Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]([CH3:33])[C@H:8]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:31]#[N:32])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:31]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:17]=2)[C:22]([OH:23])=[C:13]([C:11]([NH:10][C@H:8]([CH3:9])[C@H:7]([CH3:33])[C:6]([OH:34])=[O:5])=[O:12])[N:14]=1)#[N:32]
Reactant: C[C@H](C(=O)OC(C)(C)C)[C@@H](C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C(=O)O)[C@@H](C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of (2S,3R)-3-[(1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2-methyl-butyric acid tert-butyl ester (32 mg, 0.069 mmol) in CH2Cl2 (3 mL) was added trifluoroacetic acid (2 mL) at 0° C., and the mixture was stirred at r.t. for 2 h. The mixture was concentrated in vacuo, and the resulting residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a pale pink solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20])[CH:15]=O.Cl>CC(O)C>[OH:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:10])[CH3:9])[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[C:19]=1[OH:20]
Reactant: CC(=O)Cc1ccccc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution containing 2.68 g of 3-phenyl-2-propanone and 3.66 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 80 ml of 2-propanol was saturated with hydrogen chloride gas at 20° C. The mixture was stirred for 4 h at room temperature, filtered and washed with 2-propanol. The product was recrystallized from methanol. Yield 1.34 g, mp 170°-176° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[C:11]4[N:19]([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[C:18]([CH2:26][CH2:27][CH3:28])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[N:31](CCCCN1C2C3C=CC=CC=3N=CC=2N=C1CCC)C(=O)C>>[NH2:31][C:13]1[C:12]2[N:17]=[C:18]([CH2:26][CH2:27][CH3:28])[N:19]([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][C:15]=2[N:14]=1
Reactant: CCCc1nc2cnc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=O
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Product: CCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)=O

Procedure:
The general method described in Part G of Example 6 was followed using 5-(7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one (1.0 g, 2.69 mmol) in lieu of N-methoxy-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide. Recrystallization from hot methanol and water afforded 0.1815 g of 5-(4-amino-7-phenyl-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one as a tan powder, mp 202-204° C. MS (APCI) m/z 387.1 (M+H+); Anal. calcd for C24H26N4O 0.66H2O: C, 72.36; H, 6.91; N, 14.06. Found: C, 64.95; H, 7.78; N, 17.92.C24H26N4O 0.66H2O Exact Mass: Theor. Mass: 387.2185 Da. Meas. Mass: 387.2191 Da. Mass Dev. 1.5 ppm.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:10][CH:9]1[C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]#[N:46])[CH2:35][CH2:34]1)=[O:32])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:21][C:18]([Cl:19])([Cl:20])[CH2:17][O:16][C:14](=[O:15])[N:13]([CH:11]1[CH2:10][CH:9]([C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])[CH2:35][CH2:34]2)=[O:32])[NH:8][CH2:12]1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccc(F)cc3F)C(=O)OCC(Cl)(Cl)Cl)CN2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.6 %

Procedure:
A mixture of 2-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-4-[(2,4-difluoro-benzyl)-(2,2,2-trichloroethoxycarbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (4.5 g, 6.4 mmol) and CF3COOH (3.65 g, 32 mmol) were stirred at rt. for 5 h, and then concentrated to give the crude product as dark yellow oil (3.5 g, 5.8 mmol).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH3:26][C:20]1[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:13]2[C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:19]=1
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Yield: 55.7 %

Procedure:
7-Benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (16.11 g, 46.6 mmol), 10% palladium on carbon (4.96 g), and ethanol (380 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen and then filtered. The solids were washed with ethyl acetate, and the filtrate was concentrated. Diethyl ether was added to the residue and a green solid formed. The solid was recrystallized from acetonitrile to give 6.63 g of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol as a beige solid.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][N:15]=2)[C:8]1=[O:28])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][N:15]=2)[C:8]1=[O:28]
Reactant: CC1(C)CN(c2ccc(C#Cc3ccccc3)cn2)C(=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CN(c2ccc(C#Cc3ccccc3)cn2)C(=O)C1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
(100 mg, 0.18 mmol) (3RS)-3-(tert-Butyl-diphenyl-silanyloxy)-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 14, step 6) was dissolved in THF (1 ml) and TBAF (1M in THF) (184 μl, 0.184) was added drop wise at room temperature. The mixture was stirred for 1 hr at 60° C. The reaction mixture was extracted with sat. NaHCO3-solution and two times EtOAc. The organic layers were extracted with water, dryed over Na2SO4, filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired (3RS)-3-hydroxy-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-pyrrolidin-2-one (44 mg, 78% yield) was obtained as a white solid, MS: m/e=307.3 (M+H+).
Reaction SMILES: [O:1]([C:8]1[C:9]2[NH:16][C:15]([CH:17]=[O:18])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:20].[Na+].Cl([O-])=O.[Na+].C(=O)([O-])O.[Na+].Cl>CS(C)=O.O>[O:1]([C:8]1[C:9]2[NH:16][C:15]([C:17]([OH:20])=[O:18])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Reactant: O=P([O-])(O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc2ncnc(Oc3ccccc3)c2[nH]1
Reaction time: 2 h
Yield: 103.7 %

Procedure:
4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbaldehyde (2.17 g) was dissolved in dimethyl sulfoxide (21 mL) and a solution of sodium dihydrogen phosphate (5.45 g) in water (14 mL) was added. A solution of sodium chlorite (2.06 g) in water (14 mL) was added dropwise to this solution, and the mixture was stirred for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was gradually added to the reaction mixture, and the pH of the solution was adjusted to 2-3 with 1N hydrochloric acid. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether and dried to give the title compound (2.40 g) as a white powder.
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].N.[N:7]1C=C(C)[CH:10]=[C:9](C)[C:8]=1[CH3:15]>C(C(C)=O)C>[CH2:9]([C:8]1[CH:15]=[CH:5][C:3]([CH3:4])=[CH:2][N:7]=1)[CH3:10]
Reactant: C=C(C)C=O
Reactant: Cc1cnc(C)c(C)c1
Agent: N
Solvent: CCC(C)=O
Product: CCc1ccc(C)cn1

Procedure:
When the process of the present invention is performed in the form of a fixed bed, the catalyst of the present invention is packed in a reactor and heated to a reaction temperature. Then, the mixture of methacrolein, methyl ethyl ketone, ammonia and optionally an inert gas is supplied in the reactor to proceed the gas phase catalytic reaction while maintaining the suitable reaction temperature. Thus, a reaction product gas containing 2,3,5-collidine and 2-ethyl-5-methylpyridine is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]3[C:9]=2[C:10]([NH2:24])=[N:11][NH:12]3)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>ClCCl>[NH2:24][C:10]1[C:9]2[C:13](=[C:14]([CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:15]=[CH:16][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)=[O:34])=[CH:3][CH:4]=2)[NH:12][N:11]=1
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)c3[nH]nc(N)c23)cc1
Reactant: O=C=Nc1cccc(F)c1
Solvent: ClCCl
Product: Nc1n[nH]c2c(CN3CCOCC3)ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 15G (50 mg, 0.155 mmol) in dichloromethane was cooled to 0° C., treated with 1-fluoro-3-isocyanatobenzene (0.021 mL), stirred at room temperature overnight, and concentrated. The concentrate was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide 24 mg of the desired product as the trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6) δ 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.79 (m, 1H), 6.92 (d, J=7.12 Hz, 1H), 7.16 (m, 1H), 7.32 (m, 1H), 7.42 (m, 3H), 7.52 (m, 1H), 7.63 (d, J=8.81 Hz, 2H), 9.12 (s, 1H), 9.16 (s, 1H); MS (ESI(+)) m/e 461 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)(C)C>[CH2:29]([NH:36][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)=[O:17])=[CH:13][CH:14]=2)[N:5]=[CH:4][N:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(NC(=O)Nc2ccc(Oc3cc(NCc4ccccc4)ncn3)cc2)cc1
Temperature: 70 °C
Reaction time: 21 h

Procedure:
Under N2-atmosphere, a suspension of N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-tert-butylphenyl)-urea (397 mg, 1.00 mmol) and benzylamine (327 μM) in isopropanol (3 ml) is stirred for 21 h at 70° C. Then the reaction mixture is concentrated in vacuo, the residue re-dissolved in saturated NaHCO3 solution and AcOEt, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is dissolved in CH2Cl2 and after addition of SiO2 again concentrated. The resulting powder is put on top of a SiO2-column and eluted with AcOEt/hexane 3:1, yielding the title compound: m.p.: 118-120° C.; 1H-NMR (DMSO-d6): 8.73 (s, HN), 8.62 (s, HN), 8.13 (s, 1H), 7.84 (s, HN), 7.46 (d, 2H), 7.35 (d, 2H), 7.30 (m, 4H), 7.28 (m, 2H), 7.24 (m, 1H), 7.03 (d, 2H), 5.78 (s, 1H), 4.49 (s, 2H), 1.26 (Me3C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])[C:5]([N+:15]([O-])=O)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32].[O-]S(S([O-])=O)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.CCOC(C)=O>[NH2:15][C:5]1[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[N:7][C:2]([NH:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=2)=[N:3][CH:4]=1
Reactant: CC(=O)NCCNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)NCCNc1nc(NCc2ccc(Cl)c(Cl)c2)ncc1N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of N-(2-(2-chloro-5-nitropyrimidin-4-ylamino)ethyl)acetamide as prepared in Example 1A (100 mg, 0.39 mmol) in THF (5 mL) was added 80 μL of N,N-diisopropylethylamine followed by of 3,4-dichlorobenzylamine. The mixture was stirred at 60° C. for 16 hours. The mixture was then diluted with 5 mL of THF and a solution of 0.6 g of Na2S2O4 (85% tech. grade, 2.9 mmol) and 0.9 g of Na2CO3 (8.5 mmol) in 10 mL of water was added. The mixture was stirred at 60° C. for 10 h and allowed to cool to room temperature. The mixture was diluted with 30 mL of EtOAc and washed with 20 mL of saturated NaHCO3 solution and 20 mL of brine. The combined organic phase was dried over MgSO4 and concentrated to provide crude N-{2-[(5-amino-2-{[(3,4-dichlorophenyl)methyl]amino}pyrimidin-4-yl)amino]ethyl}acetamide which was used the without further purification. m/z (ESI) found 369.2 [M+H+].
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([F:43])[CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1.N1(S(N)(=O)=O)CCC1.[CH3:52][O:53][CH:54]1[CH2:57][N:56]([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:55]1>CO>[CH:24]1([CH2:29][O:30][C:31]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:34]([C:35]([NH:61][S:58]([N:56]3[CH2:57][CH:54]([O:53][CH3:52])[CH2:55]3)(=[O:60])=[O:59])=[O:37])=[C:33]([F:43])[CH:32]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCCC2)cc1F
Reactant: COC1CN(S(N)(=O)=O)C1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Solvent: CO
Product: COC1CN(S(=O)(=O)NC(=O)c2cc(C3CC3)c(OCC3CCCC3)cc2F)C1

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(cyclopentylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and azetidine-1-sulfonamide with 3-methoxyazetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.04 g, 11%) after trituration in methanol: 1H NMR (300 MHz, DMSO-d6) δ 11.70 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.96 (d, J=13.0 Hz, 1H), 4.24-4.11 (m, 3H), 3.99-3.91 (m, 4H), 3.17 (s, 3H), 2.43-2.26 (m, 1H), 2.08-1.95 (m, 1H), 1.86-1.73 (m, 2H), 1.69-1.50 (m, 4H), 1.45-1.31 (m, 2H), 0.93-0.85 (m, 2H), 0.71-0.64 (m, 2H); MS (ES−) m/z 425.2 (M−1).
Reaction SMILES: [C:1](Cl)(=[O:17])[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([O:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:9])[CH3:8])=[O:3].C([O-])(O)=[O:20].[Na+]>O>[C:2]([O:4][CH:5]([CH3:16])[CH2:6][C:7]([O:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:9])[CH3:8])(=[O:3])[C:1]([OH:17])=[O:20]
Reactant: O=C([O-])O
Reactant: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)Cl
Agent: [Na+]
Solvent: O
Product: CC(CC(C)(C)OOC(C)(C)C)OC(=O)C(=O)O
Temperature: 25 °C

Procedure:
A 50 mL Erlenmeyer flask equipped with a magnetic stirrer and a thermometerwas charged with 50 g of water and 2.8 g (10 mmoles) of 3-t-butylperoxy-1,3-dimethylbutyl chlorooxalate and the resulting mixture was stirred at room temperature. No reaction appeared to be occurring, therefore, 2.1 g (23 mmoles) of NaHCO3 was added. Gas evolution occurred and the organic liquid dissolved in the aqueous phase at room temperature. The pH of the solution was about 9. The aqueous solution was washed twice with 30 mL portions of MTBE in order to remove neutral impurities. Then the aqueous solution was acidified with 20 g (27 mmoles) of aqueous 5% HCl solution and a yellow organic liquid formed. The resulting mixture was extracted twice with 30 mL portions of MTBE. The MTBE extracts were combined, washed once with 50 mL of water, dried over 5% by weight of anhydrous MgSO4, and, after separation of the spent desiccant by filtration, the solvent was removed in vacuo leaving 2.2 g (85% of theory, uncorrected) of a clear yellow liquid. An IR spectrum of the product showed an acid OH band at about 3200 cm-1, a very strong carbonyl band at 1740 cm-1 and a peroxide (--OO--) band at about 875 cm-1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[N+:18]([C:13]1[C:12](=[O:15])[NH:11][CH:10]=[C:9]([C:4]2[C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=1)([O-:20])=[O:19]
Reactant: O=c1ccc(-c2ncccc2C(F)(F)F)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]cc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 92 %

Procedure:
To a solution of 3-trifluoromethyl-1′H-[2,3′]bipyridinyl-6′-one (25 g, 0.1 mol) in concentrated sulfuric acid (100 mL) at 0° C., add dropwise a solution of fuming nitric acid (35 mL) and concentrated sulfuric acid (10 mL). Heat the reaction mixture to 70° C. for 1 hour, cool and pour onto ice (500 mL). Filter the mixture and treat the filtrate with 10 M sodium hydroxide until the solution is at pH 4–5. Collect the precipitate by filtration and air dry to give the title compound (26.2 g, 92%) as a white solid.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[H-].[Na+].[S:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH:37]=O)=[CH:30]1.O>CN(C)C=O.C(O)(=O)C>[C:2]([CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:37]/[C:36]1[CH:35]=[C:34]([C:31]2[CH:32]=[CH:33][S:29][CH:30]=2)[CH:41]=[CH:40][CH:39]=1)#[N:3]
Reactant: O=Cc1cccc(-c2ccsc2)c1
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: N#CCCC/C=C/c1cccc(-c2ccsc2)c1
Yield: 95.8 %

Procedure:
44.6 g of 4-cyanobutyl(triphenyl)phosphonium bromide is suspended in 250 ml of dimethylformamide, 4.2 g of 60% oily sodium hydride is added under ice cooling and stirring, the mixture is stirred at that temperature for 30 minutes, 18 g of 3-(3-thienyl)benzaldehyde is added, and the mixture is stirred at room temperature for 20 hours. Water and acetic acid are added to the reaction solution for neutralization, the solvent is distilled off under reduced pressure, and the residue is post-treated in a conventional manner and purified by silica gel column chromatography [Wako gel C-100, 500 g; hexane/ethyl acetate=5/1] to obtain 23.2 g of (E)-3-[3-(5-cyano-1-pentenyl)phenyl]thiophene as colorless oil.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:8].[Cl-].[NH4+]>O1CCCC1>[C:7]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])(=[O:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Methyl magnesium bromide in tetrahydrofuran (1M, 36.9 ml) was added into a solution of benzyl (2S)-2-(N-methoxy-N-methylcarbamoyl)-1-pyrrolidinecarboxylate (3.6 g) in tetrahydrofuran (36 ml) under ice-cooling. After being stirred for 2 hours at the same temperature, the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:1) as an eluent to give benzyl (2S)-2-acetyl-1-pyrrolidinecarboxylate (0.81 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1.[CH3:24][C:25]1[O:29][N:28]=[C:27]([C:30](Cl)=[O:31])[CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:30]([C:27]2[CH:26]=[C:25]([CH3:24])[O:29][N:28]=2)=[O:31])[CH:17]=1
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc1-c1cccc(N)c1
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cn1c(-c2ccccc2)ccc1-c1cccc(NC(=O)c2cc(C)on2)c1
Temperature: 25 °C

Procedure:
To a solution of [2-(3-amino-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid methyl ester (0.1 mmol) in DCM (2 mL) is added 5-methyl-isoxazole-3-carbonyl chloride (0.1 mmol) and triethylamine (0.02 mmol). The reactions are agitated at room temperature over night. The solvent is removed under vacuum and the residues are subsequently dried under high vacuum at 50° C. for 2 h.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][CH2:18][OH:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:17][CH2:18][O:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: OCNc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCNc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a mixture of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamino]methanol (0.10 g, 0.37 mmol) in pyridine (2 mL) was added trimethylacetyl chloride (0.048 g, 0.40 mmol), and the mixture was agitated on an orbital shaker at 60° C. for 4 h. The reaction mixture was cooled, evaporated to dryness, and partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered, and evaporated to yield the title compound (0.078 g, 60% yield) as a white solid: mp 134-135° C.; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=2.5 Hz, 1H), 7.49-7.44 (m, 2H), 7.11-7.03 (m, 2H), 6.17 (bt, J≈7 Hz, 1H), 6.17 (d, J=7.4 Hz, 2H), 5.33 (s, 2H), 1.20 (s, 9H); HPLC-MS m/z 352 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:30]([N:12]1[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:6]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=2)[C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11]1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: O=C(c1ccccc1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 91 %

Procedure:
The compound (0.15 g) obtained in Example 1 and benzoyl chloride (0.060 ml) were reacted and treated in the same manner as in the method described in Example 2 to obtain the title compound as colorless oil (0.16 g, 91%).