Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11]2)([O-:5])=[O:4].[CH3:20][O:21][CH2:22]Cl.O>CN(C)C=O>[CH3:20][O:21][CH2:22][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[N+:3]([O-:5])=[O:4])[CH:11]=[C:12]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2n1COC
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of sodium hydride (60%, in oil, 0.51 g) in N,N-dimethylformamide (15 ml) was slowly added ethyl 7-nitro-1H-indole-2-carboxylate (2.50 g) at 0° C., and the mixture was stirred for 30 min. Chloromethyl methyl ether (1.00 ml) was added to the reaction mixture over 20 min at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.29 g, yield 77%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 62-63° C.
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.CCN(C(C)C)C(C)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6]1[S:10][C:9]([NH:11][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=2)=[O:32])=[N:8][CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cnc(N)s1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Reaction time: 8 h

Procedure:
To a solution of the HBr salt of (2-amino-thiazol-5-yl)-acetic acid methyl ester (compound 44.1; 20 mmol) in DIEA (40 mmol) and DMF (100 mL) was added 3-trifluoromethylphenyl isocyanate (20 mmol) at room temperature. After overnight stirring, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to provide {2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-acetic acid methyl ester (compound 44.2) in 60% yield. EIMS (m/z): calcd. for C14H12F3N3O3S (M+)+H 360.06. found 360.10.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>C(#N)C.O>[CH2:10]([N:14]([C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCC
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CC#N
Product: CCCCN(CC)c1cc(Cl)nc(C)n1
Yield: 99.7 %

Procedure:
A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 2.271 g (100%) of title compound as a light-brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.13 (t, 3H), 1.22–1.36 (m, 2H), 1.45–1.6 (m, 2H), 2.43 (s, 3H), 3.25–3.60 (m, 4H), 6.15 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:29]=[CH:28][C:13]3/[C:14](=[CH:23]/[C:24]([NH:26][NH2:27])=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:30]=[CH:31][CH:32]=[CH:33][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:34](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:29]=[CH:28][C:13]3/[C:14](=[CH:23]/[C:24]4[O:25][CH:34]=[N:27][N:26]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:30]=[CH:31][CH:32]=[CH:33][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NN
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1nnco1
Temperature: 120 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To (E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetohydrazide (27 mg, 0.062 mmol) obtained in Example 7, step 1 was added triethyl orthoformate (0.5 mL), and the mixture was stirred at 120° C. for 20 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 0/100) to give the title compound (compound 11) (26 mg, 93%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:21]=3[N:22](S(C3C=CC(C)=CC=3)(=O)=O)[C:23]=2[CH:24]=1.[OH-].[Na+]>CO.C(Cl)Cl>[O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:21]=3[NH:22][C:23]=2[CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(N5CCN(CCc6ccccc6)CC5=O)cc42)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(N4CCN(CCc5ccccc5)CC4=O)ccc3c2C1
Yield: 47.1 %

Procedure:
tert-Butyl 7-(2-oxo-4-phenethylpiperazin-1-yl)-5-tosyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (450 mg, 0.716 mmol) and NaOH (800 mg, 20 mmol) were stirred in MeOH/CH2Cl2 (5 mL/5 mL) for 16 h. The mixture was partitioned between CH2Cl2 and water and the organic layer removed, dried and concentrated. The residue was purified by column chromatography (40 g ISCO column eluting with methylene chloride and a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 90% methylene chloride) to provide the title compound (160 mg, 47%) as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.32-7.25 (m, 4H), 7.22-7.17 (m, 2H), 6.88-6.86 (dd, J=8.3, 1.8 Hz, 1H), 4.51 (s, 2H), 3.69 (t, J=5.6 Hz, 2H), 3.64 (t, J=5.3 Hz, 2H), 3.33 (m, 2H), 2.88-2.83 (m, 2H), 2.83-2.74 (m, 4H), 2.69-2.63 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [N+](=[CH2:3])=[N-].C(OCC)C.[C:9]([C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:32])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[C:29]([OH:31])=[O:30])=[O:23])(O)=[O:10].[CH3:33][OH:34]>O1CCCC1>[CH3:33][O:34][C:9]([C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17](=[O:32])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[C:29]([O:31][CH3:3])=[O:30])=[O:23])=[O:10]
Reactant: CO
Reactant: O=C(O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OC

Procedure:
A solution of diazomethane in diethylether (˜6 mmol) was added to a solution of 500 mg (1.5 mmol) (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid in 10 ml tetrahydrofuran. After stirring overnight methanol was added and the solvents were evaporated. The residue was taken up in dichloromethane, extracted with brine and dried with sodium sulfate. After separation from the solvent 400 mg (72%) (R)-1-{6-[(R) -2-methoxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid methyl ester were obtained as a light yellow oil, MS m/e (%): 369 (M+H+, 100).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([C@H:32]([OH:51])[CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]([O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)([CH3:43])[CH3:42])[CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([CH2:24][O:25][C:26]3[CH:27]=[C:28]([C@@H:32]([OH:51])[CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]([O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)([CH3:43])[CH3:42])[CH:29]=[CH:30][CH:31]=3)=[N:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@@H](O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 125.1 %

Procedure:
At 0° C., diethyl azodicarboxylate (7.6 mL, 48.3 mmol) was added dropwise to a solution of the alcohol of Step 8 (17.47 g, 31.97 mmol), triphenylphosphine (12.60 g, 48.04 mmol) and R-(-)-α-methoxyphenylacetic acid (8.07 g, 48.6 mmol) in 320 mL of anhydrous THF. The mixture was stirred at 0° C. for 30 min and the solvents were evaporated. Flash chromatography of the residue on silica using EtOAc:toluene 2.5:97.5, 5:95 and 7.5:92.5 afforded 21.84 g (98%) of the inverted alcohol as the mandelate ester. [α]D -6.02° (c 1.99, THF). This ester was hydrolyzed to the title alcohol as in Example 1, Method B, Step 8.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH3:20])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=CC(=O)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/C(=O)c1ccccc1
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
A mixture of 3.00 g of β-benzoylacrylic acid (cis/trans =1/2 according to 1H NMR analysis), 10 ml of ethanol and 0.63 g of sulfuric acid was refluxed for 2 hours. A pressure was gradually reduced with the aspirator and ethanol was distilled away for 10 minutes. After a pressure was finally reduced to 20 mmHg, the resultant was stirred at 85° C. for 40 minutes and then cooled, followed by the procedure as in Example 1 to give 2.45 g of ethyl trans-β-benzoylacrylate.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH2:2][OH:3].[K+].[C:7]([O:10][CH2:11]Br)(=[O:9])[CH3:8].C(OCC)C>C(#N)C>[C:1]([O:5][CH2:11][O:10][C:7](=[O:9])[CH3:8])(=[O:4])[CH2:2][OH:3]
Reactant: CC(=O)OCBr
Reactant: O=C([O-])CO
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)OCOC(=O)CO
Temperature: 50 °C
Reaction time: 6 h
Yield: 54.1 %

Procedure:
To a suspension of potassium glycolate (11.4 g) in acetonitrile (30 ml) KI (0.5 g) and acetoxymethyl bromide (19 g) were added. The mixture was stirred at 50° C. for 6 hours, and then cooled to room temperature. Diethyl ether was added and the solid filtered off. The solution was evaporated in vacuo and the oily residue was purified by column chromatography to yield 8 g of acetoxymethyl glycolate as a colourless oil.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1>[OH-].[Na+].C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:14]=[C:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]1=[O:5]
Reactant: Oc1nc2c(nc1CCc1ccccc1)CCCC2
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: O=c1c(CCc2ccccc2)nc2c(n1CCO)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
Ethylene chlorohydrin (9.0 g) was added to a solution of 2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydro quinoxaline (5.59 g, 22 mM) in aqueous 5N NaOH and t-butanol (60 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added to the residue, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 645 (6.73 g, yield: 90.9%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH2:17]([NH2:26])/[CH:18]=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:26][CH2:17]/[CH:18]=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NC/C=C\c1ccccc1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(NC/C=C\c1ccccc1)C2

Procedure:
Starting from 1.02 g (0.005 mol) of 5-acetylamino-2-tetralone and 1.7 g (0.01 mol) of cis-cinnamyl-aminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.35 g (76.5% of theory) and with a melting point of 246° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][C:12]([OH:17])=[CH:13]2)=[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:26](I)[CH2:27][CH2:28][CH3:29].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][C:12]([O:17][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13]2)=[C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)c1cc(-c2ccccc2)c2ccc(O)cn2c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc2c(-c3ccccc3)cc(C(=O)OCC)c(=O)n2c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethoxycarbonyl-7-hydroxy-1-phenyl-4H-quinolizin-4-one (5 g) in N,N-dimethylformamide (100 ml) was added sodium hydride (63.6% in mineral oil, 732 mg) at 50° C. After stirring for 30 minutes at 50° C., n-butyliodide (2.77 ml) was added. After stirring for 1 hour at 50° C., the mixture was cooled to room temperature and added to a mixture of aqueous hydrogen chloride and an ice. The mixture was extracted with chloroform and the chloroform extract was washed with 10% aqueous sodium hydrogen carbonate and aqueous saturated sodium chloride. After drying over magnesium sulfate, the chloroform extract was filtered and concentrated in vacuo. The residue was chromatographed on silica gel (Merck 70-230 mesh, 100 g), eluting with chloroform and then 10% methanol in chloroform to give 3-ethoxycarbonyl-7-(n-butoxy)-1-phenyl-4H-quinolizin-4-one (2.37 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:7][CH:6]=1
Reactant: ClCCCBr
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OCCCCl)cc1

Procedure:
A mixture of 47.4 g of methyl p-hydroxyphenylacetate, 28.5 ml of 3-bromo-1-chloropropane, 38.6 g of potassium carbonate and 700 ml of acetone is stirred and refluxed for 24 hours. The mixture is chilled, filtered and the solvent removed under reduced pressure. Distillation of the residue gives 52.1 g of colorless oil, bp 144°-146° C. at 0.25mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(OCC)C.[H-].[Na+].CN1CCCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:12][CH2:13][CH2:14][O:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: N#CC1(c2ccc(Cl)cc2)CCCOC1
Reaction time: 12 h

Procedure:
A mixture of 2-(4-chlorophenyl)acetonitrile (73 g, 483 mmol) and 1-chloro-3-(chloromethoxy)propane (69.1 g, 483 mmol) in ethoxyethane (242 mL, 483 mmol) was added dropwise to a mixture of NaH (57 g, 1437 mmol) in 1-methylpyrrolidin-2-one (1208 mL, 483 mmol) at −20° C. The reaction was stirred for 12 hours and then slowly quenched with H2O. The reaction mixture was extracted with ether (5×), and the combined organic layers were washed with H2O (3×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo to give the desired nitrile as a yellow oil. MS m/e=223.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.CN(C=O)C.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)[N:3]=1
Reactant: Fc1cccc(Br)n1
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(COc2cccc(Br)n2)c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 55.3 %

Procedure:
To 2-bromo-6-fluoropyridine (176 mg, 1.000 mmol) was added DMF (1.5 ml) and (3-fluorophenyl)methanol (139 mg, 1.100 mmol) and cesium carbonate (391 mg, 1.200 mmol), and the resulting mixture reaction mixture was stirred at 95° C. for 6 hr, as the progress of the reaction mixture was followed by LCMS. The reaction mixture was cooled to room temperature, diluted with 120 ml of ethyl acetate, washed with saturated sodium bicarbonate (1×), water (1×), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude product which was purified by silica gel chromatography using a 12 g column eluting from 0%-20% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 156 mg of the title compound as a free base. LCMS (m/z): 282.0/284.0 (MH+), retention time=1.19 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH:15]([OH:17])=[O:16].[OH-].[NH4+].O=[C:21]1C(NC=O)=CC(C2C=CN=CC=2)=CN1>O>[O:14]=[C:3]1[C:2]([NH:1][C:15](=[O:17])[O:16][CH3:21])=[CH:7][C:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[CH:5][NH:4]1
Reactant: O=CNc1cc(-c2ccncc2)c[nH]c1=O
Reactant: Nc1cc(-c2ccncc2)c[nH]c1=O
Reactant: O=CO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Nc1cc(-c2ccncc2)c[nH]c1=O

Procedure:
A reaction mixture containing 28 g. of 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and 200 ml. of 97% formic acid was heated on a steam bath for three hours, cooled and the excess formic acid distilled-off under reduced pressure. The residue was dissolved in water and the aqueous solution was made alkaline with ammonium hydroxide. The precipitated product was collected, washed with water, dried, recrystallized from dimethylformamide, washed with ether and dried to yield 26 g. of N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]formamide, m.p. 299°-300° C. with decomposition.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22](O)=[O:23])[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:55]1([N:58]2[CH2:63][CH2:62][N:61]([C:64]3([CH2:70][N:71]4[CH2:79][C:78]5[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=5)[C:72]4=[O:80])[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[CH2:60][CH2:59]2)[CH2:57][CH2:56]1>ClCCl>[CH:1]1([N:4]([CH2:18][CH2:19][O:20][CH2:21][C:22]([N:67]2[CH2:66][CH2:65][C:64]([N:61]3[CH2:62][CH2:63][N:58]([CH:55]4[CH2:56][CH2:57]4)[CH2:59][CH2:60]3)([CH2:70][N:71]3[CH2:79][C:78]4[C:73](=[CH:74][CH:75]=[CH:76][CH:77]=4)[C:72]3=[O:80])[CH2:69][CH2:68]2)=[O:23])[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCNCC1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)N2CCC(CN3Cc4ccccc4C3=O)(N3CCN(C4CC4)CC3)CC2)C2CC2)c(C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenyl-sulfonamido)ethoxy)acetic acid AC7 (0.306 mmol) in dichloromethane (10 ml/mmol) was added diisopropyl ethylamine (4.0 equiv.) at 0° C. followed by the addition of HOBT (1.0 equiv.) and EDCI (1.5 equiv.). The resultant solution was stirred at 25° C. for 15 min. It was again cooled to 0° C. and a solution of 2-((4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methyl)isoindolin-1-one AM13 (1.2 equiv) in dichloromethane (2 ml) was added. The reaction mixture was stirred for 16 h at 25° C. The mixture was diluted with dichloromethane, washed with saturated ammonium chloride solution, brine, saturated sodium bicarbonate and finally again with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by column chromatography. Yield: 50%. MS, Rt=3.4 min, m/z=694.5 [MH]+.
Reaction SMILES: [CH:1]([CH:3]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])=[O:2].[H-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][N:23]=1>O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:7]2[CH2:8][CH2:9][N:5]([CH:4]=[CH:3][CH:1]=[O:2])[C:6]2=[N:10][N+:11]([O-:13])=[O:12])=[CH:24][N:23]=1
Reactant: O=CC=CN1CCNC1=N[N+](=O)[O-]
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC=CN1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
A mixture comprising 3.0 g of 1-(formylvinyl)-2-nitroiminoimidazolidine, 0.7 g of sodium hydride and 30 ml of DMF was stirred at 40° C. for 15 minutes. After this was cooled to room temperature, 3.2 g of 2-chloro-5-chloromethylpyridine was added thereto and stirred at 60° C for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate) to give 2.3 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-(2-formylvinyl)imidazolidine.
Reaction SMILES: O=[C:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6]CC)=O.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>C(O)C>[CH2:9]([C:2]1[CH:3]=[C:4]([OH:6])[N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: NNc1ccccn1
Solvent: CCO
Product: Oc1cc(Cc2ccccc2)nn1-c1ccccn1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Compound 2a (1.03 g, 5.0 mmol) prepared in Step 1 of Example A-1 was charged in a 25 mL round-bottom flask and dissolved in 6 mL of ethanol. A solution of 2-hydrazinopyridine (0.55 g, 5.0 mmol, manufactured by Aldrich) in 5 mL of ethanol at 50° C. was gradually added thereto over 30 minutes, followed by reaction for 1 hour. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated by evaporation, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography [n-Hex/EtOAc=3/1 (v/v)] to afford a compound of 3-benzyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (3a).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[C:7](O)(=O)[CH2:8][CH3:9]>>[CH2:8]([C:9]1[O:4][CH2:3][CH:2]([CH2:5][OH:6])[N:1]=1)[CH3:7]
Reactant: NC(CO)CO
Reactant: CCC(=O)O
Product: CCC1=NC(CO)CO1

Procedure:
The procedure of Example 1 is repeated in all essential details with the exception that the initial reactants are 2-amino-1,3-propanediol and propionic acid in a 1:1 molar ratio. The reactants are combined following the method of Purcell to form 2-ethyl-4-hydroxymethyl-2-oxazoline.