Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>CC(O)C>[C:14]([NH:13][C@H:10]1[CH2:9][C@@H:8]([NH:18][C:19](=[O:21])[CH3:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide (30 g, 97 mmol) in IPA (400 ml) was added TEA (27 ml, 195 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (25 g, 107 mmol; see P. H. Carter, et al. PCT application WO 2005/021500). The mixture was stirred at room temperature overnight and then stirred at 70° C. for 1 h. The resulted solution was concentrated under reduced pressure to dryness. The residue was dissolved in dichloromethane (1 L) and extracted with acetic acid solution I (prepared by combining 700 mL of water and 22.6 mL of glacial acetic acid) twice (500 ml, 200 ml). The acidic aqueous layer (pH 4-5) was extracted with dichloromethane (2×300 ml). The dichloromethane layer was extracted with acetic acid solution II (300 ml; prepared by combining 300 mL water with 4 mL of glacial acetic acid). The combined acetic acid layers were basified with 1 M NaOH to pH>12 and extracted with dichloromethane (3×700 ml). The combined organic layers were dried and concentrated to give the crude product as a solid (45.6 g, 93% yield), The crude product was purified by recrystallization from EtOAc (400 ml)/Hexane (900 ml) to give 42.86 g (88%) N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexyl)acetamide with 99.7% purity. 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.71 (1H, br. s.), 9.02 (1H, s), 8.71 (1H, d, J=7.97 Hz), 8.59 (1H, s), 8.04 (1H, dd, J=8.66, 1.79 Hz), 7.88 (1H, d, J=8.52 Hz), 4.91-5.13 (1H, m), 4.30-4.57 (1H, m), 3.86(1H, dt, J=11.89, 3.71, 3.64 Hz), 3.43-3.57 (1H, m), 3.35-3.45 (1H, m), 3.04 (1H, t, J=3.85 Hz), 2.23-2.40 (1H, m), 2.05-2.22 (1H, m), 1.90-1.98 (1H, m), 1.86-1.93 (3H, m), 1.50-1.78 (5H, m), 0.98-1.15 (9H, m). 13C-NMR (126 MHz, DMSO-d6) δ ppm 171.23, 169.35, 159.54, 156.87, 151.17, 128.97, 128.20, 125.76 (1C, q, J=30.52 Hz), 121.55 (1C, br. s.), 124.04 (1C, q, J=272.11 Hz), 114.31, 53.26, 52.39, 50.81, 47.56, 45.70, 42.77, 34.52, 32.17, 29.14 (3C, s), 26.49, 23.29, 20.30. 19F-NMR (471 MHz, DMSO-d6) δ ppm −60.34 (s). m/z: 507.0 [M+H]. Anal. Calcd for C25H33N6O2F3: C, 59.27; H, 6.56; N, 16.59; F, 11.25 Found: C, 59.44;H, 6.64; N, 16.74; F, 10.99.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].[C:25]1(C)C=C[CH:28]=[CH:27][CH:26]=1.ClC(Cl)([O:35][C:36](=O)[O:37]C(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)CCC.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36](=[O:35])[O:37][CH2:28][CH2:27][CH2:26][CH3:25])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 87 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-butanol (17 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 87%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3C#N)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:39]=[N+:40]=[N-:41].[Na+].[CH3:43][N:44](C)C=O>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:43]3[NH:44][N:41]=[N:40][N:39]=3)[CH:15]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Agent: [Na+]
Product: CCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2)c(-c2nnn[nH]2)c1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [OH-].[Na+].CS(C)=O.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:16][C:15]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[OH:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A stirred solution of sodium hydroxide (16.8 g) in water (32 mL) at 20° C. is treated with dimethyl sulfoxide (560 mL). It is then treated with 3,4-dihydroxy-benzaldehyde (56.9 g), portionwise during 5 minutes, while keeping the temperature at 20° C. It is then treated with benzyl bromide (49.7 mL), portionwise, at 20° C. The solution is then heated at 80° C. for 6 hours and then allowed to stand at room temperature overnight. After dilution with ice-water (2240 mL) the solution is extracted with diethyl ether (1×1000 mL, 2×250 mL). The combined ether extracts are washed with water, dried over magnesium sulfate and concentrated, to give an oily solid, which is recrystallized from a mixture of ethyl acetate and isopropanol, to give 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g), in the form of pale yellow crystals, m.p. 118-120° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]([CH3:22])[CH2:19][CH2:20][OH:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]([CH2:19][CH:20]=[O:21])[CH3:22])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(CC=O)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
To a stirring solution of DMSO (1.34 g) in CH2Cl2 (10 ml) was added dropwise a solution of oxalyl chloride (1.45 g) in CH2Cl2 (5 ml) at -60° C. under nitrogen atmosphere. After five minutes, a solution of N-(tert-butoxycarbonyl)-N-methylethanolamine (1.00 g) in CH2Cl2 (5 ml) was added dropwise to the solution and the mixture was stirred at the same temperature for five minutes. To this solution was added Et3N (2.89 g) and the temperature was allowed to rise to 0° C. and the mixture was stirred at the same temperature for thirty minutes. After evaporation of the solvent, the residue was dissolved in EtOAc (50 ml) and washed with 1N aq. HCl (50 ml), water (50 ml), saturated sodium bicarbonate solution (50 ml) and brine (50 ml), successively. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give N-(tert-butoxycarbonyl)-N-methylaminoacetaldehyde (0.74 g) as an oil.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:32]=[CH:31][C:24]([C:25]([O:27]CC=C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:33])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:31][CH:32]=5)=[CH:18]4)=[CH:13][C:12]=3[O:33][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: C=CCOC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 65.4 %

Procedure:
Following the procedure of Example 12(a), but reacting 2 g (4.5 mmol) of allyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 1.4 g (6.7 mmol) of ethyl 5-bromovalerate, 1.55 g (59%) of the expected compound was obtained, which compound had a melting point of 117°-8° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[N:15]=[CH:14]1.O>S(=O)(=O)(O)O>[F:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[N:13]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([C:21]([F:23])([F:24])[F:22])[N:15]=[CH:14]1
Reactant: Cc1c(C(F)(F)F)ncn(-c2ccc(F)cc2F)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(F)(F)F)ncn(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Yield: 73.9 %

Procedure:
Fuming nitric acid (1.63 g) was added to a solution of 3-(2,4-difluorophenyl)-5-methyl-6-trifluoromethylpyrimidin-4-one (7.5 g) in conc. sulfuric acid (50 g) at 10° C. The reaction mixture was poured into water, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give 3-(2,4-difluoro-5-nitrophenyl)-5-methyl-6-trifluoromethylpyrimidin-4-one (6.4 g), m.p., 156.7° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[C:23]([O:28]CC)(=O)[C:24]([CH3:26])=O>C(O)(=O)C>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]2[N:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[C:23](=[O:28])[C:24]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:26]2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)C(C)=O
Reactant: N#Cc1ccc(N)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(NC2=CC(c3cccc(OC(F)(F)F)c3)N(c3ccc(C#N)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
Add 3-(trifluoromethoxy)benzaldehyde (10.0 g, 52.6 mmol) to a solution of 4-aminobenzonitrile (18.6 g, 157.8 mmol) in glacial acetic acid (53 mL). Stir at ambient temperature for 20 min. and a precipitate forms. Add ethyl pyruvate (5.8 mL, 52.6 mmol). Stir at ambient temperature for 18 hours. Filter the precipitate and wash with glacial acetic acid and then with 1:1 hexanes-diethyl ether to afford the titled compound (12.8 g, 53%). LC-MS ESI m/z: 461 (M+H)+, 459 (M−1)−, Tr=3.05 min., method 2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)=[CH:2]1.Cl.Cl.[NH2:20][CH:21]1[CH2:28][CH:27]2[N:29]([CH3:30])[CH:23]([CH2:24][CH2:25][CH2:26]2)[CH2:22]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:30][N:29]1[CH:23]2[CH2:24][CH2:25][CH2:26][CH:27]1[CH2:28][CH:21]([NH:20][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:3]4[CH:4]=[CH:5][S:1][CH:2]=4)=[N:10][C:9]=13)=[O:17])[CH2:22]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccsc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccsc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.8 %

Procedure:
A mixture of 2-thiophen-3-ylbenzoxazole-4-carboxylic acid (78 mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (86 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and 1-hydroxybenzotriazole (122 mg, 0.90 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then DIPEA (0.26 mL, 1.6 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and then recrystallized from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-thiophen-3-ylbenzoxazole-4-carboxamide (51 mg, 41%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=7.0 Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 8.20 (d, J=7.5 Hz, 1H), 7.78 (d, J=5.0 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.52-7.51 (m, 1H), 7.44 (t, J=7.5 Hz, 1H), 4.61-4.51 (m, 1H), 3.19-3.01 (m, 2H), 2.72-2.61 (m, 2H), 2.54 (s, 3H), 2.22-1.98 (m, 2H), 1.60-1.47 (m, 4H), 1.26-1.13 (m, 2H); MS (ESI+) m/z 382 (M+H); HPLC>99% (AUC), tR=13.40 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:16]1[CH:21]=[CH:20][C:19](Br)=[C:18]([CH:23]([CH2:34][C:35]2[N:36]=[N:37][C:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:23]([CH2:34][C:35]2[N:36]=[N:37][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:39][CH:40]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:17]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)c(C(Cc2ccc(-c3ccccc3)nn2)NS(=O)(=O)c2cccnc2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccc3)nn2)NS(=O)(=O)c2cccnc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To a solution of tert-butyl({5-bromo-6-[(6-phenylpyridazin-3-ylmethyl)-(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}tert-butoxycarbonylamino)acetate (239 mg, 0.329 mmol) obtained in Example 1-(a) in ethanol (3.3 ml) were added triethylamine (322 μl, 2.31 mmol) and 10% palladium-active carbon (55% hydrate) (48 mg), followed by stirring at room temperature for 6 hours under hydrogen atmosphere at 1 atm. After completion of the reaction, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1→1:10 (V/V)) and then to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=0:1→1:0 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (153 mg) as a white foam. (Yield: 72%)
Reaction SMILES: [CH3:1][C:2]([C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:5]OCC)=O.[C:15](#[N:19])[CH2:16][C:17]#[N:18].C([OH:22])C>>[CH3:1][C:2]1[NH:18][C:17](=[O:22])[C:16](=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)[C:15]#[N:19]
Reactant: N#CCC#N
Reactant: CCOC=C(C(C)=O)c1ccncc1
Reactant: CCO
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccncc1

Procedure:
Another aspect of the invention resides in the second step of the above process, that is, the reaction of said ketone of formula II with malononitrile in a lower-alkanol to produce 1,2-dihydro-6-R-2-oxo-5-PY-nicotinonitrile of formula III. In a preferred embodiment of this aspect, 2-ethoxy(or methoxy)-1-(4- or 3-pyridinyl)ethenyl methyl(or ethyl) ketone is reacted with malononitrile in ethanol to produce 1,2-dihydro-6-methyl(or ethyl)-5-[4(or 3)-pyridinyl]nicotinonitrile. In a particularly preferred embodiment, 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone is refluxed with malononitrile in ethanol to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][N:27]([C:2]3[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][N:11]=4)[N:3]=3)[CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1
Reactant: COc1cc(F)ccc1C1CNCCN1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1C1CN(c2nc(-c3ccncn3)cc(=O)n2C)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
2-Chloro-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (223 mg, 1:0 mmol) was added to an ice-cooled solution of 2-(4-fluoro-2-methoxyphenyl)piperazine (210 mg, 1.0 mmol), triethylamine (0.15 ml, 1.1 mmol) in N,N-dimethylformamide (10 ml) and stirred at that temperature for 0.5 hr and then at room temperature for 3 hours. Reaction was quenched by ice-water and the filtrate was washed with water and dried to give 2-(2-(4-fluoro-2-methoxyphenyl)piperazin-4-yl)-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (262 mg, 66%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:27])=[CH:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[CH3:14][C:15]([CH3:27])=[CH:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: CC(C)=CCOc1cccc(CN)c1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCOc1cccc(CNC(=O)c2ccc3ncccc3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
6-Quinolinecarboxylic acid (100 mg, 0.577 mmol), 3-(3-methyl-2-butenyloxy)-benzylamine described in Preparation Example 134 (112 mg, 0.635 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (306 mg, 0.693 mmol) and triethylamine (0.12 mL, 0.87 mmol) were dissolved in tetrahydrofuran (5 mL), and the solution was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo, the obtained residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1), and the title compound (153 mg, 80.1%) was obtained as a white solid.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=1.[I:24]I>CCOCC.C1COCC1>[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([I:24])[CH:20]=[CH:19][N:18]=1
Reactant: Clc1cccnc1Cl
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Clc1nccc(I)c1Cl
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (27.6 ml, 69 mmol, 2.5 M in hexanes) in dry Et2O (150 ml) cooled at −78° C., under a nitrogen atmosphere, was added 2,2,6,6-tetramethylpiperidine (11.64 ml, 69 mmol), dropwise. The resulting reaction mixture was stirred at −78° C. for 10 min., and then a solution of 2,3-dichloropyridine (10 g, 67.57 mmol) in dry THF (75 ml) was added dropwise. The mixture was stirred at −78° C. for 30 min. and then a solution of iodine (25.38 g, 100 mmol) in dry THF (75 ml) was added. The mixture was allowed to warm to r.t. overnight, quenched with Na2S2O3 (aqueous sat. solution) and extracted twice with EtOAc. The combined organic extracts were washed with NaHCO3 (aqueous sat. solution), dried (Na2SO4) and concentrated in vacuo. The crude residue was precipitated with heptane, filtered off and dried to yield intermediate compound D10 (8.21 g, 44%) as a pale cream solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:16][OH:17]>N1C=CC=CC=1.O>[CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[N:16][OH:17])[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(NS(C)(=O)=O)cc1
Temperature: 70 °C

Procedure:
A mixture of 4′-(Methylsulfonylamino)acetophenone (13-5, 5 mmol) and hydroxylamine hydrochloride (0.695 g, 10 mmol) in pyridine (5 mL) was heated at 70° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with H2O, and extracted with EtOAc several times. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:1) as eluant to 4′-Methylsulfonylamino)acetophenone oxime (13-8, LJO-299).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na][Na].[C:11]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]#[N:22])=[O:19])#[N:12]>CN(C)C=O>[C:21]([N:20]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]([N:13]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]#[N:12])=[O:23])#[N:22]
Reactant: N#CNC(=O)CCCC(=O)NC#N
Reactant: BrCc1ccccc1
Agent: [Na][Na]
Solvent: CN(C)C=O
Product: N#CN(Cc1ccccc1)C(=O)CCCC(=O)N(C#N)Cc1ccccc1

Procedure:
359.2 g (2.0 mols+5% excess) of benzyl bromide are added dropwise to a suspension of 224.1 g (1.0 mol) of the disodium salt of glutaric acid bis-(N-cyanamide) and 1 liter of dimethylformamide at 20°-70° C. in the course of 40 minutes, the components are reacted at 68°-78° C. for 3 hours and 50 minutes and the mixture is then filtered with suction. The filtrate is concentrated on a rotary evaporator at 100° C. in vacuo and the residue is recrystallised from 800 ml of toluene. 253.7 g (70.4% of theory) of a colourless, crystalline product which has a melting point of 97.5°-100.4° C. are obtained.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C1C[O:22]CC1.[OH2:24]>O=[Os](=O)(=O)=O>[OH:24][CH:2]1[CH:3]([OH:22])[CH2:4][CH2:5][CH2:6][CH:1]1[O:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:9]=1[C:10]#[N:11]
Reactant: C1CCOC1
Reactant: O
Reactant: N#Cc1c(OC2C=CCCC2)cccc1[N+](=O)[O-]
Agent: O=[Os](=O)(=O)=O
Product: N#Cc1c(OC2CCCC(O)C2O)cccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2-(cyclohex-2-en-1-yloxy)-6-nitrobenzonitrile (Example 133e, 5.3 g, 21.7 mmol) in THF/H2O (1:1 by volume, 110 mL) was added OsO4 (110.3 mg, 0.434 mmol) at room temperature. After it was stirred for 30 minutes, NaClO3 (2.71 g, 26.04 mmol) was added in small portions over a period of 1 h, and the reaction mixture was stirred at room temperature for 48 h. The reaction was carefully quenched with aqueous sodium bisulfite solution, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by chromatography on silica gel eluting with 80-100% EtOAc in hexanes to give the title compound as a brown solid (3.88 g, 64%). MS 279 (MH+).