Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[O:12][C:11](S)=[N:10][N:9]=1.F[C:17](F)(F)[N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:25]N)=O.F[C:30](F)(F)N1C=CC=C1C(OC)=O.N1C=CC=C1C(OC)=O>>[N:18]12[CH2:22][CH2:21][CH:20]([CH2:30][CH2:17]1)[N:25]([C:11]1[O:12][C:8]([C:4]3[N:3]([C:2]([F:15])([F:14])[F:1])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]=1)[CH2:23][CH2:19]2
Reactant: FC(F)(F)n1cccc1-c1nnc(S)o1
Reactant: NNC(=O)c1cccn1C(F)(F)F
Reactant: COC(=O)c1cccn1C(F)(F)F
Agent: COC(=O)c1ccc[nH]1
Product: FC(F)(F)n1cccc1-c1nnc(N2CCN3CCC2CC3)o1

Procedure:
May be prepared according to Methods A-D from 5-[1-(trifluoromethyl)pyrrol-2-yl]-1,3,4-oxadiazole-2-thiol (Method A), from 1-(trifluoromethyl)pyrrole-2-carbohydrazide (Method B), from methyl 1-(trifluoromethyl)pyrrole-2-carboxylate (Method C), and from methyl 1H-pyrrole-2-carboxylate (Method D).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:17]3[C:18](N)=[N:19][O:20][N:21]=3)[CH3:16])=[CH:11][CH:10]=2)[S:6][CH:7]=1.N([O-])=[O:26].[Na+].OS(O)(=O)=O>CC(O)=O.Cl.O>[F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([C:17]3[C:18]([OH:26])=[N:19][O:20][N:21]=3)[CH3:16])=[CH:11][CH:10]=2)[S:6][CH:7]=1
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nonc1N
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nonc1O
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a cooled solution of 4-[(1R)-1-{4-[(4-(trifluoromethyl)-1,3-thiazol-2-yl)amino]phenyl}ethyl]-1,2,5-oxadiazol-3-amine (0.2 g, 0.56 mmol) in AcOH (5 ml) and 37% HCl (3 ml), a solution of sodium nitrite (44 mg, 0.845 mmol) in water (3 ml) was added dropwise. The resulting reaction mixture was stirred for 30 min, then conc. H2SO4 (0.5 ml) was added and the reaction quenched with a saturated solution of NH4Cl (10 ml); the resulting mixture was extracted with Et2O (3×10 ml) and the collected organic extracts were evaporated under vacuum; the crude was purified by flash chromatography to afford pure 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1,2,5-oxadiazol-3-ol (13) (0.17 g, 0.48 mmol) as a white solid (85%). [α]D=−51 (c=1; CH3OH); 1H-NMR (DMSO-d6): δ 8.25 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.05 (s, 1H), 3.90 (q, 1H, J=7 Hz), 1.75 (d, 3H, J=7 Hz).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1.[CH2:35]([N:39]=[C:40]=[O:41])[CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:35]([NH:39][C:40]([C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([C:40](=[O:41])[NH:39][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1)=[O:41])[CH2:36][CH2:37][CH3:38]
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc(-c2sc3cc(C(=O)NCCCC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 84.6 %

Procedure:
4.47 g (9 mmol) of [6-hydroxy-2-(4-hydroxyphenyl)benzo-[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 250 mL of THF and 4 g (40 mmol) of n-butylisocyanate was added. The reaction mixture, at room temperature and under nitrogen, was allowed to react for 72 hours. The reaction mixture had evaporated by the end of this time and the residue was dissolved in a minimal amount of CHCl3. This solution was chromatographed (HPLC) on a silica gel column, eluted with a linear gradient of CHCl3 to CHCl3 -MeOH (19:1) to afford 4.87 g of the title compound as a tan amorphous powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:11]([C:18]1[O:19]CC(C)(C)[N:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)[O-].[Na+].CN1CCCC1=O>O.C1(C)C(C)=CC=CC=1>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:19])[NH:22]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC1(C)COC(Cc2ccccc2)=N1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccccc1

Procedure:
17.5 g of 2,4-dichlorobenzaldehyde, 18.9 g of 2-benzyl-4,4-dimethyl-2-oxazoline, 1 g of sodium bisulphate, 50 ml of 1-methylpyrrolidin-2-one and 30 ml of xylene are heated at a bath temperature of 170° C., using a water separator, until 2 ml of water have been separated off. 20 ml of solvent are then distilled off at a bath temperature of 220° C., the mixture is stirred under reflux at this temperature for a further 15 minutes and, after cooling, 300 ml of water are added. The precipitate which has separated out is filtered off and washed with water and methanol. Yield: 21.26 g of m. 254°-258° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:9]1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:42])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:30])([F:31])[F:29])=[N:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
To a mixture of 1-(2-chloro-phenyl)-5-[2-(4-methylsulfanyl-phenyl)-pyridin-6-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (9.0 mg, 0.02 mmol) prepared in Example 153 in dichloromethane (1.0 mL), was slowly added meta-chloroperbenzoic acid (77%, 2.0 mg, 0.01 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/1) to give 2.0 mg of the titled compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl.O>CN(C)C=O>[CH3:18][O:19][CH2:20][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:10])([F:11])[F:1]
Reactant: COCCl
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccccc1C(F)(F)F
Reaction time: 1 h

Procedure:
2-trifluoromethylphenol (50.00 g) was dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (85.14 g) and chloromethyl methyl ether (34.7 mL) were added to the solution, and then the mixture was stirred under water cooling for 1 hour. Water was added to the reaction solution, and then the mixture was extracted with n-hexane. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (64.13 g) as a colorless oily substance.
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].[C:7]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=O)[CH3:8].B(F)(F)F.CCOCC>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[CH2:4][S:5][C:7]([CH3:8])([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[S:6]1
Reactant: COC(=O)CCCC(C)=O
Reactant: SCC(S)CS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCCC1(C)SCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (5 g, 0.0355 mol), methyl 4-acetylbutyrate (5.1 g, 0.0355 mol) and boron trifluoride etherate (1 ml) in methylene chloride (125 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 6.5 g (69%) of product.
Reaction SMILES: ClC1C(Cl)=CC(O)=C(OC)C=1.C(C1OC1)Cl.C([O-])([O-])=O.[K+].[K+].[F:23][C:24]([F:42])([F:41])[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][C:34]3[N:35]([C:37](=[O:40])[NH:38][N:39]=3)[CH:36]=2)=[CH:27][CH:26]=1.[Cl:43][C:44]1[C:54]([Cl:55])=[CH:53][C:47]([O:48][CH2:49][CH:50]2[CH2:52][O:51]2)=[C:46]([O:56][CH3:57])[CH:45]=1>CN(C=O)C.O>[Cl:43][C:44]1[C:54]([Cl:55])=[CH:53][C:47]([O:48][CH2:49][CH:50]([OH:51])[CH2:52][N:38]2[C:37](=[O:40])[N:35]3[CH:36]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:41])[F:42])=[CH:26][CH:27]=4)[CH:32]=[CH:33][C:34]3=[N:39]2)=[C:46]([O:56][CH3:57])[CH:45]=1
Reactant: COc1cc(Cl)c(Cl)cc1OCC1CO1
Reactant: O=c1[nH]nc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Agent: COc1cc(Cl)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCC1CO1
Product: COc1cc(Cl)c(Cl)cc1OCC(O)Cn1nc2ccc(-c3ccc(C(F)(F)F)cc3)cn2c1=O
Temperature: 70 °C
Yield: 27.2 %

Procedure:
4,5-dichloro-2-methoxyphenol (200.0 mg, 1.036 mmol), epichlorohydrin (958.6 mg, 10.36 mmol, 10 equiv.) and K2CO3 (1.43 g, 10.36 mmol, 10 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added DMF (3 mL) at ambient temperature. The mixture was heated at 70° C. for 16 hour. To the mixture was added water (30 mL). And then the whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure. Crude product (2-((4,5-dichloro-2-methoxyphenoxy)methyl)oxirane, 248.7 mg, 0.998 mmol, 96.4%) was used for the subsequent step without further purification. 6-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (47.2 mg, 0.169 mmol), 2-((4,5-dichloro-2-methoxyphenoxy)methyl)oxirane (50.5 mg, 0.2028 mmol, 1.2 equiv.) and K2CO3 (46.8 mg, 0.339 mmol, 2.0 equiv.) were placed in a 50 mL round bottomed flask under a nitrogen atmosphere. To the flask were added DMF (3 mL) at ambient temperature. The mixture was heated at 80° C. for 1 hour. The mixture was filtered through Celite and the filtrate was injected to preparative HPLC to give compound 198 as a colorless oil (24.3 mg, 0.0460 mmol, 27.2%). LCMS (EI: 70 eV) 552 (M++2+Na), 551 (M++1+Na), 550 (M++Na), 530 (M++2), 529 (M++1), 528 (M+).
Reaction SMILES: C(=O)([O:7][C:8]1[N:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[C:10]([CH:17]([CH3:19])[CH3:18])[N:9]=1)OC(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:14]([C:12]1[CH:11]=[C:10]([CH:17]([CH3:19])[CH3:18])[N:9]=[C:8]([OH:7])[N:13]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1cc(C(C)C)nc(OC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(C(C)C)nc(O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Tert-butyl 4,6-diisopropylpyrimidine-2-yl carbonate (42 mg) was dissolved in methylene chloride (4 mL). While the solution was cooled with ice, trifluoroacetic acid (1 mL) was added to the solution. The mixture was then stirred at room temperature (20 to 30° C.) for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride: methanol=10:1) to give 8.5 mg (30% yield) of the desired product as a brown amorphous.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CC(N(C)C)=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([NH:1][CH2:12][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: COc1ccc(N)cc1OC
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Reaction time: 8 h
Yield: 66.8 %

Procedure:
In a 50 ml flask, a mixture of 4-aminoveratrole (1.53 g, 10 mmol), 4-formyl-benzoic acid (1.50 g, 10 mmol), dibutyltin dichloride (304 mg, 1 mmol), phenylsilane (2.47 ml, 20 mmol) in anhydrous THF (10 mL) and DMA (10 ml) was stirred overnight. at room temperature. After solvents removal, the crude residue was dissolved in ethyl acetate (100 ml) and then washed with saturated aqueous solution of NaHCO3 (50 ml×3). The combined aqueous layers were acidified with 6% of NaHSO4 to pH=4. The resulting white suspension was filtrated and then the filter cake was washed with water (5 ml×3). The cake was dried over freeze dryer to afford acid (1.92 g, 67%) white solid product. LRMS=288 (MH)+.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22](/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:32])=[CH:13][C:12]=3[F:33])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C[O:37]CC1.C[N+]1([O-])CCOCC1.[OH2:47]>[Os](=O)(=O)(=O)=O>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C@@H:27]([OH:37])[C@@H:28]([OH:47])[CH2:29][CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:32])=[CH:13][C:12]=3[F:33])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC/C=C\c1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1
Reactant: O
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Product: CCC[C@H](O)[C@H](O)c1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1

Procedure:
Firstly, osmium tetroxide (solution in tert.-butanol, 0.1 equiv.) was added to a mixture of 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-((Z)-pent-1-enyl)-2H-isoquinolin-1-one (0.10 g) and THF (10 mL), and then a solution of N-methyl-morpholine-N-oxide (89 mg) in water (1 mL) was added. After 48 hours the reaction mixture was concentrated and the residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 479.60 (C28H34FN3O3); MS (ESI): 480 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[CH3:15][CH:16]([CH3:26])[C:17](=O)[CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:4][C:3]1[NH:5][CH:17]([CH:16]([CH3:26])[CH3:15])[C:18]([C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20])=[C:11]([C:10]2[CH:13]=[CH:14][C:7]([F:6])=[CH:8][CH:9]=2)[N:2]=1
Reactant: CC(C)OC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C1=C(c2ccc(F)cc2)N=C(N)NC1C(C)C
Temperature: 70 °C
Yield: 67 %

Procedure:
Guanidine hydrochloride (12.1 g), 4-Fluorobenzaldehyde (7.0 g), isopropyl 4-methyl-3-oxo-pentanoate (8.9 g) and DMF (150 ml) were charged to a vessel equipped with a condenser and connected to a nitrogen line. The resultant mixture was stirred until a clear solution was obtained. Potassium carbonate (17.5 g) was charged and the mixture heated to 70° C. for 3 hours. The reaction mixture was cooled to ambient temperature, filtered, and the solvents removed by evaporation under reduced pressure. The resultant oil was triturated in water at 80° C. and cooled to give a slurry that was filtered and dried to give isopropyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-1,6-dihydropyrimidine-5-carboxylate in 67% yield.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:48]2[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH:40]3[C:44]([OH:46])([CH3:45])[CH2:43][O:42][CH2:41]3)[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[NH:3][C:4](=[O:7])[O:5][N:55]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:33]2[CH2:34][CH2:35][C@H:36]([O:39][CH:40]3[C:44]([OH:46])([CH3:45])[CH2:43][O:42][CH2:41]3)[CH2:37][CH2:38]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC3COCC3(C)O)CC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OC3COCC3(C)O)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.13 g), sodium hydrogen carbonate (0.22 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-[(4-{trans-4-[(4-hydroxy-4-methyltetrahydrofuran-3-yl)oxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.077 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.025 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.022 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.029 g, 34%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH3:21])[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:19](=[O:20])[N:18]([CH3:21])[C:9]2[N:10]=[C:11]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:12]=[CH:13][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c2cnc(S(C)(=O)=O)nc2n(C)c1=O
Reactant: C1CCNC1
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cnc(N3CCCC3)nc2n(C)c1=O

Procedure:
A stirred mixture of 3.27 g. (0.01 mole) of 7.8-dihydro-5-hydroxy-8-methyl-2-(methylsulfonyl)-7-oxo-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester and 0.71 g. (0.01 mole) of pyrrolidine in 50 ml. of ethanol was heated under reflux for 1 hour. The mixture was cooled and was filtered. The filter cake was recrystallized twice from ethyl acetate to afford 1.1 g. of title product--m.p. 174°-177° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=1[CH3:23])=[N:3][N:4]=[CH:5]2
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: Clc1ccc2c(Cl)nncc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: COCCOC
Product: Cc1cc(F)ccc1-c1nncc2cc(Cl)ccc12
Temperature: 80 °C

Procedure:
A mixture of 1,6-dichlorophthalazine (5.39 g, 27.1 mmol), 4-fluoro-2-methylphenylboronic acid (5.00 g, 32.5 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.950 g, 1.35 mmol), and sodium carbonate (8.61 g, 81.2 mmol) in a 2:1 mixture of DME and EtOH (40 mL) was heated at 80° C. in an oil bath for 18 h. The mixture was cooled to room temperature, diluted with MeOH and filtered through a pad of Celite. The filtrate was concentrated over silica gel and purified using column chromatography (0-25% EtOAc in hexanes) to provide the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 272.8 (M+1).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:15]Br.O>C(O)(=O)C>[C:9]1([C:6]2[S:5][C:4]([C:1]([CH2:2][Br:15])=[O:3])=[CH:8][CH:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(-c2ccccc2)s1
Solvent: CC(=O)O
Solvent: O
Product: O=C(CBr)c1ccc(-c2ccccc2)s1
Reaction time: 0.5 h

Procedure:
A solution of 2-acetyl-5-phenylthiophene (11.7 g, 0.058 mole), described in Examples 1 and 2, in 100 ml of glacial acetic acid is treated dropwise with bromine (9.3 g, 0.058 mole). The mixture is stirred for 1/2 hr, poured into cold water and extracted with chloroform. The extract is washed with water, 5% NaHCO3 and brine, dried (K2CO3) and concentrated to give a yellow solid. The solid is subjected to chromatography on silica gel to give bromomethyl 5-phenyl-2-thienyl ketone (ArCOCHR2Y; Ar is 5-phenyl-2-thienyl, R2 = H and Y = Br); mp 114° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[CH:23]=[N:24][C:25]([N:29]4[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[CH3:35])=[C:26]([CH3:28])[CH:27]=3)[S:21][C:14]=12>>[CH3:34][C:33]1[N:29]([C:25]2[N:24]=[CH:23][C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[CH:27][C:26]=2[CH3:28])[C:30]([CH3:35])=[CH:31][CH:32]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cc1cc(-c2cc3nccc(Cl)c3s2)cnc1-n1c(C)ccc1C
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(-n6c(C)ccc6C)c(C)c5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-5-methyl-pyridin-3-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.71 (s, 1H), 8.17 (s, 1H), 8.08 (d, 1H), 7.77 (s, 1H), 7.30 (m, 2H), 6.95 (d, 1H), 6.58 (d, 1H), 6.11 (s, 1H), 5.84 (s, 2H), 2.40 (s, 3H), 1.99 (s, 3H), 1.91 (s, 6H); RP18-HPLC RT: 6.67 minutes.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].IC[CH2:21][CH2:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26]>>[F:29][C:24]([F:30])([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][CH2:21][CH2:14][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: FC(F)(F)C(F)(F)CCCCI
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Product: C=CCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with diethyl 2-(6-heptenyl)malonate and the 1-iodo-5,5,6,6,6-pentafluorohexane prepared in Example 2, the same procedure as shown in Example 5 was repeated to give ethyl 2-(5,5,6,6,6-pentafluorohexyl)-8-nonenoate.