Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[I:2][C:3]1[CH:11]=[C:10]([I:12])[CH:9]=[C:8]2[C:4]=1[C:5]([CH3:16])([CH3:15])[C:6]([CH3:14])=[N+:7]2[CH3:13].Cl.[C:18]1([NH:24][CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=NC2C=CC=CC=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OC(=O)C)(=O)C>[I-:2].[NH:24]([CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=[CH:14][C:6]1[C:5]([CH3:16])([CH3:15])[C:4]2[C:8](=[CH:9][C:10]([I:12])=[CH:11][C:3]=2[I:2])[N+:7]=1[CH3:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1=[N+](C)c2cc(I)cc(I)c2C1(C)C
Reactant: C(=CC=Nc1ccccc1)C=CNc1ccccc1
Agent: Cl
Agent: [I-]
Solvent: CC(=O)OC(C)=O
Product: C[N+]1=C(C=CC=CC=CNc2ccccc2)C(C)(C)c2c(I)cc(I)cc21

Procedure:
100 mg (0.18 mmol) of 4,6-diiodo-1,2,3,3-tetramethyl-3H-indolium iodide and 51 mg (0.18 mmol) of N-[5-(phenylamino)-2,4-pentadienylidene]aniline monohydrochloride were stirred in 2 mL of acetic anhydride at 110-120° C. for 15 min. After cooling the product was precipitated with ether, filtered off and washed with ether. Yield: 67 mg (53%). λmax (abs) 483 nm (methanol). This product was used for following step without additional purification.
Reaction SMILES: O[C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]#[N:14].O.C1(P(Cl)([Cl:24])=O)C=CC=CC=1>>[Cl:24][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: Cc1nn(C)c2nc(O)c(C#N)cc12
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: O
Product: Cc1nn(C)c2nc(Cl)c(C#N)cc12
Temperature: 150 °C
Reaction time: 17 h

Procedure:
6-Hydroxy-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrile (2.18 g) was dissolved in phenylphosphonic dichloride, and stirred at 150° C. for 17 hours. The solution was allowed to cool to room temperature and poured into water, then extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and dried over Na2SO4. Evaporation of the solvent gave 6-chloro-1,3-dimethylpyrazolo[5,4-b]pyridine-5-carbonitrile as a white solid.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:22][OH:23]>CO>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH:20]=[N:22][OH:23])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C=NO)cnc32)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.150 g, 0.498 mmol) in MeOH (10 mL) was added hydroxylamine (50% solution in water, 0.061 mL, 1.0 mmol). The reaction mixture was heated to about 45° C. After about 2 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to provide the crude 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde oxime as a tan solid. LC/MS (Table 2, Method a) Rt=2.15 min; MS m/z: 317 (M+H)+. To a solution of the crude oxime in THF (20 mL) was added AcOH (0.285 mL, 4.98 mmol) followed by zinc dust (<10 micron, 0.130 g, 1.99 mmol). After a further 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zinc dust (<10 micron, 0.130 g, 1.99 mmol) were added to the reaction mixture. After about an additional 2 h, additional AcOH (0.285 mL, 4.98 mmol) and zinc dust (<10 micron, 0.130 g, 1.99 mmol) were added to the reaction mixture. After about 15 h, the reaction mixture was diluted with DCM (about 5 mL) and filtered. The filtrate was washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered, treated with HCl (4 M in 1,4-dioxane, 1 mL) and concentrated under reduced pressure to provide (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride: LC/MS (Table 2, Method a) Rt=1.64 min; MS m/z: 303 (M+H)+. To a suspension of the crude amine hydrochloride in DCM (10 mL) was added TEA (0.208 mL, 1.49 mmol) followed by cyclohexanecarbonyl chloride (0.101 mL, 0.747 mmol). After about 30 min, the reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude amide was purified by silica gel chromatography eluting with a gradient of 40-80% EtOAc in DCM to provide N-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)cyclohexanecarboxamide as a tan solid (0.081 g, 39% over 2 steps). LC/MS (Table 2, Method a) Rt=2.40 min; MS m/z: 413 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])(C)C.Cl.C([O-])(O)=O.[Na+].C(=O)(ON1C(=O)CCC1=O)OCC1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>O1CCOCC1.O>[CH:36]1[C:35]2[CH:4]([CH2:1][O:5][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]3)=[O:7])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:39]=[CH:38][CH:37]=1
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.50 g, 6.17 mmol, Example #13, Step G) in 1,4-dioxane (10 mL) was added aqueous HCl (4N in 1,4-dioxane (4.62 mL, 18.5 mmol). The reaction mixture was heated at about 60° C. for about 16 h before being allowed to cool to ambient temperature. To the mixture was added NaHCO3 (2.07 g, 24.7 mmol) and water (10.0 mL) followed by (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (4.16 g, 12.3 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was acidified to about pH 1 with aqueous 1N HCl and was extracted with EtOAc (75 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (40 g column) eluting with a gradient of 1-5% MeOH in DCM to give 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpiperidine-3-carboxylic acid (0.72 g, 31%) as a clear oil: LC/MS (Table 2, Method a) Rt=2.44 min; MS m/z: 366 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][N:8]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29])[CH2:9][CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[I-].C[S+](C)C.CN(C)C=O>O1CCCC1.O>[CH3:1][C:20]1[C:19]([N+:28]([O-:30])=[O:29])=[C:18]([N:8]([CH3:7])[CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH:23]=[CH:22][C:21]=1[C:24]([F:26])([F:27])[F:25]
Reactant: CN(CCOC1CCCCO1)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)ccc(N(C)CCOC2CCCCO2)c1[N+](=O)[O-]
Temperature: 17.5 °C

Procedure:
A solution of potassium tert-butoxide (3.22 g, 28.7 mmol) in tetrahydrofuran (40 ml) was added dropwise to a mixture of 4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]amino]-3-nitrobenzotrifluoride (5.00 g, 14.4 mmol), trimethylsulfonium iodide (5.86 g, 28.7 mmol) and N,N-dimethylformamide (80 ml) with stirring at 15-20° C. After stirring at 15-16° C. for another 1 hour, the reaction mixture was cooled to 0° C. The reaction mixture was poured into cold water and extracted three times with ethyl acetate. The extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/97) to obtain an oil of 2-methyl-4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]amino]-3-nitrobenzotrifluoride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Br.[OH:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:13][C:14]=1[F:20])[CH2:31]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Oc1cccc2c1CNC2
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3Cc4cccc(O)c4C3)c(F)cc2c1=O
Yield: 23.5 %

Procedure:
178 mg of 1-(4-fluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 130 mg of 4-hydroxyisoindoline hydrobromide, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 56 mg of the target compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:23]=1.[CH3:24][N:25]([CH2:27]N(C)C)[CH3:26]>C(Cl)(=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][CH2:24][N:25]([CH3:27])[CH3:26])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[CH:23]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(C)n1-2
Reactant: CN(C)CN(C)C
Solvent: CC(=O)Cl
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCN(C)C)n1-2

Procedure:
In the manner given in Example 1, a solution of 8-methylthio-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide N,N,N',N',-tetramethyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N',N',-tetramethyldiaminomethane) are reacted together to give 8-methylthio-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2O.O([CH3:22])[Na]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:22])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2
Reactant: CO[Na]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Solvent: CO
Product: COc1nc2ccc(Br)cc2cc1-c1ccccc1

Procedure:
In a 100-mL round-bottom flask was placed a mixture of 6-bromo-2-chloro-3-phenylquinoline (550 mg, 1.73 mmol, Intermediate 4, step b) and NaOCH3 (931 mg, 17.2 mmol) in methanol (50 mL). The resulting mixture was refluxed for 5 hours and concentrated under vacuum. The residue was purified by chromatography (silica gel column, 1:5 EtOAc/petroleum ether) to provide the title compound as a white solid.
Reaction SMILES: CC1C(C#C)=CC2C(C)(C)CCC(C)(C)C=2C=1.CN(C)S(N1C=C(I)N=C1)(=O)=O.[CH3:30][C:31]1[C:32](/[C:45](/[CH3:58])=[CH:46]/[C:47]2[N:48]=[CH:49][N:50]([S:52](=[O:57])(=[O:56])[N:53]([CH3:55])[CH3:54])[CH:51]=2)=[CH:33][C:34]2[C:35]([CH3:44])([CH3:43])[CH2:36][CH2:37][C:38]([CH3:42])([CH3:41])[C:39]=2[CH:40]=1.C([Li])CCC.Cl[C:65]([O:67][CH2:68][CH3:69])=[O:66]>>[CH3:30][C:31]1[C:32](/[C:45](/[CH3:58])=[CH:46]/[C:47]2[N:48]=[C:49]([C:65]([O:67][CH2:68][CH3:69])=[O:66])[N:50]([S:52](=[O:56])(=[O:57])[N:53]([CH3:55])[CH3:54])[CH:51]=2)=[CH:33][C:34]2[C:35]([CH3:44])([CH3:43])[CH2:36][CH2:37][C:38]([CH3:41])([CH3:42])[C:39]=2[CH:40]=1
Reactant: C/C(=C\c1cn(S(=O)(=O)N(C)C)cn1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)Cl
Agent: C#Cc1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CN(C)S(=O)(=O)n1cnc(I)c1
Agent: [Li]CCCC
Product: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1S(=O)(=O)N(C)C

Procedure:
It should be noted in connection with Reaction Schemes 1, 2 and 3 that in all of these reaction schemes heterocycle derivatives corresponding respectively to Formula 7, 11 and 15 can be employed where in the A-B' substituent A is (CH2)n, n is 0, and B' is hydrogen. A carboxylic acid group is then introduced into the molecule, after coupling with the tetrahydronaphthalene moiety, by reaction with strong base (such as n-butyl lithium) and carbon dioxide or ethyl chloroformate. Reaction Scheme 4 illustrates specifically the synthesis of Compound 3 and Compound 4 of the present application. In accordance with this scheme (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)acetylene (Compound 10) is reacted with trimethylaluminum in the presence zirconocene dichloride. The resulting "carboaluminated adduct" (not shown in Scheme 4) is reacted in the presence of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) catalyst, with 1-(N,N-dimethylsulfamoyl)-4-iodoimidazole (Compound 11) which is obtained by iodination from 1-(N,N-dimethylsulfamoyl)imidazole. The latter compound can be obtained in accordance with the chemical literature: Chadwick et al. J. Chem. Soc., Perkin Trans. I 1984, 481-486. The result of the coupling reaction between between the carboaluminated adduct derived from Compound 10 and Compound 11 is (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-1-(N,N-dimethylsulfamoyl)imidazole (Compound 12). The carboxylic acid ethyl ester moiety is introduced into the molecule by reacting the anion of Compound 12 generated with strong base such as n-butyl lithium, with ethyl chloroformate, to yield ethyl (E)-4-[2-(5,6,7,8-tetrahydro- 3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-1-(N,N-dimethylsulfamoyl)-2-imidazolecarboxylate (Compound 4). The dimethylsulfamoyl group is removed from the imidazole nitrogen by treatment with acid, to yield ethyl (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-2-imidazolecarboxylate (Compound 3). ##STR10##
Reaction SMILES: C(O)C.[CH2:4]([S:9]([NH:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([N:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[CH3:24])[CH:15]=1)(=[O:11])=[O:10])[CH2:5][CH2:6][CH2:7][CH3:8].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][S:9]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:11])=[O:10])=[O:34])=[CH:15][C:16]=1[N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[CH3:24]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N(C)Cc2ccc(Cl)cc2Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCS(=O)(=O)NC(=O)c1ccc(N)c(N(C)Cc2ccc(Cl)cc2Cl)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 22.2 %

Procedure:
Four milliliters of ethanol and 4 ml of tetrahydrofuran were added to 0.605 g of N-(n-pentanesulfonyl)-3-(N-methy-2,4-dichlorobenzylamino)-4-nitrobenzamide, and subsequently 10 ml of an aqueous solution containing 3.10 g of sodium hydrosulfite was added thereto. The mixture was stirred at 80° C. for 20 minutes and then extracted with water and ethyl acetate. The organic layer was washed with water and concentrated. The resulting residue was crystallized from ether, filtrated, and dried to obtain 0.126 g of 4-amino-3-(N-methyl-2,4-dichlorobenzylamino)-(N-(n-pentanesulfonyl))benzamide (32).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[OH-].C([N+:11]([CH2:20]CCC)([CH2:16][CH2:17][CH2:18][CH3:19])CCCC)CCC.[C:24]([C:26]1[C:31](F)=[CH:30][CH:29]=[CH:28][N:27]=1)#[N:25]>CN(C=O)C>[N:1]1([C:31]2[C:26]([C:24]#[N:25])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:5]=[N:4][N:3]=[N:2]1.[N:11]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:31][C:26]=2[C:24]#[N:25])[CH:20]=[N:1][CH:5]=[N:4]1
Reactant: c1nnn[nH]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: N#Cc1ncccc1F
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cncn1
Product: N#Cc1ncccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of tetrazole (1.0 g, 14 mmol) in DMF (150 mL) was added 40% aqueous tetrabutylammonium hydroxide (7.8 g, 12 mmol). The solvent was removed under reduced pressure. To ensure removal of all the water from the tetrabutylammonium hydroxide solution, the residue was redissolved in DMF and the solution was evaporated under reduced pressure. This procedure was repeated a total of three times. The residue was then dissolved in DMF (60 mL) and 2-cyano-3-fluoro-pyridine (1.5 g, 12 mmol, preparation described in Sakamoto et. al., Chem. Pharm. Bull. 1985, 33(2), 565–571) was added. The reaction was stirred at ambient temperature under inert atmosphere for four days, at which time hplc analysis indicated about 65% conversion of the 3-fluoro-2-cyanopyridine to new products. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient elution of 1:4 to 100:0 EtOAc:hexanes to give 3-(tetrazol-1-yl)cyanopyridine as a white crystalline solid (TLC Rf=0.5, 1:1 EtOAc-hexanes; hplc retention time=2.04 min, 5% to 100% CH3CN in water containing 0.1% TFA, Zorbax C8, 4.6 mm ID×7.5 cm, 3.5 micron); 1H NMR (CDCl3) δ 9.42 (s, 1H), 8.94 (dd, J=1.3, 4.6 Hz, 1H), 8.31 (dd, J=1.3, 8.4 Hz, 1H), 7.87 (dd, J=4.6, 8.4 Hz, 1H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].[NH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>CO>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:14][O:15][CH2:16][CH2:17][NH:18][C:19]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:25])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCCON
Solvent: CO
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)-glyoxylic acid (1.59 g.), tert-butyl N-aminooxyethylcarbamate (1.40 g.) and methanol (25 ml.) was stirred at room temperature for 6 hours. After removal of methanol from the resultant solution under reduced pressure, the residue was pulverized with diethyl ether. The precipitates were collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2.20 g.).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CC[O:30]CC.O>O1CCCC1>[CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:10][CH2:11][CH2:12][OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a mixture of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentene (2.86 g., 10 mmoles), sodium borohydride (0.47 g., 12.5 mmoles), and tetrahydrofuran (25 ml.) is added dropwise a solution of boron fluoride etherate (2.1 ml., 16.7 mmoles) in tetrahydrofuran (5 ml.) at ice-bath temperatures under a nitrogen atmosphere. The resulting mixture is further stirred at room temperature overnight (ca.15 hours). The reaction flask is chilled in an ice bath and water (2 ml.) is very cautiously added to destroy the excess hydride, followed by the additions of sodium hydroxide (5N, 4 ml.) and hydrogen peroxide (30%, 8 ml.). The final mixture is stirred at room temperature for one-half hour, diluted with cold water and then extracted with chloroform three times. The combined extracts are washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo leaving the title compound as a viscous oil (3.00 g., 10 mmoles, 100%). ir (neat) 2.97, 3.30, 3.41, 6.22, 6.68, 6.90, 8.03, 8.30, 9.16, 9.44, 12.10, 13.20, 13.60, 14.40μ; pmr (CCl4)δ1.4-1.9 (4H, m), 3.2-4.2 (6H, m), 4.58 (2H, broad s), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)=[CH:5][CH:4]=[N:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl.O>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cn1nccc1-c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24 %

Procedure:
To a solution of 3-(1-methyl-1H-pyrazol-5-yl)benzoic acid (130 mg, 0.64 mmol) in DCM (6 mL) was added EDCI (245 mg, 1.28 mmol), HOBt (173 mg, 1.28 mmol), Et3N (195 mg, 1.93 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (132 mg, 0.64 mmol). The mixture was stirred at room temperature for 16 h until completion of the reaction was indicated by which TLC. The reaction solution was then diluted with water (10 mL) and extracted with DCM (2×10 mL) then the combined organic layers were concentrated. The residue was purified by prep-HPLC to give the desired product (60 mg, Yield 25%). 1H NMR (400 MHz, MeOD): 7.55 (s, 1H), 7.52 (s, 1H), 7.24-7.15 (m, 3H), 6.85-6.73 (m, 4H), 6.03 (s, 1H), 4.22 (br.s, 1H), 4.03-3.99 (m, 1H), 3.45 (s, 3H), 3.17-2.73 (m, 7H). LCMS (m/z): 391.2 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10]
Reactant: O=Cc1cccs1
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCC=Cc1cccs1
Yield: 46 %

Procedure:
This compound was synthesized from 2-thiophenecarboxaldehyde (2.24 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (hexanes-ethyl acetate) afforded the product (2.45 g, 46%) as white crystals (mp 61°-62° C.); IR: 3450-2500, 1715 cm-1 ; 1H-NMR: 1.31 (m, 8H), 1.45 (m, 2H), 1.65 (m, 2H), 2.34 (t, 2H), 2.38 (t, 2H) 5.55 (m, 1H), 6.50 (d, 1H), 6.95 (m, 2H), 7.23 (d, 2H), 10.05 (bs, 1H). Anal. Calcd. for C15 H22O2S: C, 67.63, H, 8.32%; Found: C, 67.60, H, 8.34%. Z:E=19:81.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[C:9]([C:11]1[C:12]([F:38])=[C:13]([NH:18][C:19]([C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[C:22]=2[C:34]([F:37])([F:36])[F:35])=[O:20])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10].O>CN(C=O)C>[C:9]([C:11]1[C:12]([F:38])=[C:13]([N:18]([CH3:1])[C:19]([C:21]2[N:25]([CH3:26])[N:24]=[C:23]([C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])[C:22]=2[C:34]([F:36])([F:37])[F:35])=[O:20])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(F)c(C#N)c1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(C(=O)c1c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn1C)c1ccc(F)c(C#N)c1F
Reaction time: 5 h
Yield: 98.5 %

Procedure:
Potassium carbonate (1.28 g, 5.58 mmol, 2.0 eq.) and iodomethane (0.5 ml, 1.2 g, 8.4 mmol, 3.0 eq.) were added to a solution of N-(3-cyano-2,4-difluorophenyl)-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (1.25 g, 2.79 mmol) in DMF (4 ml). After 5 h, water was added, the mixture was extracted with ethyl acetate and the extract was washed with sat. aq. sodium chloride solution and dried over MgSO4. Filtration through silica gel gave N-(3-cyano-2,4-difluorophenyl)-N,1-dimethyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (1.27 g, 98%) as a mixture of rotamers which was reacted further without additional purification.