CH2:33][CH2:9][CH:8]([C:6]2[CH:5]=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:7]=2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C2CCN(Cc3ccccc3)C2)cc1F
Reaction time: 2 h
Yield: 139.4 %

Procedure:
2-Fluoro-1-nitro-4-vinyl-benzene (360 mg, 2.15 mmol) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (70 μl, 0.88 mmol) was added, followed by slow addition of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (633 mg, 2.67 mmol). Stirring was continued for 2 h at room temperature. Another portion of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (300 mg, 1.26 mmol) was added and stirring continued for another 30 minutes. The reaction mixture was diluted with ethyl acetate (25 ml), washed with aqueous NaHCO3 (15 ml). The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield an oil (900 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-25%). Fractions containing the product were combined, the solvent evaporated to yield an oil (550 mg, 85%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:9])[CH2:8][CH:4]2[CH2:3][NH:2]1.[N:10]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:10]1([C:15]([N:2]2[CH2:3][CH:4]3[CH2:8][C:7](=[O:9])[CH2:6][CH:5]3[CH2:1]2)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CC2CNCC2C1
Reactant: O=C(Cl)N1CCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2CN(C(=O)N3CCCC3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one triflutate 1f (478 mg, 2 mmol) was dissolved in 20 mL dichloromethane, and pyrrolidine-1-carbonyl chloride (0.276 mL, 2.5 mmol) and triethylamine (0.84 mL, 6 mmol) were then added to the solution in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred overnight at room temperature, 10% citric acid solution was then added to the mixture to adjust to pH 4. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-(pyrrolidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 8a (0.26 g, yield 58.5%) as a colorless oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[OH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[OH:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:6][C@H:5]([C:4]([OH:3])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)=[O:29]
Reactant: O=C(O)c1cccnc1O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O)c1cccnc1O

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2-hydroxynicotinic acid. δH (DMSO-d6) 10.15 (1H, d, J 7.4 Hz), 8.31 (1H, dd, J 7.1, 2.0 Hz), 7.71 (1H, br s), 7.65-7.45 (3H, m), 7.16 (2H, d, J 8.4 Hz), 6.97 (2H, d, J 8.4 Hz), 6.46 (1H, t, J 6.8 Hz), 5.17 (2H, s), 4.68 (1H, m), 3.2-3.0 (2H, m); m/z (ESI, 60V) 461 (MH+).
Reaction SMILES: Cl.Cl.[N:3]1([C@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:14])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[CH3:15][C:16]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:19]
Reactant: N[C@@H]1CCCC[C@@H]1N1CCCC1
Reactant: Cc1cc(C(F)(F)F)ccc1C(=O)O
Agent: Cl
Product: Cc1cc(C(F)(F)F)ccc1C(=O)NC1CCCCC1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=355.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride (intermediate F) and 2-methyl-4-trifluoromethyl-benzoic acid (CAS 23984-82-9).
Reaction SMILES: CC(C)([O-])C.[Na+].[O:7]=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[NH:9]1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.Cl>CN1CCCC1=O.O>[CH3:20][O:19][C:17]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([OH:7])=[C:16]2[C:22]1[C:23]2[CH:30]=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1)=[O:18]
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: Clc1ncnc2sccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2[nH]c(O)c(-c3ncnc4sccc34)c2c1
Temperature: 25 °C
Yield: 36.6 %

Procedure:
Sodium tert-butoxide (40.3 mg, 0.42 mmol) and methyl 2-oxo-5-indolinecarboxylate (17.6 mg, 0.092 mmol) in N-methylpyrrolidinone (1 mL) under nitrogen atmosphere were stirred for 5 min at room temperature. A solution of 4-chlorothieno[2,3-d]pyrimidine (0.1 mL, 0.84 M, corresponding to 14.3 mg, 0.084 mmol) in N-methylpyrrolidinone was added and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with water (20 mL) and acidified with hydrochloric acid (1 M) and extracted with ethyl acetate (2×15 mL). The combined organic layer was washed with brine, dried with sodium sulphate, filtered and concentrated. The crude product was triturated with methylene chloride to give 10 mg (36% yield) of the title compound as a bronze solid. MS (AP−) m/z 324 (M−1).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])Cl)[CH3:18]>CCCCCC>[CH3:16][CH:17]([SiH:19]([CH:21]([CH3:23])[CH3:22])[O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:18]
Reactant: CCCCCCCCO
Reactant: CC(C)[SiH](Cl)C(C)C
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCCCCCCO[SiH](C(C)C)C(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Di(2-propyl)octyloxysilane was prepared in the following manner. Dry octanol (52.5 g, 0.40 mole) and dry pyridine (32.9 g, 0.42 mole) were added to a 500 ml round-bottom flask. The solution was cooled to -5° C. with stirring. Di(2-propyl)chlorosilane (67.1 g, 0.44 mole) was added in a dropwise fashion over 60 minutes. After this addition, the temperature of the reaction mixture was maintained at -5° C. for another 30 minutes, then allowed to come to room temperature overnight. Hexane (100 ml) was then added to this reaction mixture. The organic phase was extracted with 500 ml 0.1N aq. HCl and 500 ml water. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled to produce di(2-propyl)octyloxysilane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.[OH-:18].[Na+]>C(O)C>[CH3:4][C:5]1[N:1]=[C:2]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][N:3]2[C:8](=[O:18])[C:6]=1[CH2:7][CH3:2]
Reactant: [OH-]
Reactant: CCOC(=O)c1ccnc(N)c1
Agent: [Na+]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccn2c(=O)c(CC)c(C)nc2c1
Yield: 42 %

Procedure:
0.02 moles of 2-amino-4-ethoxycarbonylpyridine and 0.02 moles of ethyl-2-ethylacetacetate are stirred in a mixture of 10 ml. of phosphorus oxychloride and 2 g. of polyphosphoric acid at 120° C. for 2 hours. The reaction mixture is treated with 20 ml. of ethanol at 70° to 80° C., whereupon it is neutralized with a 10% (w/v) aqueous sodium hydroxide solution with ice cooling. The ethanol is evaporated, the residue is extracted with four 25-ml. portions of chloroform and the combined extracts are dried and evaporated. The evaporation residue is triturated with ether to give crystalline 2-methyl-3-ethyl-8-ethoxycarbonyl-4-oxo-4H-pyrido[1,2-a]pyrimidine, melting at 95° to 96° C. Yield: 42%. The product does not give any melting point depression when admixed with the product of Example 17.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].C(O)C.Br[CH2:22][C:23]1[C:36]2[C:37]3=[C:38]4[C:33](=[CH:34][CH:35]=2)[CH:32]=[CH:31][CH:30]=[C:29]4[CH:28]=[CH:27][C:26]3=[CH:25][CH:24]=1>C1COCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:22][C:23]1[C:36]2[C:37]3=[C:38]4[C:33](=[CH:34][CH:35]=2)[CH:32]=[CH:31][CH:30]=[C:29]4[CH:28]=[CH:27][C:26]3=[CH:25][CH:24]=1)([NH:4][C:1](=[O:3])[CH3:2])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: BrCc1ccc2ccc3cccc4ccc1c2c34
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc2ccc3cccc4ccc1c2c34)(NC(C)=O)C(=O)OCC
Reaction time: 0.08 h
Yield: 83.1 %

Procedure:
A 9.78 g (45.04 mmol) sample of diethyl acetamidomalonate, and 1.08 g sodium hydride (45.04 mmol) were suspended in 100 mL of anhydrous THF, under nitrogen, and at 0°C. After stirring for 5 min., 2.5 mL of anhydrous ethanol were added slowly, and the solution returned to room temperature. A solution of 1-(bromomethyl)pyrene (12.03 g, 40.9 mmol, dissolved in 100 mL dry THF) was slowly added to the reaction mixture, and the solution brought to reflux for 18 h. The bulk of the THF was removed under reduced pressure, and the remaining yellow slurry was dissolved in 400 mL 1:1 CH2Cl2:H2O. The organic fraction was washed 3× with 100 mL H2O, and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to produce Diethyl-2-(1-pyrenylmethyl)-2-acetamidomalonate (14.70 g, 83.1%) as a light yellow powder. TLC (SiO2, 1:1 Hexane:EtOAc) Rƒ=0.57. Mp=135-140° C. 1H NMR (CDCl3), δ1.37 (t, 6H), 1.95 (s, 3H), 3.76 (s, 2H), 4.30 (q, 6H), 6.42 (s, NH), 8.00-825 (m, 9H from pyrene).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]CCCC.[K+].[CH:37]([C:39]1[N:40]=[C:41]([NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])[S:42][CH:43]=1)=O>O.C(OCC)(=O)C.CN(C)C=O>[CH3:47][CH:46]([CH3:48])[C:45]([NH:44][C:41]1[S:42][CH:43]=[C:39](/[CH:37]=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:40]=1)=[O:49]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)C(=O)Nc1nc(C=O)cs1
Agent: CCCC[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.4 %

Procedure:
A mixture of 4-nitrobenzyl bromide (381 mg), triphenylphosphine (463 mg) and N,N-dimethylformamide (3 ml) was stirred for 5 hours at room temperature. To the mixture were added potassium butoxide (238 mg) and then N-(4-formyl-1,3-thiazol-2-yl)-2-methylpropanamide (350 mg), and the mixture was stirred for 13 hours at the same temperature. The reaction mixture was poured into ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with water (20 ml), dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed to give 2-methyl-N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}propanamide (36.0 mg).
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C:24](O)=O.[CH2:27]([NH:30][CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[O:41][CH3:42])[CH2:32]1)[CH2:28][CH3:29]>>[CH3:42][O:41][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:38]=1[CH2:39][CH2:40][CH:31]([N:30]([CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=1)[CH2:27][CH2:28][CH3:29])[CH2:32]2
Reactant: CCCNC1CCc2c(cccc2OC)C1
Reactant: O=C(O)COc1ccc2ccccc2c1
Agent: O=C(O)COc1ccccc1
Product: CCCN(CCOc1ccc2ccccc2c1)C1CCc2c(cccc2OC)C1

Procedure:
In Example 29, phenoxyacetic acid was replaced with (2-naphthoxy)acetic acid and (-)-2-(N-n-propylamino)-5-methoxy-tetralin was replaced with (±)-2-(N-n-propylamino)-5-methoxytetralin. The resulting oil was subjected to flash chromatography (Silica: 8:2 pet ether/EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ7.8-6.6(m, 10H), 4.15(t, 2H), 3.8(S, 3H), 0.9(t, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[N:34][C:33](Cl)=[CH:32][N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[N:31]=[CH:32][C:33]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:34][CH:35]=1
Reactant: Clc1cnc(Cl)cn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cnc(Cl)cn2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0507 g, 0.132 mmol) and 2,5-dichloropyrazine (0.0320 g, 0.215 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.67 (s, 1H), 8.30 (d, J=2.5, 1H), 8.21 (d, J=8.7, 2H), 8.02 (d, J=2.5, 1H), 7.49 (d, J=8.8, 2H), 6.17 (t, J=5.6, 1H), 4.57 (s, 2H), 3.79-3.65 (m, 6H), 3.50 (d, J=4.3, 4H), 3.12 (dt, J=14.1, 7.1, 2H), 2.86 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1>CS(C)=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)[N:7]3[N:8]=2)=[CH:18][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Solvent: CS(C)=O
Product: Fc1ccc(-c2nn3c(-n4ccnc4)cccc3c2-c2ccncc2)cc1
Temperature: 120 °C

Procedure:
A mixture of 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (100 mg) and imidazole (5 eq.) in dimethylsulfoxide (2 mL) in sealed tube was heated at 120° C. overnight. The mixture was evaporated to dryness and purified by preparative thin layer chromatography to give 2-(4-fluorophenyl)-7-(1H-imidazol-1-yl)-3-pyridin-4-ylpyrazolo[1,5-α]pyridine. 1H NMR (CDCl3): δ 8.65 (d, 2H, J=5,6 Hz), 7.96 (s, 1H), 7.60 (d, 1H, J=9.5 Hz), 7.44–7.47 (m, 2H), 7.34–7.38 (m, 4H), 7.28 (d, 2H, J=5.7 Hz), 7.02 (m, 2H); MS m/z 356 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:22])[C:18]=3[CH2:20][CH3:21])[CH:13]=[CH:12][C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)(Cl)[Cl:53]>>[ClH:53].[ClH:53].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[N:15][CH:16]=[C:17]([F:22])[C:18]=5[CH2:20][CH3:21])[CH:13]=[CH:12][C:11]4=[O:23])[CH2:6][CH2:7]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(N)CC3)c12
Reactant: ClC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CCc1c(F)cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
1-[2-(4-amino-1-piperidinyl)ethyl]-8-ethyl-7-fluoro-1,5-naphthyridin-2(1H)-one (0.056 g, 0.184 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (0.030 g, 0.184 mmol) was dissolved in CHCl3 (1 ml) and MeOH (0.1 ml) at rt under argon. NaBH(OAc)3 (0.117 g, 0.552 mmol) was then added and the reaction was allowed to stir at rt for 16 h. After which it was purified by chromatography on silica gel (10 g) using a 0-30% MeOH in DCM gradient to give the free base of the title compound as a yellow oil (0.041 g, 48%).
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=O)[CH:17]=3)[C:12]2=[O:34])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+]>C(O)C.ClCCl>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=[N:2][OH:3])[CH:17]=3)[C:12]2=[O:34])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C=O)ccc2c(=O)n1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C=NO)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Hydroxylamine hydrochloride (314 mg, 4.52 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-formyl-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (638 mg, 1.507 mmol) and sodium acetate (742 mg, 9.04 mmol) in ethanol (10 mL), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with dichloromethane (60 mL), washed with brine (saturated, 1×30 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (658 mg, 1.501 mmol) as a white solid.