Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[CH:22][NH:23]4)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[CH:22][NH:23]4)[CH:13]=[N:12]2)[C:8]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4cccc5[nH]ccc45)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 74) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a light tan solid as a mixture of diastereomers (0.95 g, 64%).
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CO.ClCCl>[C:1]([O:5][C@@H:6]([C:10]1[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[N:28][CH:29]=2)=[C:12]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:18]=3[S:17][C:13]2=[N:14][C:15]=1[CH3:16])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2sc3c(c2c(-c2cncnc2)c1C(OC(C)(C)C)C(=O)O)CCCC3
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2sc3c(c2c(-c2cncnc2)c1[C@H](OC(C)(C)C)C(=O)O)CCCC3

Procedure:
A sample of the product from Example 1 may be dissolved in a mixture of methanol and dichloromethane (1:1) loaded onto a Chiralpak IC column (250×20 mm internal diameter) and eluted with methanol/CO2 (60:40) at ambient temperature and a flow rate of 60 g/min. Fractions containing a single enantiomer may be combined and evaporated under reduced pressure to give the product enantiomer. Chiral purity may be assessed by chiral hplc using a Chiralpak IC column eluting with hexane/isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[N:11]=[C:10]([CH3:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCCC1.CO.[BH4-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[NH:11][CH:10]([CH3:19])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(Cl)c2)n2ncc(C#N)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1CC(c2cccc(Cl)c2)n2ncc(C#N)c2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an unweighed amount of 7-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in Ex. 14) in a stirred mixture of one liter of tetrahydrofuran and one liter of methyl alcohol, under nitrogen was added 20.0 g of sodium borohydride, portionwise. The mixture was stirred for 8 hours at room temperature, then allowed to stand for 3 days providing two layers. The top layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a yellow oil. The oil was dissolved in 250 ml of chloroform and filtered through hydrous magnesium silicate and evaporated to a yellow oil. The oil was triturated with ether, forming crystals on scratching. The crystals were collected to give the desired product as white crystals, mp 192°-195° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([O:31][C:32](=[O:37])[CH:33](Br)[CH2:34]Br)[CH3:30]>C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32]([CH:33]1[CH2:34][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][N:11]1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])=[O:37])[CH3:30]
Reactant: CCOC(=O)C(Br)CBr
Reactant: Cc1cc(F)ccc1NCCNCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccc(F)cc1C
Temperature: 135 °C

Procedure:
To N-benzyl-N′-(4-fluoro-2-methyl-phenyl)-ethane-1,2-diamine (15.1 g) in toluene (150 mL) was added N,N-diisopropylethylamine (33.8 mL) and 2,3-dibromopropionic acid ethyl ester (25.61 mL) in toluene (350 mL). The reaction mixture was heated to 135° C. for 18 h, cooled to room temperature, and the precipitated solid was removed by filtration. The solution was concentrated, and the crude material was redissolved in TBME and washed with an aqueous 2M solution of Na2CO3 and brine, dried (Na2SO4), filtered and evaporated. Chromatography (SiO2, n-heptane/ethyl acetate 97:3) gave 4-benzyl-1-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid ethyl ester (5.5 g) as yellow oil, MS: 357.3 ([M+H]+) and 1-benzyl-4-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid ethyl ester (3.3 g) as yellow oil, MS: 357.1 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=O)=[N:5][C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH2:50]([C:52]1[C:53]([NH:59][NH2:60])=[N:54][C:55]([CH3:58])=[N:56][CH:57]=1)[CH3:51]>CN(C)C=O>[CH2:50]([C:52]1[C:53]([NH:59][NH:60][C:9](=[O:11])[CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[N:5]=2)=[N:54][C:55]([CH3:58])=[N:56][CH:57]=1)[CH3:51]
Reactant: Cn1nc(N2CCCC2)nc1CCC(=O)O
Reactant: CCc1cnc(C)nc1NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cnc(C)nc1NNC(=O)CCc1nc(N2CCCC2)nn1C
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
3-(1-Methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)propanoic acid (140 mg, 0.624 mmol), HATU (712 mg, 1.87 mmol) and N,N-diisopropylethylamine (600 μl, 3.53 mmol) were dissolved in dimethylformamide (18 mL). The mixture was stirred for 20 minutes. 5-Ethyl-4-hydrazinyl-2-methylpyrimidine (99 mg, 0.655 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. The mixture was concentrated to an oil. Preparative HPLC afforded the desired product (71 mg, 31%) as a yellow gum. MS: m/z=359.23 (M+H+)
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:8][C:7](=O)[CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C@@H:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H]1CN(Cc2ccccc2)CCN1
Temperature: 25 °C

Procedure:
To a solution of the product of example 69 part a) (5.68 g) in THF (30 ml) at 0° C. was added LAH (100 ml, 1.0M in THF) dropwise. The resulting solution was heated at reflux overnight. The reaction mixture was cooled to RT and quenched by cautious sequential addition of water (3.8 ml), 15% aq NaOH (3.8 ml), and water (11.4 ml). The precipitous solution was diluted with EtOAc and filtered through Celite. The residue was washed with EtOAc (3×100 ml) and the combined organics concentrated in vacuo. The crude product was dissolved in DCM, filtered through Celite and the solvent removed in vacuo to give the sub-titled product as a yellow oil (4.74 g).
Reaction SMILES: [IH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][N:5]=[C:4]1SC.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CO>[IH:1].[C:21]1([CH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:18][CH2:19][NH:20][C:4]2[N:3]([CH3:2])[CH2:8][CH2:7][CH2:6][N:5]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CSC1=NCCCN1C
Agent: Cl
Agent: I
Solvent: CO
Product: CN1CCCN=C1NCCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A flask containing 1-methyl-2-methylthio-1,4,5,6-tetrahydropyrimidine hydroiodide (6.00 g, 2.20×10-2 mole) and 3,3-diphenylpropylamine (4.91 g, 2.32×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-165° C. for 50 minutes. The resulting yellow glass was dissolved in methanol. The methanol was partially evaporated at reduced pressure and isopropanol was added. The evaporation was continued being stopped periodically for the addition of small portions of isopropanol. A solid formed which was subsequently collected by filtration. This material was dissolved in a two phase mixture of 5 molar aqueous NaOH (100 ml) and CH2Cl2 (100 ml). After stirring overnight, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2×). The CH2Cl2 layers were combined, washed with H2O (2×), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a colorless foam which was dissolved in methanol (50 ml). The solution was cooled to 0° C. before being treated with a methanolic solution of HCl. The methanol was partially evaporated at reduced pressure. 2-Butanone was added and the evaporation was continued on the steam bath until the temperature of the solution reached 78°-79° C. After cooling to room temperature, the solution deposited a solid which was collected by filtration. The product was recrystallized from methanol/2-butanone affording 2-(3,3-diphenyl-propylamino)-1-methyl-1,4,5,6-tetrahydropyrimidine hydroiodide as a colorless solid: 3.44 g (45%), m.p. 178°-180° C.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([OH:21])=[N:8][C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:10][C:11]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:9]2[N:8]=[C:7]([OH:21])[C:6]3[N:5]=[C:1]([SH:2])[O:12][C:11]=3[N:10]=2)=[CH:15][CH:16]=1
Reactant: Nc1c(O)nc(Cc2ccc(Cl)cc2)nc1O
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Oc1nc(Cc2ccc(Cl)cc2)nc2oc(S)nc12
Temperature: 5 °C
Reaction time: 2 h

Procedure:
3 ml of thiophosgene were added slowly to a suspension of 9.65 g of 5-amino-2-(4-chloro-benzyl)-pyrimidine-4,6-diol and 5.3 g of potassium carbonate in 75 ml of N-methyl-pyrrolidin-2-one (NMP) while maintaining the temperature below 10° C. The reaction mixture was stirred for 2 h at 0-10° C. Then 300 ml of water were added and the resulting solution was extracted three times with 200 ml of dichloromethane and three times with 200 ml of a mixture of dichloromethane and isopropanol (3:1). The combined organic phases were dried over sodium sulfate and filtered. The solvents were removed in vacuo to yield approximately 7 g of 5-(4-chloro-benzyl)-2-mercapto-oxazolo[5,4-d]pyrimidin-7-ol as a solution in NMP. 45 ml of NMP and a solution of 2.38 g of sodium hydroxide in 64 ml of water were added at 0° C., and the mixture was stirred for 30 min at 0° C. while the color changed to brown. Then a solution of 1.5 ml of iodomethane in 1.5 ml of NMP was added dropwise. After stirring at 0° C. for 90 min the reaction was complete. The solution was extracted twice with 80 ml of ethyl acetate, and the combined organic phases were dried over sodium sulfate and filtered. The solvents were removed in vacuo to yield 2.2 g of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([O:17]C)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:7]=1>Br>[N+:19]([C:4]1[C:5]([OH:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:7]=[C:2]([F:1])[CH:3]=1)([O-:21])=[O:20]
Reactant: COc1c(-c2cccc(C(=O)O)c2)cc(F)cc1[N+](=O)[O-]
Agent: Br
Product: O=C(O)c1cccc(-c2cc(F)cc([N+](=O)[O-])c2O)c1
Temperature: 120 °C
Yield: 85.9 %

Procedure:
5′-Fluoro-2′-methoxy-3′-nitro-biphenyl-3-carboxylic acid 2d (2.91 g, 10.0 mmol) was dissolved in 10 mL of hydrobromic acid (40%). The reaction mixture was heated to reflux at 120° C. overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound 3′-nitro-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid 2e (2.38 g, yield 85.7%) as a yellow solid, which was directly used in the next step.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.[Cl:15][C:16]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](Cl)=[O:27])[CH:22]=[CH:23][CH:24]=1.O>CN(C)C(=O)C>[Cl:15][C:16]1[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[CH:29][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([S:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CCOC(=O)CS
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)CSC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 81 %

Procedure:
1.2 g of ethyl thioglycolate and 1.2 g of triethylamine were dissolved in 20 ml of N,N-dimethylacetamide. To the thus obtained solution was dropwise added 3.5 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetyl chloride at 10° C. After completion of the dropwise addition, the reaction was allowed to proceed at room temperature for 3 hours to complete reaction. After completion of the reaction, 50 ml of water was added to the reaction mixture, followed by extraction twice with 30 ml portions of ether. The ether layer was washed with water and dried over anhydrous sodium sulfate, and the ether was distilled off under reduced pressure to obtain a crude product. The obtained crude product was subjected to purification by the silica gel column chromatography to obtain 3.5 g of S-ethoxycarbonylmethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylthioacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([Mg]Br)[CH:22]([CH3:24])[CH3:23]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:18])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([CH3:19])[C:13]=2[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[Mg]Br
Reactant: Cc1c(C=O)oc2ccc(OCc3ccccc3)cc12
Solvent: C1CCOC1
Product: Cc1c(C(O)CC(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a solution (15 mL) of 5-(benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde (1.2 g) synthesized in the above-mentioned (3) in tetrahydrofuran was added dropwise isobutylmagnesium bromide (1M, tetrahydrofuran solution) under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 15 min, and aqueous ammonium chloride solution was added to quench the reaction. The reaction mixture was extracted with ethyl acetate, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give 1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-3-methylbutan-1-ol (0.82 g, 56%) as a pale-yellow oil. This was dissolved in tetrahydrofuran (15 mL), and thionyl chloride (0.35 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min then ice-cooled, and saturated aqueous sodium hydrogen carbonate solution (15 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (15 mL), sodium iodide (0.56 g), sodium carbonate (0.38 g) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.63 g) synthesized in Example 2(2) were added to the solution, and the mixture was stirred at 80° C. for 12 hr. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give the title object compound (0.46 g, 33%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:29][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC#N>[C:1]([C:5]1[C:9]([F:29])=[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: COc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)O)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc(Nc2c(F)c(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8 %

Procedure:
To a solution of 2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}-5-methoxybenzoic acid (Example 4), (49 mg, 0.13 mmol) in CH3CN (1 mL) was added [(1-(chloromethyl)4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR®) (46 mg, 0.13 mmol), and the mixture was stirred at rt for 16 h. The solid was filtered off and the filtrate was subjected to HPLC purification with a gradient elution from 10% to 90% acetonitrile in water to afford 4 mg (8%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 8.62 (s, 1H), 7.40 (d, 1H), 7.16-7.35 (m, 4H), 7.05 (dd, 1H), 7.76 (dd, 1H), 3.75 (s, 3H), 2.12 (s, 3H), 1.40 (s, 9H). ES-MS m/z 398.2 (MH+); HPLC RT (min) 4.06.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26](I)[S:27][C:20]=12)[NH2:14]>>[F:10][C:11]1[CH:12]=[C:13]([NH2:14])[CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]2[CH:25]=[C:26]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[S:27][C:20]=12
Reactant: C#CCN1CCCCC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(C#CCN4CCCCC4)sc23)c(F)c1
Temperature: 50 °C
Yield: 82.7 %

Procedure:
Prepared from 1-(prop-2-ynyl)piperidine (24 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 5 hours. The crude was purified by preparative TLC [5% MeOH (containing 7N NH3) in CHCl3]. The product was obtained as a waxy solid (41 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6 Hz, 1H), 7.58 (s, 1H), 7.03 (t, J=9 Hz, 1H), 6.52 (m, 3H), 3.85 (br s, 2H), 3.56 (s, 2H), 2.60 (m, 4H), 1.66 (m, 4H), 1.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15])[CH:5]=[CH:6][CH:7]=1.[Cl:20]N1C(=O)CCC1=O>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:20])=[C:4]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15])[CH:3]=1
Reactant: N#CCNC(=O)C1CCCCN1c1cccc(Br)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: N#CCNC(=O)C1CCCCN1c1cc(Br)ccc1Cl
Temperature: 60 °C

Procedure:
To a suspension of 1-(3-bromophenyl)-N-(cyanomethyl)-2-piperidinecarboxamide (2.25 g, 6.98 mmol, prepared as described in example 25) in 70 mL of isopropyl alcohol was added N-chlorosuccinimide (1.02 g, 7.68 mmol). The suspension was heated to 60° C. and the resultant solution was stirred at 60° C. for 2 h. The mixture was cooled and partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate (3 ×) and the combined organic layers were dried over Na2SO4 and concentrated. Purification by flash chromatography (50% Et2O/hexanes) yielded 1-(5-bromo-2-chlorophenyl)-N-(cyanomethyl)piperidine-2-carboxamide (faster eluting compound) and 1-(3-bromo-4-chlorophenyl)-N-(cyanomethyl)piperidine-2-carboxamide (slower eluting compound).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]([F:26])([F:25])[C:8]([F:24])([F:23])[C:9]([F:22])([F:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:1]([O:5][CH2:6][C:7]([F:25])([F:26])[C:8]([F:23])([F:24])[C:9]([F:21])([F:22])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][C:39]2[CH:40]=[CH:41][C:36]([O:35][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:37][CH:38]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(C(=O)O)cc1
Reactant: CCCCCCCCOc1ccc(O)cc1
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(OCC(F)(F)C(F)(F)C(F)(F)COCCCC)cc2)cc1

Procedure:
4-Octyloxyphenyl 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)benzoate (Compound 4, Table 1) was prepared by esterification of 4-(5-butoxy-2,2,3,3,4,4-hexafluoropentoxy)benzoic acid (prepared essentially as in Example 9) with 4-octyloxyphenol .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9](O)[CH2:10][OH:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1csc(C2OCCO2)c1
Yield: 97.8 %

Procedure:
A mixture of 4-bromo-thiophene-2-carbaldehyde (175 g, 916 mmol), ethylene glycol (71.1 g, 1.15 mol) and p-toluenesulfonic acid (0.19 g, 1.0 mmol) in toluene (250 mL) is heated to reflux for 7 h using a Dean-Stark apparatus. After cooling, the solution is washed with aq NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. The residue is distilled to give 2-(4-bromo-thiophen-2-yl)-[1,3]dioxolane (210.6 g, 98%) as a colorless liquid: bp 133-143/11-14 mBar; 1H NMR (CDCl3, 300 MHz) δ 7.21 (s, 1 H), 7.04 (s, 1 H), 6.04 (s, 1 H), 3.95-4.18 (m, 4 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1>>[CH2:10]1[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:14]([NH:15][C:2]3[N:7]=[C:6]([NH:15][C:14]4[CH:16]=[CH:17][C:18]5[O:19][CH2:20][CH2:10][O:11][C:12]=5[CH:13]=4)[C:5]([F:9])=[CH:4][N:3]=3)=[CH:13][C:12]=2[O:11]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc3c(c2)OCCO3)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-ethylenedioxyaniline were reacted to yield N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.88 (d, 1H, J=3.6 Hz), 7.23 (d, 1H, J=2.3 Hz), 7.15 (d, 1H, J=2.4 Hz), 7.00 (dd, 1H, J=3 and 8.1 Hz), 6.98 (dd, 1H, J=3 and 8 Hz), 6.83 (d, 1H, J=8.7 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.7 (s, 1H), 6.58 (s, 1H), 4.23 (m, 4H), 4.24 (m, 4H); 19F NMR (CDCl3): δ −47445; LCMS: ret. time: 21.81 min.; purity: 96%; MS (m/e): 397 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=1)=[O:8]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)c1cnccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(OC(=O)c2cnccn2)cc1
Yield: 28.2 %

Procedure:
To 3.5 g (25 mmol) of pyrazinoyl chloride dissolved in methylene chloride (20 mL) and pyridine (2 mL) cooled to 0° C. in a 50 mL round bottom flask was added 4-methyl-phenol (3.2 g, 30 mmol). Upon completion of the reaction and isolation as described above, recrystallization from hexanes yielded 1.51 g (24% yield) of the crystalline title compound; m.p.: 120°-123° C. Elemental Analysis: C12H10N2O2Calcd: C:67.28, H:4.71. Found: C:67.4, H:4.66.