Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[CH:5]#[CH:6].[Cl-].[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)(Cl)(Cl)Cl>[Cl:1]/[CH:5]=[CH:6]/[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCO
Reactant: [Cl-]
Reactant: C#C
Agent: [Al+3]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(=O)/C=C/Cl

Procedure:
To a slurry of 233.5 g. (1.75 moles) of aluminum chloride in 390 ml. of carbon tetrachloride, saturated with acetylene and cooled in an ice bath, is added over 20 minutes 201.9 g. (1.50 moles) of hexanol chloride. After the addition is complete, acetylene is bubbled into the mixture as rapidly as it is absorbed and for 1 hour after absorption becomes slow. The mixture is poured onto 1700 g. of ice and 720 ml. of saturated brine. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are washed with saturated brine, dried (Na2SO4) and evaporated. The residual oil is combined with 10 g. of hydroquinone and distilled to yield a colorless oil, b.p. 51°-52° C. (0.10 torr).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH3:23][N:24]([CH3:29])[CH:25]1[CH2:28][NH:27][CH2:26]1>C(N(CC)CC)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH:25]([N:24]([CH3:29])[CH3:23])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CN(C)C1CNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1

Procedure:
A mixture of 1.5 g (5.3 mmoles) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.4 g (8 mmoles) of 3-dimethylaminoazetidine dihydrochloride and 6.6 g of triethylamine is heated under reflux in 15 ml of pryidine for 3 hours. It is evaporated, water is added and the resulting mixture is made alkaline with 1N sodium hydroxide, heated, filtered while hot, acidified with acetic acid, and filtered. After washing with water, 1.7 g (88%) of 1-cyclopropyl-6,8-difluoro-7-(3-dimethylamino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 256°-60° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[C@H:17]([NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=O)[CH2:16][CH2:15][S:14](=[O:32])(=[O:31])[CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C([O-])([O-])=O.[K+].[K+].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]2[C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=[N:18][C@@H:17]3[CH2:16][CH2:15][S:14](=[O:32])(=[O:31])[CH2:13][C@@H:12]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc([C@H]2CS(=O)(=O)CC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)OC)cc1)=N[C@@H]1CCS(=O)(=O)C[C@H]21
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of methyl 4-{[(3R,4R)-3-(3-ethoxy-4-methoxyphenyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]carbamoyl}benzoate (22.8 g; compound C4) and K2CO3 (6.82 g) in absolute ACN (200 ml) is added POCl3 (13.6 ml) at 0° C. (ice bath). The suspension is allowed to come to RT within 1 h and is subsequently refluxed at 85° C. for 6 h. Afterwards the mixture is stirred for 12 h at RT under nitrogen atmosphere. The mixture is quenched with water (500 ml) and adjusted to pH7 by addition of 0.4 M NaOH. The ACN is destilled of and to the remaining suspension DCM (500 ml) is added. The pH value is adjusted to 8.1 by addition of aqueous sodium hydroxide solution (0.4 M) and saturated aqueous solution of sodium bicarbonate and the mixture is stirred at RT for 12 h. The organic layer is separated and the aqueous layer is extracted with DCM (300 ml). The combined organic layers are dried over sodium sulfate, filtered and evaporated in vacuo to dryness. The resulting residue is purified by flash column chromatography [silica gel, eluent system: n-hexane/EtOAc/triethylamine 11/8/1 (v/v/v)] to obtain a crude solid. The residue is treated with DIP (400 ml) and stirred at reflux temperature for 3 h. The suspension is cooled to 0° C. with an ice bath and filtered off. The filter cake is washed with DIP and dried in vacuo at 70° C. to obtain the title compound as a solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([OH:36])([CH3:37])[CH3:35])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 1-amino-2-methylpropan-2-ol (9.30 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.9 min) to provide (R/S)-2-hydroxy-N-(2-hydroxy-2-methylpropyl)-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (20 mg, 0.037 mmol, 52.6% yield): LCMS=503.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.20 (2 H, m), 7.54-7.85 (7 H, m), 5.17 (1 H, s), 3.25 (2 H, s), 1.17 (3 H, s), 1.15 (3 H, s); HPLC peak RT=8.7 min (Method A).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[F:22][C:23]([F:33])([F:34])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccc(C(F)(F)F)c3)CC1)O2

Procedure:
Compound 54 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-(trifluoromethyl)benzoyl chloride and conditions outlined in procedure N. M.p.=165-166° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.70-7.98 (m, 7H), 7.57 (m, 1H), 4.40 (m, 1H), 3.55 (brm, 2H), 3.30 (m, 1H), 3.11 (s, 2H), 2.10 (m, 1H), 1.85 (m, 3H); LCMS: 474 [M+H].
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]2)[CH2:2]1.[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1)[CH3:14]
Reactant: COC(=O)N1CCCC2(CO2)C1
Reactant: CCN
Product: CCNCC1(O)CCCN(C(=O)OC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.3 g (54.3 mmol) of methyl 5-aza-1-oxaspiro[2,5]octane-5-carboxylate are added dropwise to 50 ml of ethylamine solution (50% strength in water) and the mixture is stirred overnight at room temperature. It is then concentrated and the residue is distilled.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:10]([CH3:12])=O)=[C:7]([CH3:9])[N:8]=1)[CH2:2][CH3:3].[C:13](OCC)(=[O:16])[NH:14][NH2:15]>C(O)(=O)C.C(O)CCC>[CH3:12][C:10]1[C:6]2[N:5]([C:4]([CH2:1][CH2:2][CH3:3])=[N:8][C:7]=2[CH3:9])[C:13](=[O:16])[NH:14][N:15]=1
Reactant: CCCc1nc(C)c(C(C)=O)[nH]1
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCCc1nc(C)c2c(C)n[nH]c(=O)n12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 59.7 g. of methyl 2-n-propyl-4-methyl-5-imidazolyl ketone, 41.14 g. of ethyl carbazate, 200 ml. of n-butanol and 4 drops of glacial acetic acid is warmed until solution is complete and then heated under reflux for 5 hours. The solution is concentrated in vacuo to an oily residue, 250 ml. of diphenyl ether are added and the resulting solution is heated with stirring in an oil bath for 30 minutes after the start of gas evolution. The temperature is maintained as closely as possible to the point at which gas evolution starts (150°-250° C.). The reaction is removed from the oil bath, cooled to 50° C. and diluted with 1-2 volumes hexane. The product is collected, washed with petroleum ether and then dissolved in 200 ml. of chloroform. This solution is filtered through 250 ml. of Magnesol® followed by an 800 ml chloroform wash. The filtrate is concentrated in vacuo and the residue is recrystallized from 250 ml. of ethyl acetate, giving 48.2 g. of the desired product as off-white crystals, m.p. 154°-155° C.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]=[C:15]([O:24][CH2:25][C:26]([O:28]C)=[O:27])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.[Li+].[OH-]>CCO.O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]=[C:15]([O:24][CH2:25][C:26]([OH:28])=[O:27])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:23])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: COC(=O)COc1nc([C@H](C)Nc2ncnc3[nH]cnc23)cc2cccc(Cl)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(OCC(=O)O)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of (S)-methyl 2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)acetate 127 (200 mg, 0.47 mmol, 1.0 eq) in EtOH (5 mL) and H2O (2 mL), LiOH (78 mg, 3.25 mmol, 6.9 eq) was added in one portion. The resulting mixture was stirred at 60° C. for 2 h and then concentrated in vacuo. The residue was suspended in ice-water (15 mL) and the resulting mixture was neutralized with acetic acid at 0-5° C. to adjust pH to 7-8. The precipitate was collected by filtration and dried in vacuo to afford the product (S)-2-(3-(1-(9H-purin-6-ylamino)ethyl)-8-chloroisoquinolin-1-yloxy)acetic acid 128. ESI-MS m/z: 399.0 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O.CN(C)CCCN=C=NCC.Cl.[C:32]([CH2:34][C@@H:35]1[CH2:43][C@@H:42]2[C@@H:38]([CH2:39][NH:40][CH2:41]2)[C@@:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:51][CH3:52])([OH:44])[CH2:36]1)#[N:33]>ClCCl.O.OC1C2N=NNC=2C=CC=1>[C:32]([CH2:34][C@@H:35]1[CH2:43][C@@H:42]2[C@@H:38]([CH2:39][N:40]([C:17](=[O:19])[CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH3:8])[CH2:41]2)[C@@:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:51][CH3:52])([OH:44])[CH2:36]1)#[N:33]
Reactant: COc1ccccc1CC(=O)O
Reactant: COc1ccccc1[C@]1(O)C[C@H](CC#N)C[C@H]2CNC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3OC)[C@@H]2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32.5 %

Procedure:
1.82 cm3 of triethylamine, 2.0 g of 2-methoxy-phenylacetic acid, 25 mg of hydroxybenzotriazole hydrate and 2.54 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide are added to a solution of 3.96 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 60 cm3 of dichloromethane. The reaction mixture is stirred at room temperature for 20 hours, washed with 50 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica gel column (particle size 0.06-0.20 mm, diameter 3.6 cm, height 30 cm) under a pressure of 0.5 bar of nitrogen with ethyl acetate, collecting fractions of 100 cm3. Fractions 6 to 16 are concentrated to dryness under reduced pressure (2.7 kPa), the residue is recrystallized from ethyl acetate and then from ethanol, and the crystals are filtered, washed with a little ethanol and ethyl ether, drained and then dried under reduced pressure (2.7 kPa). 1.7 g of (3aS, 4S, 6S, 7aR)-6-cyanomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl) acetyl]-perhydroisoindol-4-ol are obtained in the form of white crystals. M.p.K =160° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:14][C:15]([O:17]C(C)=O)=O.[N+:21]([O-])([OH:23])=[O:22].[OH-].[NH4+]>C(Cl)Cl.O.OS(O)(=O)=O>[N:1]1([C:6]2[CH:11]=[C:10]([N+:21]([O-:23])=[O:22])[C:9]([NH:12][C:15](=[O:17])[CH3:14])=[C:8]([CH3:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-n2ccnc2)ccc1N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1c(C)cc(-n2ccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 41 %

Procedure:
To a solution of 4-imidazol-1-yl-2-methyl-phenylamine (1 g, 5.78 mmol) in CH2Cl2 (20 mL) was added Ac2O (0.7 mL, 7.28 mmol) at 0° C. The reaction mixture was stir at room temperature for 14 h and diluted with water. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to give a white solid. The white solid was suspended in H2SO4 (conc.) (15 mL). Then HNO3 (conc.) (0.312 mL) was added to the suspension at 0° C. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 4 h. After cooling to −10° C., the reaction mixture was neutralized with ammonium hydroxide and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (1:9:5 MeOH/THF/hexane) to yield the title compound (0.61 g, 41%). 1H NMR (300 MHz, CD3OD) δ 8.11 (1H, s), 7.45–7.56 (2H, m), 7.38 (1H, dd, J=2.4, 8.4 Hz), 7.14 (1H, s), 2.33 (3H, s), 2.18 (3H, s).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CN1CCOCC1.CN(C1C=CC=CN=1)C.[CH3:21][C:22]1[C:26]([C:27](O)=[O:28])=[CH:25][S:24][N:23]=1>ClCCl.C(OCC)(=O)C>[CH:1]1([NH:4][C:27]([C:26]2[C:22]([CH3:21])=[N:23][S:24][CH:25]=2)=[O:28])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1nscc1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Cc1nscc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
At -5° C., 3.7 g (65.0 mmol) of cyclopropylamine, 18.7 g (185.0 mmol) of methylmorpholine, 2.0 g (16.7 mmol) of dimethylaminopyridine and 43.5 g of a 50% strength solution of propanephosphonic anhydride in dichloromethane (=68.4 mol) were dripped one after the other into 7.2 g (50.0 mmol) of 3-methyl-isothiazole-4-carboxylic acid in 200 ml of dichloromethane, and the mixture was stirred for 12 hours at room temperature. The solvent was stripped off under reduced pressure, and the residue was taken up in 250 ml of ethyl acetate and extracted twice with saturated sodium bicarbonate solution and once with 5% strength citric acid solution, once with saturated sodium carbonate solution and once with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and the solvent was stripped off under reduced pressure. Yield: 84%; m.p.: 106°-108° C.
Reaction SMILES: FC1C=CC=C(F)C=1CN1CC[N:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13](=[O:32])[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:15]3=[O:20])CC1.C(N1CCNCC1)(OC(C)(C)C)=O.F[C:52]1[CH:59]=[CH:58]C=C(F)[C:53]=1[CH2:54]Br.C([O-])([O-])=O.[K+].[K+].[CH3:67][CH2:68][N:69]([CH:73]([CH3:75])[CH3:74])[CH:70]([CH3:72])[CH3:71]>>[CH2:68]([N:69]1[C@@H:73]([CH3:75])[CH2:74][N:8]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[C:13](=[O:32])[N:14]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[C:15]3=[O:20])[CH2:71][C@H:70]1[CH3:72])[C:67]1[CH:58]=[CH:59][CH:52]=[CH:53][CH:54]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(CN2C(=O)c3cccc(N4CCN(Cc5c(F)cccc5F)CC4)c3C2=O)cc1OC
Reactant: Fc1cccc(F)c1CBr
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN2C(=O)c3cccc(N4C[C@@H](C)N(Cc5ccccc5)[C@@H](C)C4)c3C2=O)cc1OC

Procedure:
Compound 42 was prepared by the methods described in Example 1 for the synthesis of Compound 16, substituting 2,6-dimethylpiperazine (26 mg) for 1-Boc-piperazine in Example 1, Step C; and substituting benzylbromide (0.05 mL) for 2,6-difluorobenzylbromide and K2CO3 (0.09 g) for DIEA in Example1, Step D. Compound 42 was isolated as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.51-7.87 (m, 7 H), 7.10 (d, J=8.2 Hz, 1 H), 6.91-6.94 (m, 2 H), 6.76 (d, J=8.2 Hz, 1H), 4.70 (s, 2 H), 4.62 (s, 2 H), 3.85 (s, 3 H), 3.83 (s, 3 H), 3.71-3.75 (m, 2 H), 3.43-3.52 (m, 4 H), and 1.71 (d, J=5.9 Hz, 6 H); MS (ES+) 500 (M+1); Anal. Calcd for C30H33N3O4.1.67 CF3CO2H.0.3H2O: C, 57.58; H, 5.11; N, 6.04; F, 13.69; H2O, 0.78. Found: C, 57.24; H, 5.08; N, 6.27; F, 13.33; H2O, 0.45.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:6](=[O:23])[NH:7][C:8](=[O:22])[NH:9][C:10]=1[CH:11](C#N)[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[CH3:4].[CH:24]1([CH2:29]Br)[CH2:28][CH:27]=[CH:26][CH2:25]1.[O:31]=O>CN(C)C=O.O>[CH:24]1([CH2:29][N:9]2[C:10]([C:11](=[O:31])[C:12]3[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:5]([CH2:3][CH3:4])[C:6](=[O:23])[NH:7][C:8]2=[O:22])[CH2:28][CH:27]=[CH:26][CH2:25]1
Reactant: BrCC1CC=CC1
Reactant: O=O
Reactant: CCc1c(C(C#N)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CC=CC2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
48 mg of 60% sodium hydride (1.20 mmol) was slowly added to 0.28 g of 5-ethyl-6-(α-cyano-3,5-dimethylbenzyl)-2,4-pyrimidinedione (1.0 mmol) dissolved in 10 ml of dimethyl formamide, and the mixture was stirred at room temperature for one hour. Then, 0.32 g of (cyclopent-3-en-1-yl)methyl bromide (2.0 mmol) was added to the resulting mixture and stirred at the temperature of 50˜60° C. for 48 hours with injection of oxygen. After cooling, 20 ml of distilled water was added to the resulting product, and extracted with 20 ml of ethyl acetate (2×). The obtained extract was dried with anhydrous magnesium sulfate and concentrated under the reduced pressure. Then, the concentrated residue was separated and purified with column chromatography (hexane:ethyl acetate=2:1) to obtain 0.23 g of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].[O:23]1[C:25]2([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:24]1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:24][C:25]3([OH:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:19][CH2:18]2)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: C1CCC2(CC1)CO2
Reactant: Cc1c(Cl)cc(C(=O)NCC2CCNCC2)c(=O)n1C(C)C
Solvent: CO
Product: Cc1c(Cl)cc(C(=O)NCC2CCN(CC3(O)CCCCC3)CC2)c(=O)n1C(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of 5-chloro-1-isopropyl-6-methyl-2-oxo-N-(piperidin-4-ylmethyl)-1,2-dihydropyridine-3-carboxamide as prepared in Example 6(2) (484 mg, 1.49 mmol) and 1-oxaspiro[2.5]octane (200 mg, 1.78 mmol, prepared according to Blake, Alexander J et al., J. Chem. Soc. Dalton Trans., 1998, 14, 2335) in methanol (5 mL) was stirred at 50° C. for 16 h. Then, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 751 mg (99%) of the title compound as a white solid.
Reaction SMILES: CO.[CH2:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:4].[S:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([OH:13])(=[O:12])=[O:11].C([O:24][C:25](=O)[CH:26]=[C:27]([NH:31][C:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)OCC)C>C(O)(=O)C>[CH2:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:4].[C:32]([NH:31][C:27]1[NH:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([S:10]([OH:13])(=[O:11])=[O:12])=[CH:19][CH:18]=2)[C:25](=[O:24])[CH:26]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)C=C(NC(=O)c1ccccc1)OCC
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(Nc1cc(=O)n(-c2ccc(S(=O)(=O)O)cc2)[nH]1)c1ccccc1

Procedure:
Into a mixed solution of 50 ml of methanol, 50 ml of triethylamine and 50 ml of glacial acetic acid there was dissolved 18.8 g of p-sulfophenyl hydrazine, to which 26.3 g of ethylβ-benzoylamino-β-ethoxyacrylate was then added. The resulting solution was allowed to stand at room temperature for one week. The crystals which precipitated were collected and recrystallized from methanol; thus, 32 g of pale yellow crystals of the objective compound of a melting point of 275° to 278° C. was obtained.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:32])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(C#N)cc2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(C#N)cc1)C(=O)O

Procedure:
In analogy with Example 1i), 0.50 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(p-cyanophenyl)methyl]dihydrofuran-2-(3H)-one in 19 ml of dimethoxyethane and 10 ml of water is hydrolysed with 4.8 ml of a 1M lithium hydroxide solution to form the title compound: TLC Rf (B)=0.3.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[NH2:18][C:19]([CH:23]([F:25])[F:24])=[CH:20][C:21]#[N:22]>CC(O)C.C(N(CC)CC)C>[F:24][CH:23]([F:25])[C:19]1[NH:18][C:15]([CH3:16])=[C:12]([C:13]#[N:14])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:20]=1[C:21]#[N:22]
Reactant: N#CC=C(N)C(F)F
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)F)N1

Procedure:
A suspension of 3.42 g (15.2 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A) and 7.27 g (60.7 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (20 ml) and triethylamine (0.21 ml) was stirred at reflux temperature overnight. After cooling, the precipitate was collected by filtration and washed twice with cold 2-propanol. The crude product was purified by silica gel chromatography (tert-butyl methyl ether/ethanol gradient, final mixture 94:6 v/v) to yield 0.36 g (7% of th.) of the racemic title compound as a pale yellow solid.