Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH2:3][CH2:2]1.O>CN(C=O)C>[CH2:3]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH2:3][CH2:2]1)[CH:4]([CH3:12])[CH3:5]
Reactant: NC(=O)C1=Cc2ccccc2NCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN1CCC(C(N)=O)=Cc2ccccc21
Temperature: 50 °C
Reaction time: 96 h
Yield: 38.4 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(1-trityl-1H-imidazol-4-yl)methyl]thio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.50 g) in DMF (10 ml), 2-iodinated ethanol (0.25 ml) was added at room temperature, and the mixture was stirred at 50° C. for 4 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:49→1:19), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[1-(2-hydroxyethyl)-1H-imidazol-5-yl]methyl]thio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 438) (124.6 mg) as yellow amorphous.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH2:2][CH3:3].[F:12][C:13]([F:23])([F:22])[C:14](=O)[CH2:15][C:16](OCC)=[O:17]>[Cl-].[Zn+2].[Cl-].O>[OH:11][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:9]2[C:8]([C:14]([C:13]([F:23])([F:22])[F:12])=[CH:15][C:16](=[O:17])[O:10]2)=[CH:7][CH:6]=1
Reactant: CCCc1c(O)cccc1O
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Yield: 77 %

Procedure:
2-propylbenzene-1,3-diol (J. Med. Chem., 38, pp 4411-4432, 1995) (3.65 g, 24.0 mmol), zinc chloride (3.60 g, 26.4 mmol), and ethyl 4,4,4-trifluoroacetoacetate (4.86 g, 26.4 mmol) were stirred overnight at 110° C. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The obtained residue was purified using silica-gel chromatography (chloroform) and then recrystallized with chloroform, and 5.01 g of the title compound (yield 77%) was obtained as pale-brown crystalline powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:11]([O-])=O)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH2:4][CH2:3]1
Reactant: CN1CCc2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CN1CCc2c(N)cccc21
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
A solution of Intermediate 70 (0.50 g) in ethanol (30 ml) was added to 10% palladium on carbon (0.050 g) and the mixture was stirred under an atmosphere of hydrogen for 20 min. The mixture was filtered through ‘hyflo’ filter aid and the solvent removed in vacuo to give the title compound as a brown oil (0.405 g).
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22]CCCC(OC)=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]CCO>N1C=CC=CC=1>[CH3:50][O:51][C:52](=[O:65])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:22][CH2:21][O:20][C:1]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCCCCCCCO
Reactant: COC(=O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 72 h
Yield: 40 %

Procedure:
The synthesis procedure of 15a was followed. Trityl chloride (1412 mg, 5.1 mmol), 14c (583 mg, 2.5 mmol), and pyridine (10 mL) were used and the reaction was prolonged to 3 days. The filtration step was omitted, instead the crude material was purified by flash column chromatography (10% EtOAc in hexanes) yielding 477 mg (40%) of a pale yellow oil 15c. 1H-NMR (400 MHz, CDCl3, δH ppm): 7.44 (6H, m, p-Ar), 7.28 (6H, m, m-Ar), 7.21 (3H, m, o-Ar), 3.66 (3H, s, CO2CH3), 3.03 (2H, t, 3JH—H=6.6 Hz, H)—CH2), 2.29 (2H, t, 3JH—H=7.5 Hz, CH2CO2), 1.55-1.65 (4H, m, 2CH2), 1.10-1.39 (14H, m, 7CH2). HRMS (EI): m/z calcd 472.2977 (C32H40O3), found 472.2968 [M]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][CH2:22][CH:23]([OH:25])[CH3:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:18][C:19]([NH:21][CH2:22][C:23](=[O:25])[CH3:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)CNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
To a solution of oxalyl chloride (37 mL, 2 M solution in CH2Cl2, 74 mmol) in CH2Cl2 (60 mL) at −78° C. under argon was added DMSO (7.8 g, 100 mmol). The mixture was stirred at −78° C. for 20 min, and to this mixture was added a solution of 1-benzyloxycarbonylamino-2-propanol (2) (12.9 g, 61.8 mmol) in CH2Cl2 (40 mL). The mixture was stirred at −78° C. for 1 h, and then Et3N (21 mL) was added to the mixture. The mixture was warmed to room temperature and washed with 1 N hydrochloric acid followed by aqueous sodium bicarbonate solution. The organic solution was dried over Mg2SO4 and concentrated to afford 1-benzyloxycarbonylamino-2-propanone (10.2 g, 81%) as a solid, which was used without further purification in the next step. 1H NMR (CDCl3): □ 7.32 (m, 5H), 5.50 (s, 1H), 5.06 (s, 2H), 4.07 (s, 2H), 2.1 (s, 3H)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li]CCCC.[C:19]([S:23]([N:25]=[CH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:24])([CH3:22])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:26]([NH:25][S:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Reactant: Ic1ccccc1-c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of commercially available 2-iodo-1,1′-biphenyl (617 mg; 2.20 mmol) in anh. THF (5 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.50 ml; 2.40 mmol). The resulting solution was further stirred at −78° C. for 10 min. A solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (514 mg; 2.20 mmol) in anh. THF (2 ml) was added to the cooled reaction mixture, and stirring at −78° C. was continued for 10 min., and then at −20° C. for 2 h. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (15 ml), Et2O (30 ml) and water (15 ml). The separated organic layer was then washed with brine (15 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=7/3) afforded methyl 5-([1,1′-biphenyl]-2-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow oil. LC-MS (conditions A): tR=0.85 min.; [M+H]+: 387.83 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][CH2:25][O:26][CH2:27][CH2:28]Cl>CN(C=O)C>[O:26]1[CH2:27][CH2:28][N:1]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:24][CH2:25]1
Reactant: ClCCOCCCl
Reactant: CC(C)n1nc(Br)c2ccc(N)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1nc(Br)c2ccc(N3CCOCC3)cc2c1=O
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 20.3 %

Procedure:
To a solution of 7-Amino-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.8 g, 0.0028 mol) in DMF (8 ml), was added potassium carbonate (2 g, 0.014 mol). After five minutes, bis (2-chloroethyl)ether (0.41 g, 0.0028 mol) was added and the solution was heated to 140° C. for 24 hours. After this time LC-MS indicated the complete consumption of starting material and the mixture was cooled, concentrated under vacuum and purified by flash column chromatography (elution: 70% heptane, 30% ethyl acetate) to give the title compound (0.2 g, 20% yield) as a white solid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.S(=O)(=O)(O)O.[F:22][C:23](I)([F:25])[F:24].OO>S([O-])([O-])(=O)=O.[Fe+2].CS(C)=O>[F:22][C:23]([F:25])([F:24])[C:15]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([CH:16]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: FC(F)(F)I
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
0.23 g (1.0 mmol) of 2′-deoxyuridine was weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 ml of a 30% hydrogen peroxide aqueous solution and 0.3 ml of a 1.0 mol/l aqueous solution of iron (II) sulfate. The mixture was stirred at 40 to 50° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyl-2′-deoxyuridine (19F-NMR yield: 85%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. 5-Trifluoromethyl-2′-deoxyuridine was obtained as a white solid (0.17 g, yield: 58%) by column chromatography.
Reaction SMILES: [CH2:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][NH2:40])=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].C1(C)C=CC=CC=1>O>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([NH:39][N:40]2[C:17](=[O:19])[CH2:18][CH:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[O:16])=[O:38])[CH:25]=[C:24]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:29]=1[OH:30])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCC1CC(=O)OC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCC1CC(=O)N(NC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-dodecylsuccinic anhydride (42.17 g, 147.4 mmol), 3-(3,5-di-t-butyl-4-hydroxyphenyl)propanoic acid hydrazide (43.31 g, 147.4 mmol) and 70 ml of toluene was refluxed for one hour under a nitrogen atmosphere with the azeotropic removal of water (Dean-Stark assembly). The bulk of the solvent was distilled off followed by vacuum stripping of the hot (160° C.) melt for about 10 minutes. The resulting yellow liquid was then cooled under vacuum to about 120° C. The vacuum was released and the melt was quickly poured into a container. Upon cooling, the liquid became a clear yellow glass. The product was recrystallized from acetone/water at ice bath temperatures to afford, after drying, a nearly quantitative recovery of the product as a white powder having a melting range of 55°-60° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.[Br:38][C:39]1[CH:44]=[N:43][C:42](I)=[CH:41][N:40]=1>CCOC(C)=O.O>[Br:38][C:39]1[N:40]=[CH:41][C:42]([C:14]2[C:15]([F:18])=[C:16]([F:17])[C:9]([N:4]3[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]3)=[C:10]([CH:13]=2)[CH:11]=[O:12])=[N:43][CH:44]=1
Reactant: Brc1cnc(I)cn1
Reactant: CC1CN(c2c(C=O)cc(B3OC(C)(C)C(C)(C)O3)c(F)c2F)CC(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC1CN(c2c(C=O)cc(-c3cnc(Br)cn3)c(F)c2F)CC(C)O1
Temperature: 55 °C
Yield: 64.5 %

Procedure:
To a suspension of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (Example 22, step 2) (1.5 g, 3.9 mmol) and sodium carbonate (1.1 g, 11 mmol) in previously degassed acetonitrile/water (1/1) mixture (4 mL) was added 2-bromo-5-iodo-pyrazine (1.0 g, 3.5 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.099 g, 0.14 mmol) was added at room temperature and the reaction was heated overnight at 55° C. The mixture was cooled to room temperature, diluted with EtOAc and water then neutralized. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated. Purified by column chromatography eluting with ethyl acetate in hexanes (5-40%) to obtain 931 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 3.02 (m, 2H), 3.40 (m, 2H), 4.19 (m, 2H), 8.28 (dd, J=8.2, 2.1 Hz, 1H), 8.74 (d, J=1.4 Hz, 1H), 8.78 (m, 1H), 10.29 (s, 1H) ; MS(APCl+) m/z 412, 414 (MH+).
Reaction SMILES: CO.C([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:31])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C@H:12]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([OH:40])[CH:34]=2)[CH2:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].O>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1)[C:16]([N:13]1[CH2:14][CH2:15][NH:10][CH2:11][C@H:12]1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([OH:40])[CH:34]=1)=[O:31]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Into a mixed solution of methanol (270 l) and water (30 l) were charged (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine (30.0 kg), ammonium formate (8.8 kg) and 10% palladium on carbon (wet condition: 50%, 1.5 kg). They were allowed to react at an inside temperature of 50 to 55° C. for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, clarified and filtered, and washed with methanol (90 l). Water (480 l) was added dropwise to the combined filtrate and washings at room temperature and crystallization was effected under ice-cooling for 8 hours. Crystals were collected by filtration, washed with water (90 l) and dried under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)-piperazine (23.7 kg, yield 94.8%) in the form of white crystals.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([O:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[N:16]1[CH2:22][C:23]#[C:24][CH2:25][O:26][CH2:27][C:28]#[N:29])C)C>C(Cl)Cl>[OH:13][CH2:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[N:16]1[CH2:22][C:23]#[C:24][CH2:25][O:26][CH2:27][C:28]#[N:29]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCOCC#CCN1C(=O)CCC[C@@H]1CO
Reaction time: 1 h
Yield: 53.1 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.5 mmol) was added to a solution of {4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetonitrile (290 mg, 0.94 mmol) in CH2Cl2 (3 mL). After 1 h at rt, the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). Combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 118 mg (53%) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C(O)(=O)C.Cl>C(O)(C)C.CC(C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[CH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1nccc2ccccc12
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Fc1cccc(C=Cc2nccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 6.44 g (0.045 mole) of 1-methylisoquinoline, 6.2 g (0.05 mole) of 3-fluorobenzaldehyde and 18 ml of acetic acid is stirred at a temperature between 130° C. and 140° C. for 3 hours. The termination of the reaction is controlled by thin layer chromatography. The reaction mixture is cooled and 100 ml of anhydrous acetone are added to it. Then it is acidified with a mixture of hydrogen chloride and isopropanol until pH=1 under stirring and cooling with ice-water. The suspension is stirred at a temperature between 0° C. and 5° C. for 2 hours. The separated hydrogen chloride salt is filtered, washed with cold acetone and dissolved in 180 ml of water. To the thus-obtained mixture 20% sodium hydroxide solution is dropped until pH=11-12 under stirring and cooling with ice-water, and the solution is extracted three times with 75 ml each of dichloromethane. The extracts are combined, washed with an aqueous sodium chloride solution, dried over Na2SO4 and evaporated. The crude product is recrystallized from 30 ml of isopropanol. Thus 8.7 g (78%) of 1-(3-fluorostyryl)-isoquinoline are obtained.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:18]1[CH:23]=[C:22]([S:24]([N:27]([CH2:29][CH2:30][CH2:31][CH3:32])[CH3:28])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[CH3:33])(C)(C)C>C(OCC)C.CCCCC>[CH2:29]([N:27]([CH3:28])[S:24]([C:22]1[CH:21]=[CH:20][C:19]([CH3:33])=[C:18]([C:17]#[C:16][C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:34])=[O:5])[CH:23]=1)(=[O:25])=[O:26])[CH2:30][CH2:31][CH3:32]
Reactant: CCCCN(C)S(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1
Solvent: CCOCC
Solvent: CCCCC
Product: CCCCN(C)S(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1
Yield: 96 %

Procedure:
Following the general method as outlined in Example 15, starting from tert-butyl{2-[(5-{[butyl(methyl)amino]sulfonyl}-2-methylphenyl)ethynyl]-4-chlorophenoxy}acetate (Intermediate 161), the title compound was obtained as a beige solid in 96% yield after trituration in diethyl ether/pentane.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.CCCCCC.[CH3:35][O:36][N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1>C1COCC1>[CH3:35][O:36][N:37]1[CH2:42][CH2:41][C:40](=[CH:2][O:3][CH3:4])[CH2:39][CH2:38]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CON1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C1CCN(OC)CC1
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
A mixture of (methoxymethyl)triphenylphosphonium chloride (35.8 g, 104 mmol) in THF (160 mL) was cooled to −60° C. and treated with a 2.5M solution of n-BuLi in hexane (42 mL, 105 mmol). After 20 min, a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (9 g, 70 mmol) in THF (80 mL) was added, and the reaction mixture was allowed to warm to 10° C. over 2 h. The reaction was quenched with saturated ammonium chloride, and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform and the organic layer dried with sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel. Yield: 9.2 g of 1-methoxy-4-methoxymethylene-piperidine as an oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:34][C:35](=[NH:44])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][CH:37]=1>CN(C=O)C.O>[C:1]1([N:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:18][N:44]=[C:35]([C:36]4[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][CH:37]=4)[N:34]=3)[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (2 g, 7.81 mmol), HOBT (1.315 g, 8.59 mmol) and EDC (1.646 g, 8.59 mmol) were dissolved in DMF (18 mL) under nitrogen at room temperature. The resulting clear, pale yellow solution was stirred for 20 minutes, then N-hydroxy-4-(hydroxymethyl)benzimidamide, Int.2, (1.297 g, 7.81 mmol) was added in several portions. The reaction was placed in an oil bath preheated to 140° C. for 10 hours. The reaction was cooled to room temperature, poured into water (150 mL), stirred vigorously and placed in a sonicator bath for 1 hour. The solids were collected by filtration, washed with water, air dried and then placed under vacuum to give (4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (2.5 g, 6.47 mmol) as a very light yellow solid. The compound had an HPLC retention time=3.76 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=387.1 1H NMR (500 MHz, MeOD) δ ppm 4.70 (s, 2H), 7.53-7.57 (m, 4 H), 7.57-7.62 (m, 1H), 7.61 (d, J=6.4 Hz, 2H), 8.12 (d, J=8.2 Hz, 2H), 8.48 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[C:31]([C:33]1[CH:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1)#[N:32].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:39](=[O:40])[C:36]3[CH:35]=[CH:34][C:33]([C:31]#[N:32])=[CH:38][N:37]=3)[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (2a, 0.125 g, 0.404 mmol) in DCM (3 mL) was added N,N-diisopropylethylamine (0.074 mL, 0.424 mmol, Aldrich), 5-cyanopicolinic acid (0.060 g, 0.404 mmol, Aldrich) and 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate; 0.238 mL, 0.404 mmol, Alfa Aesar). The reaction was stirred at ambient temperature for 15 minutes. The reaction was diluted with water and DCM. The organic layer was separated and washed sequentially with aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel flash chromatography (gradient of 10-70% EtOAc in hexanes) to afford the title compound as a white solid. (0.0745 g, 0.170 mmol, 42.0% yield). MS m/z=440.0 [M+H]+. Calculated for C19H14F5N5O2: 439.34