Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.Cl.[NH2:62][C@@H:63]([C@H:83]([OH:85])[CH3:84])[C:64]([NH:66][C:67]1([C:70]2[N:75]=[CH:74][C:73]([C:76]3[C:77]([CH3:82])=[N:78][N:79]([CH3:81])[CH:80]=3)=[CH:72][N:71]=2)[CH2:69][CH2:68]1)=[O:65]>C1COCC1>[CH3:81][N:79]1[CH:80]=[C:76]([C:73]2[CH:74]=[N:75][C:70]([C:67]3([NH:66][C:64]([C@@H:63]([NH:62][C:16]([C:13]4[N:12]5[C@@:8]([CH2:7][C:6]6[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=6)([CH3:29])[C:9](=[O:28])[N:10]([C:19]6[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=6)[C:11]5=[N:15][CH:14]=4)=[O:18])[C@H:83]([OH:85])[CH3:84])=[O:65])[CH2:68][CH2:69]3)=[N:71][CH:72]=2)[C:77]([CH3:82])=[N:78]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
Reactant: Cc1nn(C)cc1-c1cnc(C2(NC(=O)[C@@H](N)[C@@H](C)O)CC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C)cc1-c1cnc(C2(NC(=O)[C@@H](NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)c(F)c(Cl)c3)[C@@H](C)O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask was added (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (0.80 g, 2.18 mmol), TBTU (0.73 g, 2.28 mmol) and Et3N (0.91 mL, 6.54 mmol) and THF (10 mL). The mixture was allowed to stir at RT for 30 min. The mixture was transferred to a separate flask containing (2S,3R)-2-amino-N-{1-[5-(1,3-dimethyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-cyclopropyl}-3-hydroxy-butyramide hydrochloride (1.0 g, 2.18 mmol) in THF (30 mL). The mixture was stirred at RT for 24 h. The mixture was concentrated and purified by silica gel chromatography to provide 1.45 g of the title compound as a white solid following removal of the solvent, m/z=771.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][C:36](O)=[O:37])=[O:33])([CH3:30])([CH3:29])[CH3:28]>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:36](=[O:37])[CH2:35][NH:34][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:33])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH2:25][CH3:26])[N:3]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CO)cc2)nc(N)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)CNC(=O)OC(C)(C)C)cc2)nc(N)n1
Reaction time: 6 h

Procedure:
To a stirred suspension of the title compound of Example 44 (0.400 g, 1.08 mmol), N-(tert-butoxycarbonyl)-glycine (0.227 g, 1.29 mmol) and 4-dimethyl-amino-pyridine (0.184 g, 1.51 mmol) in dichloromethane (20 ml) was added 1-[3-(dimethyl-amine)-propyl]-3-ethyl carboduimide (0.282 g, 1.51 mmol). After stirring for 6 hours, the mixture was purified by flash chromatography on silica gel eluting in ethyl acetate-hexane (2:3) to provide tert-butoxycarbonylamino-acetic acid 4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl ester.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH3:5][O:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1>C1COCC1>[CH3:5][O:6][C:7]1[CH:20]=[CH:19][C:18]2[O:17][C:16]3[C:11](=[CH:12][C:13]([C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)=[CH:14][CH:15]=3)[C:10]([CH:1]=[CH2:2])([OH:27])[C:9]=2[CH:8]=1
Reactant: COc1ccc2oc3ccc(-c4cncnc4)cc3c(=O)c2c1
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC1(O)c2cc(OC)ccc2Oc2ccc(-c3cncnc3)cc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of vinylmagnesium chloride (1.6M solution in THF; 0.82 mL, 1.314 mmol) was added dropwise to a solution of 2-methoxy-7-(pyrimidin-5-yl)-9H-xanthen-9-one (200 mg, 0.657 mmol) in THF (10 mL) at −78° C. After 30 min, the reaction mixture was allowed to warm to −10° C. and was then quenched with saturated aqueous ammonium chloride. The reaction was extracted with EtOAc, and the organic phase was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography to give 2-methoxy-7-(pyrimidin-5-yl)-9-vinyl-9H-xanthen-9-ol as a pale yellow gum.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[C:8](F)=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)(=O)C>CNN>[CH3:1][N:4]1[C:8]2=[N:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:11][CH:12]=[C:7]2[CH:6]=[N:5]1
Reactant: CC(=O)NN=Cc1ccc(N2CCN(C)CC2)nc1F
Agent: CNN
Product: CN1CCN(c2ccc3cnn(C)c3n2)CC1

Procedure:
2-Fluoro-6-(4-methyl-1-piperazinyl)pyridine-3-carboxaldehyde acetylhydrazone (2.30 g, 8.23 mmole) was warmed at 90° C. in 10 mL of methylhydrazine. After 30 minutes the reaction mixture was concentrated under reduced pressure and the resulting solid triturated with water. The product was filtered off and the aqueous filtrate was extracted three times with CH2Cl2. The CH2Cl2 was evaporated and the residual product was combined with the product that had been previously filtered off and the two were recrystallized together from pentane, giving 1.37 g (72%), mp 106°-107° C.
Reaction SMILES: IC.[Br:3][C:4]1[C:5]([Cl:23])=[C:6]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:21])[CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:22])[CH:7]=[CH:8][CH:9]=1.[CH3:24]N(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O>[Br:3][C:4]1[C:5]([Cl:23])=[C:6]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:21])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:24])[C:11]2=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2c(F)cccc2c(=O)n1-c1cccc(Br)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(-c2cccc(Br)c2Cl)c(=O)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Iodomethane (0.102 mL, 1.62 mmol) was added slowly to a mixture of 3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione (300 mg, 0.812 mmol), DMF (5 mL) and Cs2CO3 (529 mg, 1.62 mmol). The mixture was stirred at room temperature for 2 h, then was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-30%), to provide 3-(3-bromo-2-chlorophenyl)-8-fluoro-1-methylquinazoline-2,4(1H,3H)-dione as a yellow solid (280 mg, 90% yield). Mass spectrum m/z 383, 385 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.09 (dq, J=7.8, 0.8 Hz, 1H), 7.79-7.71 (m, 1H), 7.49 (ddd, J=13.9, 8.1, 1.5 Hz, 1H), 7.32-7.29 (m, 2H), 7.29-7.22 (m, 2H), 3.88 (s, 1.5H), 3.86 (s, 1.5H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[N:39][C:40]([CH3:43])=[CH:41][CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
(S)-6-(2-Hydroxy-2-methyl-propyl)-3-{(S)-1-[4-(6-methyl-pyridazin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 3-chloro-6-methyl-pyridazine following a procedure analogous to that described in Example 138 Method 2. Yield: 3.09 g (62% of theory). Mass spectrum (ESI+): m/z=446 [M+H]+.
Reaction SMILES: C([O:8][C:9](=[O:31])[C:10]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)C1C=CC=CC=1.C(O)(=O)C>[Pd].CO>[C:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][C:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])([C:9]([OH:31])=[O:8])[CH2:15][CH2:14]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccccc1CC1(C(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 4-(2-methylbenzyl) N-t-butoxycarbonyl isonipecotic acid benzyl ester (2.36 g, 5.57 mmol), 5% Palladium on charcoal catalyst (250 mg), and glacial acetic acid (3 ml) in methanol (75 ml), was hydrogenated at 51 p.s.i. overnight, in a Parr shaker. The reaction mixture was then filtered through a pad of Celite and the pad washed several times with methanol. The combined filtrates were then concentrated in vacuo to the product, a white solid. 30 mg of this material was recrystallized from toluene to afford fine white crystals m.p. 176°-179° C. dec.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(N(CC)CC)C.Cl[C:17](=[C:22]([Cl:27])[C:23]([F:26])([F:25])[F:24])[C:18]([F:21])([F:20])[F:19]>C(#N)C>[Cl:27][CH:22]([C:17]1([C:18]([F:19])([F:20])[F:21])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)[C:23]([F:26])([F:25])[F:24]
Reactant: Oc1ccccc1O
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2ccccc2O1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
110 g of pyrocatechol were dissolved in 1500 ml of acetonitrile, and 200 g of triethylamine were added. 235 g of 2,3-dichloro-1,1,1,4,4,4-hexafluoro-2-butene were added dropwise to the mixture at 75° C. The mixture was subsequently stirred at 75° C. for 2 hours. 1200 ml of the solvent were then distilled off in vacuo and the residue was taken up in 1500 ml of water. The product was extracted with diethyl ether and the organic phase was washed twice with 10% strength by weight aqueous sodium hydroxide solution and once with water. After drying with magnesium sulphate, the organic phase was concentrated and the residue was subjected to fractional distillation in vacuo. The yield was 258 g (=84% of theory). The boiling point was 63° C. under 12 mbar. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -66.8 and -79.7 ppm. 1H-NMR: 4.71 ppm.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[N:26]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:32]1([NH:31][C:27]2[N:26]=[C:25]([C:15]3[N:11]4[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]4=[N:17][C:16]=3[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:30]=[CH:29][N:28]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: [H][H]
Reactant: Fc1ccc(-c2nc3c(OCc4ccccc4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Yield: 61.1 %

Procedure:
To a solution of 4-[8-(benzyloxy)-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopentylpyrimidin-2-amine (30 mg, 0.063 mmol) in ethanol (2 mL) was added 10% palladium on carbon (4 mg). The mixture was stirred under 10 psi of hydrogen for 3 hours. Additional 10% palladium on carbon (5 mg) was added and the mixture stirred under 15 psi of hydrogen for 1 hour. The catalyst was removed by filtering the mixture through Celite. The filtrate was concentrated and the residue purified by silica chromatography, eluting with 10% acetone in dichloromethane to yield 15 mg (60%) of 3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-8-ol. 1H NMR (CDCl3): δ 9.10 (m, 1H), 8.13 (d, 1H), 7.64 (dd, 2H), 7.15 (t, 2H), 6.86 (m, 2H), 6.41 (d, 1H), 5.27 (d, 1H), 4.38 (m, 1H), 2.13 (m, 2H), 1.73 (m, 6H); MS m/z 390 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([CH:13]=[CH:14][N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1.[CH3:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([C:13]([C:19]4[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=4)=[CH:14][N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: COc1cc2c3c(ccn3CCC2)c1
Reactant: CN1CCCCC1=O
Product: COc1cc2c3c(c1)c(C1=CCN(C)CC1)cn3CCC2

Procedure:
By a method similar to Preparation 11, using 8-methoxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (0.28 g, 1.5 mmol), and N-methylpiperidone (Aldrich, 0.68 g, 6.0 mmol) 0.12 g (27%) of title compound was obtained: 1H NMR (300 MHz, CDCl3): 2.18-22.24 (m, 2H), 2.77 (s, 3H), 2.89-2.97 (m, 4H), 3.21 (t, 2H, J=61 Hz), 3.68-3.49 (m, 2H), 3.85 (s, 3H), 4.10 (t, 2H, J=5.7 Hz), 6.02 (m, 1H), 6.65-6.66 (m, 1H), 7.04-7.06 (m, 2H); MS (ELECTROSPRAY): m/e 283.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O.O>[Br:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:10]=1)[CH:6]=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
To 3-(trifluoromethyl)benzaldehyde (5 gm, 28.72 mmol) in sulfuric acid (13.5 ml) at 60° C., N-bromosuccinimide (6.13 g, 34.45 mmol) was added in 3 portions. After 2 h, the reaction mixture was cooled, diluted with cold water and filtered. Filter cake was washed with hexane. Volatiles were removed under reduced pressure and the crude residue of 3-bromo-5-(trifluoromethyl)benzaldehyde was carried to the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[C:4]([CH2:16]O)[CH:3]=1.C([Mg]Cl)(C)C.CN(C)P(Cl)(N(C)C)=O>O1CCCC1.CN1CC(=O)C=C1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:14][CH:15]=1)[C:6](=[O:7])[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:16]2
Reactant: O=C(NCC(F)(F)F)c1ccc(Br)cc1CO
Agent: CC(C)[Mg]Cl
Agent: CN(C)P(=O)(Cl)N(C)C
Agent: CN1C=CC(=O)C1
Solvent: C1CCOC1
Product: O=C1c2ccc(Br)cc2CN1CC(F)(F)F
Temperature: 5 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a stirred solution of 4-bromo-2-(hydroxymethyl)-N-(2,2,2-trifluoroethyl)benzamide (3.37 g, 10.8 mmol) in anhydrous tetrahydrofuran (50 ml), N-methyl-2-pyrrolinone (20 mL), cooled to 5° C. under a nitrogen atmosphere was added a solution of 2M isopropyl magnesium chloride in anhydrous THF (25 ml) at such a rate to keep the temperature of the reaction mixture under 10° C. After complete addition, approximately 45 minutes, the reaction mixture was stirred at this temperature for an additional 60 minutes, and then at room temperature for 60 minutes. After that time, the reaction mixture was cooled down to 5° C. and a solution of bis(dimethylamino)phosphoryl chloride (1.85 g, 14.1 mmol) was added dropwise. No exotherm was observed and the reaction was heated at reflux for 72 hours once the addition was complete. After this time no starting material was observed by both TLC and LCMS and the reaction mixture was carefully quenched with water, and acidified with 1M aqueous hydrochloric acid. The aqueous was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure to leave a mobile oil which was purified by column chromatography eluting with 20% ethyl acetate/petroleum ether to afford the title compound as a white solid (2.81 g, 88% yield). 1H NMR (DMSO D6, 400 MHz) 4.36-4.43 (2H, m), 4.62 (2H, s), 7.68-7.74 (2H, m) and 7.93 (1H, s); MS (ES+) 296, (ES−) 292.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[N:29]=[CH:28][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:25]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCCOc1ccc(N)cn1
Product: COCCOc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-(2-methoxy-ethoxy)-pyridin-3-ylamine. LCMS calcd for C19H16F3N3O4 (m/e) 407, obsd 408 (M+H).
Reaction SMILES: FC1C(O[C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=3)=[O:10])=C(F)C(F)=C(F)C=1F.[CH:39]1([CH2:42][NH2:43])[CH2:41][CH2:40]1>C1COCC1>[CH:39]1([CH2:42][NH:43][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=3)=[O:10])[CH2:41][CH2:40]1
Reactant: NCC1CC1
Reactant: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)Oc5c(F)c(F)c(F)c(F)c5F)cc4c3)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4[nH]c(C(=O)NCC5CC5)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(6,7-dimethoxy-quinolin-4-yloxy)-1H-indole-2-carboxylic acid pentafluorophenyl ester (0.5 g, above) in 5 mL of THF was added cyclopropylmethylamine (0.175 g, 2.46 mmol, Aldrich) and resulting solution was stirred at RT for 8 h. The mixture was concentrated in vacuo. The residue was diluted with 50 mL of EtOAc and washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (30% to 100% EtOAc/hexane) to afford white solid as desired product. MS (ESI pos. ion) m/z: 418 (M+H). Calc'd Exact Mass for C24H23N3O4: 417.46.
Reaction SMILES: F[C:2](F)(F)[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=O.[CH2:13](Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH:2]=[CH2:13]
Reactant: O=C(N1CCNCC1)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCNCC1
Reaction time: 8 h
Yield: 155.1 %

Procedure:
To a stirred solution of 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (515 mg, 2.83 mmol) in dry CH3CN (6 mL) was added allyl bromide (0.32 mL, 3.7 mmol) and powdered potassium carbonate (0.78 g, 5.65 mmol) and the mixture stirred overnight. The reaction was concentrated under reduced pressure, diluted with CH2Cl2 (30 mL) and water (30 mL) and the aqueous layer extracted with CH2Cl2 (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude di-protected piperazine (0.554 g) which was used without further purification in the next reaction.
Reaction SMILES: CS[C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6].[NH2:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1>CO>[CH3:9][S:8][C:3]([NH:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:14]=[CH:15][CH:16]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CO
Product: CSC(=C[N+](=O)[O-])Nc1cccc(NC(=O)c2sccc2NCc2ccnc3ccccc23)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-bis(methylthio)-2-nitroethylene (1.4 g, 8.33 mmol) in MeOH (75 mL) was added N-(3-Aminophenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (2.1 g, 8.33 mmol) and the mixture was stirred at 85° C. overnight. The reaction mixture was cooled to rt and the yellow precipitate formed was filtered, washed with MeOH, and dried under vacuum to give N-(3-{[1-(methylthio)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide as yellow solid. MS (ES): m/z 492.02 (100) [MH+]; 1H NMR (DMSO-d6, 400 MHz): δ 2.47 (s, 2H), 3.17 (d, J=5.6 Hz, 1H), 5.10 (d, J=5.2 Hz, 2H), 6.78 (s, 1H), 6.81 (d, J=5.2 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 7.35-7.43 (m, 2H), 7.63 (d, J=5.2 Hz, 1H), 7.65-7.72 (m, 2H), 7.77-7.85 (m, 3H), 8.05-8.15 (m, 2H), 8.24 (dd, J=8.0, 7.2 Hz, 1H), 8.42 (d, J=4.0 Hz, 1H), 9.56 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])C)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39](OB(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][C:25]([O:31][CH2:32][CH2:34][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:22])([F:23])[F:21])(=[O:18])=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: OB(O)Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)(OCCCc1ccccc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
329 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-isopropoxypropionate was dissolved in 4 ml toluene. 110 mg of 4-fluorophenylboric acid, 74 mg of tetrakistriphenyl phosphine palladium and 440 mg of potassium carbonate were added, followed by stirring overnight at 100° C. in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, filtered through Celite and the filtrate was evaporated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (6:1), 262 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-(4-fluorophenyl)phenylpropoxypropionate was obtained.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[NH:14][CH2:13][CH2:12][CH:11]=2)=[CH:6][CH:5]=1.Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[ClH:1].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]3([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[NH:14][CH2:13][CH2:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=CCCNC23CCCCC3)cc1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: Oc1ccc(C2=CCCNC23CCCCC3)cc1

Procedure:
A mixture of 5-(4-methoxyphenyl)-1-azaspiro[5.5]undec-4-ene hydrochloride (1.0 g), glacial acetic acid (20 ml) and hydrobromic acid (48%, 20 ml) was heated under reflux for 6.5 hours then allowed to cool. The mixture was neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution and the product extracted into ether (3×100 ml). The extracts were combined, dried over magnesium sulphate and the solvent removed in vacuo to give a solid which was purified via flash chromatography over silica using toluene/triethylamine (4:1) as eluent. Appropriate fractions were combined, the solvents were removed in vacuo, and the resulting product was dissolved in ether. The solution was filtered, and the filtrate cooled in ice and saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ether and dried in vacuo at ambient temperature to give 5-(4-hydroxyphenyl)-1-azaspiro[5.5]undec-4-ene hydrochloride as a white solid. Yield 0.7 g, mp 285°-295° C.