Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.N1CCCC1C(N)=O.[Br:21][C:22]1[CH:41]=[CH:40][C:25]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([OH:39])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:24]([F:42])[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:63][CH2:64][CH2:65][N:66]1[CH2:70][CH2:69][CH2:68][C@H:67]1[C:71]([NH2:73])=[O:72].C(Cl)[Cl:75]>>[ClH:75].[Br:21][C:22]1[CH:41]=[CH:40][C:25]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:63][CH2:64][CH2:65][N:66]4[CH2:70][CH2:69][CH2:68][C@H:67]4[C:71](=[O:72])[NH2:73])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[C:24]([F:42])[CH:23]=1
Reactant: ClCCl
Reactant: NC(=O)[C@@H]1CCCN1CCCO
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: NC(=O)C1CCCN1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCN1CCC[C@H]1C(N)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of diethyl azodicarboxylate (209 mg, 1.2 mmol) in methylene chloride (1 ml) and then (S)-1-3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.4 mmol), (prepared as described for the starting material in Example 48), and triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature and further triphenylphosphine (109 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (40 mg, 0.23 mmol) were added followed by the dropwise addition of diethyl azodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 30 minutes at ambient temperature and further (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (34 mg, 0.2 mmol) was added. The mixture was then stirred for 2 hours at ambient temperature and the mixture was purified by pouring directly onto a column of silica and eluting with methylene chloride/ethyl acetate/methanol (60/35/5). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and 3M hydrogen chloride in ethyl acetate (0.4 ml) was added. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum to give (S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-6-methoxyquinazoline hydrochloride (110 mg, 47%).
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.I([O-])(=O)(=O)=[O:16].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[O:16]=[C:2]([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)Cc1ccc2c(c1)COC2=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc2c(c1)COC2=O
Reaction time: 0.17 h

Procedure:
To a solution of 5-(2-methylprop-2-en-1-yl)-2-benzofuran-1(3H)-one (175 mg, 0.930 mmol) in THF was added osmium tetroxide (295 mg, 0.0460 mmol) and the mixture was stirred for 10 minutes. Then a solution of sodium periodate (497 mg, 2.32 mmol) in water was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with DCM, and washed with Na2S2O3 solution. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (30% ether/hexanes) to afford the title compound. LC-MS (IE, m/z): 191.3 [M+1]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1.Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CC(C)([O-])C.[Na+]>CO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:28]3[N:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:20][CH:19]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: Brc1ncccn1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ncccn2)cc1)N1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 25.8 %

Procedure:
A mixture of (4-{[4-(1H-benzimidazol-2-yl)piperidin-1-yl]carbonyl}phenyl)boronic acid (0.349 g, 1.00 mmol), 2-bromopyrimidine (0.175 g, 1.10 mmol) and sodium tert-butoxide (0.106 g, 1.10 mmol) are suspended in a mixture of MeOH/1,4-dioxane (1 mL/2 mL). The suspension is purged with N2 before adding 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (41 mg, 5 mol %). The reaction is heated to 90° C. for 18 h. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is triturated with MeCN and DCM to give 99 mg of [4-(1H-Benzimidazol-2-yl)piperidin-1-yl][4-(pyrimidin-2-yl)phenyl]methanone.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[C:11]=1[CH2:12][CH2:13][CH2:14][NH:15][C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(Cl)C1CC1
Reactant: NCCCc1c(F)ccc2c1CCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1c(F)ccc2c1CCO2)C1CC1
Reaction time: 16 h

Procedure:
3-(2,3-Dihydro-5-fluorobenzofuran-4-yl)propylamine hydrochloride (0.27 g) in dichloromethane (5 ml) containing triethylamine (0.5 ml) was cooled in ice. Cyclopropanecarbonyl chloride (0.12 ml) was added and stirring continued at 5° for 2 h and at room temperature for 16 h. The mixture was washed with water and passed through a solid phase extraction cartridge using ethyl acetate/hexane (1:1) to give the title compound as a white solid (0.21 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A mixture of 2-tert-butoxycarbonylaminoethanol (32.7 g, 203 mmol), triethylamine (34 ml), p-toluenesulfonyl chloride (38.7 g, 203 mmol), 4-dimethylaminopyridine (0.10 g) and dichloromethane (500 ml) was stirred at 0° C. for 4 hours. The reaction mixture was washed successively with water, 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane= 1/5) to obtain 48.2 g of 2-tert-butoxycarbonylaminoethyl 4-toluenesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[C:12]1([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]1[C:19]([OH:20])=[C:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24]([OH:25])=[N:11][C:6]=21
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2c3ccc(Br)cc3nn2c(O)c1-c1ccccc1
Yield: 97.4 %

Procedure:
9.9 g (46.7 mmol) 6-Bromo-1H-indazol-3-ylamine, 11 g (46.7 mmol) diethyl phenylmalonate and 19.8 mL (83.1 mmol) tributyl amine were heated for 15 h at 180° C. The reaction mixture was treated with 2M sodium hydroxide and water and extracted three times with tert-butyl methyl ether. The organic phase was discarded and the aqueous phase was acidified with conc. hydrochloric acid. The precipitate was collected by filtration and washed with water to obtain the desired product (16.2 g) which was however contaminated and which was used in the next step without further purification.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:13])C>O1CCCC1>[O:13]=[C:8]1[NH:9][CH2:10][CH2:11][CH2:12][N:7]1[CH2:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(CCN1CCCNC1=O)OCC
Solvent: C1CCOC1
Product: O=CCCN1CCCNC1=O
Yield: 67.7 %

Procedure:
A mixture of 1-(3,3-diethoxypropyl)tetrahydropyrimidin-2-one (1 g, 4.35 mmole), and 1.0 g Dowex 50W2-200 ion exchange resin in 3% aqueous tetrahydrofuran (30 mL) was heated under reflux for 24 hours. The mixture was filtered, the filtrate was concentrated and the residue dissolved in dichloromethane (30 mL), dried with magnesium sulfate, and concentrated to give 3-(2-oxo-tetrahydropyrimidin-1-yl)propionaldehyde (0.46 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Cl.[Li].Cl.[CH3:13][N:14]([CH3:16])[NH2:15].O1CC[CH2:19][CH2:18]1>>[CH3:13][N:14]([CH3:16])[N:15]=[CH:18][CH2:19][CH2:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10]
Reactant: CN(C)N
Reactant: C1CCOC1
Reactant: ClCc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Li]
Product: CN(C)N=CCCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Separately, a 100-mL three-necked flask equipped with a thermometer, a dropping funnel, a three-way stopcock, and a magnetic stirrer was purged with nitrogen. Thereto, were added 10.2 g (52.2 mmol) of 2,6-dichlorobenzyl chloride (produced by Tokyo Kasei K.K.), and 25 mL of tetrahydrofuran. To this solution, the above obtained solution of the lithium salt compound was added dropwise by keeping the temperature of the reaction system in the range from 15 to 20° C. The reaction mixture was aged at room temperature for 2 hours, and the cooled with ice. Thereto 3N hydrochloric acid solution was added to stop the reaction. The mixture was extracted with ether. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. To the flask containing the concentration residue, 10 g of Molecular Sieve 4A was added and the flask was purged with nitrogen. The concentration residue was dissolved by addition of 10 mL of toluene, and was cooled with ice. Thereto, 3.45 g (57.4 mmol) of N,N-dimethylhydrazine was added. The mixture was stirred at room temperature for 3 hours, and filtered. The filtrate was concentrated under a reduced pressure. The obtained concentration residue was purified by silica gel chromatography (Solvent: hexane, ratio of hexane:ethyl acetate=20:1) to obtain 7.42 g (30.3 mmol) of 3-(2,6-dichlorophenyl)propionaldehyde N,N-dimethylhydrazone. (Yield: 58% based on 2,6-dichlorobenzyl chloride).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][NH:22][O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:15])[CH3:14]>>[C:13]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]([O:23][CH3:24])[C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)=[CH:19][CH:18]=1)(=[O:15])[CH3:14]
Reactant: CONCc1ccc(NC(C)=O)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(NC(C)=O)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 92 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-acetamidobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (92% yield): mp 212-215° C. (dec.) (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.73 (6H, s, CH3), 2.16 (3H, s, CH3), 3.67 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.39 (1H, s, CH), 7.32 (3H, m, aromatics and NH), 7.45 (2H, m, aromatics). Anal. calcd. for C17H20N2O6: C, 57.87; H, 5.86; N, 7.94. Found: C, 57.76; H, 5.68; N, 8.51.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.CS([C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:13]2[N:26]=[CH:27][N:28]=[C:12]2[N:11]=1)(=O)=O>O>[CH3:1][O:2][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:13]2[N:26]=[CH:27][N:28]=[C:12]2[N:11]=1
Reactant: CS(=O)(=O)c1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(-c2ccc(C(F)(F)F)cn2)n2ncnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
62 mg of a sodium methoxide 28% methanol solution was added to a methanol 3 mL solution of 100 mg of 5-(methylsulfonyl)-7-(5-(trifluoromethyl)pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidine, followed by stirring at room temperature for 5 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 85 mg of the desired product.
Reaction SMILES: [CH3:1][C:2](O)([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.[Cl:13][CH2:14][C:15]#[N:16].S(=O)(=O)(O)[OH:18]>C(O)(=O)C>[Cl:13][CH2:14][C:15]([NH:16][C:2]([CH3:11])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:18]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(CC(C)(C)O)cc1
Reactant: N#CCCl
Solvent: CC(=O)O
Product: Cc1ccc(CC(C)(C)NC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
8.21 g, (50 mmol) of 2-methyl-1-p-tolylpropan-2-ol and 12.0 mL of acetic acid were dissolved in 11.3 g (0.15 mol) of chloroacetonitrile, mixed with 12.0 mL (0.15 mol) of sulfuric acid under cooling with ice and stirred at room temperature for 5 hours. The reaction solution was poured into 200 mL of ice-cold water and extracted with diisopropyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 10.8 g of the desired product as white crystals.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CBr
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 59.9 %

Procedure:
3.3 g (0.01 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in 50 ml of dimethylformamide are heated at 90° C. with 2.5 g (0.015 mole) of ethyl bromoacetate, 1.2 g (0.02 mole) of triethylamine and 2.5 g of potassium iodide for 5 hours. The reaction mixture is poured into 30 ml of water and the precipitate is filtered off with suction, washed with water and recrystallized from methanol. 2.5 g of 1-cyclopropyl-6-fluoro-7-[4-(ethoxycarbonylmethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 192° to 194° C. are obtained.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[NH2:20].ClC([O:25][C:26]1C=CC(Cl)=CC=1)=O.[CH3:33][S:34]([NH:37][NH2:38])(=[O:36])=[O:35].CCN(C(C)C)C(C)C>O1CCOCC1>[O:25]=[C:26]1[N:38]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])[C:3](=[O:21])[C:4]2[C:5](=[CH:6][C:7]([C:16]([F:18])([F:19])[F:17])=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[N:14][CH:15]=3)[CH:9]=2)[NH:20]1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2cncnc2)c(C(F)(F)F)cc1N
Reactant: CS(=O)(=O)NN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(-c3cncnc3)cc2c1=O
Temperature: 25 °C
Yield: 36.1 %

Procedure:
A solution of 2-amino-5-pyrimidin-5-yl-4-trifluoromethyl-benzoic acid methyl ester (518 mg, 1.74 mmol) and 4-chlorophenyl chloroformate (244 μL, 1.74 mmol) in dioxane (8 mL) was stirred at 80° C. for 2 h. After cooling to r.t., CH3SO2NHNH2 (230.4 mg, 2.1 mmol) and i-Pr2NEt (609 μL, 3.49 mmol) were added. The mixture was heated to 80° C. for 4 h and, cooled to r.t., and the solvent was removed in vacuo. The residue was purified by flash chromatography (120 g silica gel, DCM→MeOH in DCM (2% to 5%)). The product was sonicated in MeOH/Et2O to furnish the title compound (252 mg, 36%) as a beige powder. API-ES: m/z 402 [M+H]+, rt 2.52 min.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([CH2:10][C:11]([CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>N1C=CC=CC=1.C(O)C>[N:2](=[C:11]([CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(Cc1ccccc1)=NO
Yield: 29.8 %

Procedure:
A mixture of hydroxylamine hydrochloride (9 g.) and a solution of 1-phenyl-3-phthalimidoacetone (23.4 g.) in pyridine/ethanol (80 ml.-80 ml.) was stirred at ambient temperature for 3 days. The resulting solution was concentrated, the residue washed twice with a mixture of toluene and methylene chloride and dried. The residue was purified by column chromatography on activated silica gel using cyclohexane/EtOAc 7:3 v/v as eluant to give 2-oximino-1-phenyl-3-phthalimidopropane (7.35 g.) as a mixture of syn and anti isomers.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:26]=[CH:27][CH:28]=1)[CH3:20]
Reactant: CCOc1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: CCOc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 68.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 540 mg of 3-ethoxyaniline in place of the 2,4-difluoroaniline. 235 mg of N-(3-ethoxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(O)=O.[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.O>[C:15]([NH:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(N)C#N
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C#N)NC(=O)c1ccccc1
Yield: 21.5 %

Procedure:
To a stirred solution of compound ethyl 2-amino-2-cyanoacetate (0.64 g, 5 mmol) in DCM (15 mL) was added a saturate solution of NaHCO3 in water (15 mL). With vigorously stirring, benzoyl chloride (0.84 g, 6 mmol) was added. The reaction mixture was stirred at ambient temperature for additional 30 min at which time it was extracted with DCM (3×15 mL). Combined organic layers were washed with brine (20 mL) and dried over Na2SO4, filtered, concentrated in vacuo. Resulted residue was purified by silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl 2-benzamido-2-cyanoacetate (0.25 g, 22%) as white solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 7.83-7.85 (m, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.49 (t, J=7.5 Hz, 2H), 7.02 (d, J=7.0 Hz, 1H), 5.72 (d, J=7.5 Hz, 1H), 4.40 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 233 [M+H+].
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1.ClC[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:32][CH2:31][CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH:23]([CH3:22])[CH3:33])[CH2:29][CH2:28]3)[CH:13]=2)[N:8]=[C:7]([C:16]#[N:17])[N:6]=1
Reactant: CC(C)(C)CNc1nc(C#N)nc2ccc(O)cc12
Reactant: O=C([O-])[O-]
Reactant: CCCN1CCN(CCCCl)CC1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(CCCOc2ccc3nc(C#N)nc(NCC(C)(C)C)c3c2)CC1

Procedure:
4-(2,2-Dimethyl-propylamino)-6-hydroxy-quinazoline-2-carbonitrile (0.31 mmol), 1-(3-chloro-propyl)-4-propyl-piperazine (0.62 mmol) and cesium carbonate (3.1 mmol) are stirred in DMF (3 ml) at RT for 20 hours. Water is added until a clear solution is formed. Then more water is added until the solution gets turbide. The precipitate formed is filtered off, washed with water and dried (vacuum). A powder with mp. 103-105° C., Rf=0.4 (CH2Cl2/MeOH=9:2) is obtained.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7](=[O:20])[CH2:6]1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:3][CH2:4][CH:5]1[CH2:9][N:8]([C@@H:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:7](=[O:20])[CH2:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1CC(CO)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)OC(C)(C)C)N1CC(COCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37.1 %

Procedure:
In a 100 ml 3 necked flask, fitted with magnetic stirrer and reflux condenser under inert atmosphere, 1.1 g (60%, 27.5 mmoles, 1.1 eq) of sodium hydride are suspended in 60 ml of DMF and the mixture cooled down to 0° C. 6.37 g (24.8 mmoles, 1 eq) of tert-butyl(2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 in 10 ml of DMF are added cautiously. After 10 min, 3.3 ml (4.75 g, 27.8 mmoles, 1 eq) of benzyl bromide in 10 ml of DMF are added, and stirring continued for 30 min at 0° C., followed by 3 hours at room temperature. The mixture is concentrated to dryness, the residue is suspended in brine/CH2Cl2, decanted and extracted with CH2Cl2. The combined organic phases are dried over MgSO4, concentrated to dryness and the residue is purified by Prep LC (1 kg SiO2, hexane/MTBE, 40:60→0:100) to give 3.2 g of a mixture of t-Bu and Benzyl esters in two fractions, 37% total yields. It is used as such for the next step 7.3.1.b. 1H NMR (250 MHz, (CDCl3): 0.85 (t, 3H), 1.44 (s, 9H), 1.55-1.95 (m, 2H), 2.10 (dd, 1H), 2.45 (dd, 1H), 2.55-2.70 (m, 1H), 3.45-3.55 (m, 1H), 4.40 (dd, 1H), 4.55 (s, 2H), 7.20-7.40 (m, 5H).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([C:7]([F:10])([F:9])[F:8])=O)=O.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].C(C1C(=O)NC(C)=CC=1C)#N.C(C1C(=O)NC(C)=C(C)C=1C)#N.C(CC(=O)C)(=O)C.CC(C(=O)C)C(=O)C>>[C:11]([C:13]1[C:14](=[O:15])[NH:16][C:2]([CH3:1])=[CH:4][C:5]=1[C:7]([F:10])([F:9])[F:8])#[N:12]
Reactant: N#CCC(N)=O
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: CC(=O)C(C)C(C)=O
Agent: Cc1[nH]c(=O)c(C#N)c(C)c1C
Agent: Cc1cc(C)c(C#N)c(=O)[nH]1
Solvent: CC(=O)CC(C)=O
Product: Cc1cc(C(F)(F)F)c(C#N)c(=O)[nH]1

Procedure:
3-Cyano-6-methyl-4-trifluoromethylpyrid-2-one was prepared from 1,1,1-trifluoroacetylacetone and cyanoacetamide following the procedure of Kametani and Sato (Yakugaku Kenkyu 34, 117, 1962). 3-Cyano-4,6-dimethylpyrid-2-one and 3-cyano-4,5,6-trimethylpyrid-2-one were similarly prepared from acetylacetone and cyanoacetamide, and 3-methylpentan-2,4-dione and cyanoacetamide respectively.