Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].Br[CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29].Cl>O1CCCC1.C([Li])CCC.CCCCCC.C1(C)C=CC=CC=1>[CH2:18]([CH:17]([CH2:29][CH2:28][CH2:27][CH:26]=[CH2:25])[C:16]([O:22][CH3:23])=[O:21])[CH2:19][CH3:20]
Reactant: C=CCCCBr
Reactant: CCCCC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: C=CCCCC(CCC)C(=O)OC
Reaction time: 4 h
Yield: 43.2 %

Procedure:
To a solution of lithium diisopropyl amide, which was prepared from diisopropylamine (6.6 g) in dry tetrahydrofuran (50 ml) and 15% butyl lithium in hexane solution (38 ml) at -65° to -60° C. in a nitrogen atmosphere, were added dropwise a solution of methyl pentanoate (7 g) in dry tetrahydrofuran (65 ml) followed by a solution of 5-bromo-1-pentene (9 g) in dry tetrahydrofuran (30 ml) at the same temperature. The mixture was stirred for 4 hours at -65° to 0° C. All the operations described above were carried out in a nitrogen atmosphere. Diluted hydrochloric acid (25 ml) and toluene (200 ml) were added at 0° C. to the mixture, which was further stirred. The organic layer was separated, washed with water, dried and concentrated. The resulting oily residue (9 g) was purified by silica gel column chromatography to give colorless oil of methyl 2-propyl-6-heptenoate (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9]Br)=[CH:4][N:3]=1.[CH3:11][S-:12].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][S:12][CH3:11])=[CH:4][N:3]=1
Reactant: C[S-]
Reactant: Fc1cc(CBr)cnc1Cl
Agent: [Na+]
Solvent: CCO
Product: CSCc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A solution of 2-chloro-3-fluoro-5-bromomethylpyridine (3.7 g, 16.5 mmol) in ethanol (40 mL) was treated with sodium thiomethoxide solid (2.31 g, 33 mmol) portionwise at 0° C. After the addition was over, the mixture was stirred at room temperature overnight. Most of the solvent ethanol was removed under reduced pressure and the residue was re-taken into dichloromethane. Brine solution was added and two phases mixed and separated. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified on silica gel using 8% EtOAc in hexane as eluent to give 2.04 g of the desired 2-chloro-3-fluoro-5-methylthiomethylpyridine in 65% yield. GC-MS calcd. for C7H7ClFNS: 191.66. Found: 191.
Reaction SMILES: ClC1C=C2C(C=CC(C)=N2)=CC=1O.C[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[CH3:26])[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:26][C:25]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[CH:17][C:16]=1[OH:15]
Reactant: COc1cc2cccnc2cc1C
Agent: Cc1ccc2cc(O)c(Cl)cc2n1
Product: Cc1cc2ncccc2cc1O

Procedure:
Compound 3C was prepared following the procedure used to prepare compound 1C of Example 1, except that 6-methoxy-7-methylquinoline (3B) was used instead of compound 1B. LCMS-ESI+ (m/z): 160.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH3:2].Br[C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:19]1[C:18]2[CH:23]=[CH:24][C:15]([CH:7]([C:6]3[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[OH:8])=[CH:16][C:17]=2[O:22][CH2:21][CH2:20]1
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: Brc1ccc2c(c1)OCCO2
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: CCOc1cc(C(O)c2ccc3c(c2)OCCO3)ccc1OC
Yield: 56.2 %

Procedure:
3-ethoxy-4-methoxybenzaldehyde (0.92 g, 5.12 mmol), 6-bromo-2,3-dihydro-benzo[1,4]dioxine (1.21 g, 5.63 mmol), and n-butyl lithium (2.25 ml, 5.63 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxy-phenyl)-methanol as a yellow solid (0.91 g, 56%): 1HNMR (CDCl3) 6.92-6.80 (m, 6H, Ar), 5.68 (d, J=3 Hz, 1H, CHOH), 4.23 (s, 4H, 2CH2), 4.07 (q, J=6.90, 14 Hz, 2H, CH2CH3), 3.85 (s, 3H, OCH3), 2.13 (d, J=2 Hz, 1H, OH), 1.44 (t, J=7 Hz, 3H, CH2CH3). The product was carried over to the next step.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([O:17]C(C)(C)C)=[O:16])[CH3:14])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>FC(F)(F)C(O)=O>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C@H:7]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
470 mg of Z-Sta-Ala-OC(CH3)3 (from stage 13.1) are dissolved in 10 ml of trifluoroacetic acid and the solution is stirred for 10 minutes at 25° C. The solvent is then removed in a rotary evaporator and the residue is flash-chromatographed over 200 g of silica gel (eluant first chloroform/methanol/concentrated aqueous ammonia solution [40:10:1], then chloroform/methanol/concentrated aqueous ammonia solution [5:3:1]). The product-containing fractions are combined and concentrated by evaporation, the residue is taken up in chloroform and the chloroform solution is extracted with dilute hydrochloric acid and saturated sodium chloride solution, dried and concentrated by evaporation. After drying the residue in a high vacuum, Z-Sta-Ala-OH is obtained in the form of a colourless foam; Rf (G)=0.43.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[C:25]1[CH:26]=[CH:27][C:28]2[S:32][CH:31]=[CH:30][C:29]=2[CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[S:32]1[C:28]2[CH:27]=[CH:26][C:25]([NH:1][C:2]3[CH:14]=[C:13]([N:15]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH2:17][CH2:16]4)[CH:12]=[CH:11][C:3]=3[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:33][C:29]=2[CH:30]=[CH:31]1
Reactant: Brc1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1Nc1ccc2sccc2c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To toluene 3.0 mL solution of tert-butyl 2-amino-4-(indolin-1-yl)benzoate 0.12 g were added 5-bromobenzothiophene 0.21 g, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg at room temperature, and it was stirred at 110° C. for 12 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 110° C. for 6 hours. 5-Bromobenzothiophene 0.21 g, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added at room temperature, and it was stirred at 110° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give tert-butyl 2-((benzothiophen-5-yl)amino)-4-(indolin-1-yl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=O)[CH2:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]2[O:17][C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:10]=[C:4]2[CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cc(Cl)c(Cl)cc1O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C1=CC=C2C=C(Cl)C(Cl)=CC2O1
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of 4.62 g of crude product of the preceding Preparation, 4-(3,4-dichloro-6-hydroxyphenyl)-1,1,1-trifluoro-butan-2,4-dione (about 40% by NMR) and 4.6 ml trifluoroacetic acid in 27.6 ml methylene chloride was heated at reflux for 8 hours, then allowed to stand at 23° C. for 16 hours. The reaction was washed with 3×25 ml 1N sodium hydroxide and 25 ml brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2.0 g (86%) of product; m.p. 98°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)CNc1ccc(Cl)cc1
Yield: 87.8 %

Procedure:
N-(4-Chlorophenyl)-trifluoroacetamide (2.22 g, 10 mmol) was dissolved in THF (100 mL) and treated with powdered lithium aluminum hydride (0.57 g, 15 mmol) under argon. The mixture was heated with stirring to reflux for 12 hours at which point both TLC and LC/MS analysis indicated the reaction was complete. The suspension was cooled in an ice bath prior to quenching with saturated aqueous sodium sulfate solution. The solution was dried with excess sodium sulfate and concentrated under reduced pressure to give 1.84 g of a viscous oil which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 3.70 (2H, dt, J=8.96, 15.81 Hz), 3.91 (1H, br s), 6.58 (2H, m), 7.13 (2H, m).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:25][C:26](=[O:28])[CH3:27])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:29].[Na+]>CC(C)=O>[C:26]([O:25][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:14][CH2:13][CH2:12][I:29])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(CCCOS(=O)(=O)c1ccc(C)cc1)COc1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OC(CCCI)COc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A solution of 4-acetoxy-5-(4-fluorophenoxy)-1-pentanol tosylate (73.5 g., 0.179 mole) and sodium iodide (79.5 g., 0.53 mole) in acetone (500 ml.) is allowed to stand at 25°-27° for 18 hours. The precipitated sodium tosylate is filtered off. Most of the acetone is evaporated from the filtrate and the residue is treated with 300 ml. of water. The oily product is taken up in ether, washed with dilute sodium thiosulfate solution, water and brine and dried over sodium sulfate. The solvent is distilled in vacuo to give 66 g. (a quantitative yield) of the crude title compound as a yellowish oil which is used without further purification; pmr (CDCl3) δ 2.05 (3H, s CH3CO); 3.20 (2H, t CH2I); 3.97 (2H, d CH2O); 5.20 (1H, m CHO); 6.85 (4H, m aryl).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5]([CH2:11][CH2:12][CH2:13][CH3:14])=[N:6]2.[C:15]([O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[CH2:11]([C:5]1[N:6]([CH2:34][C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[CH:29][CH:30]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([Cl:1])[N:10]=[CH:9][N:8]=2)[CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc2ncnc(Cl)c2[nH]1
Product: CCCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The titled compound was prepared by the alkylation of 6-chloro-8-butyl purine (0.063 g, 0.3 mmol) with t-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.104 g, 0.3 mmol) according to the procedure described in Step 3 of Example 12. After flash-chromatographic purification of the crude product using ethyl acetate-hexane (1:1), the product was obtained as a foam (0.085 g, 60%). NMR (CDCl3): δ 0.946 (t, J=9Hz, 3H), 1.26 (s, 9H), 1.464 (m, 2H), 1.86 (m, 2H), 2.91 (m, 2H), 5.51 (s, 2H), 7.16-7.51 (m, 7H), 7.78 (m, 1H) and 8.723 (s, 1H). FAB-MS: m/e 477 and 479 (M+H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].[O-]CC.[Na+].Br[CH2:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=O>C(O)C>[CH2:2]([O:4][C:5]([C:6]1[CH:16]=[C:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[NH:9][C:7]=1[NH2:8])=[O:10])[CH3:3]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(C#N)cc2)[nH]c1N
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
A mixture of 42.53 g (0.255 mol) carbamimidoyl-acetic acid ethyl ester hydrochloride in 70 ml absolute ethanol is treated at 0 to 5° C. with 95.3 ml of a 21% sodium ethoxide solution in ethanol (0.255 mol) and stirred 5 min at 0 to 5° C. 4-Bromoacetyl-benzonitrile (28.6 g, 0.128 mol) is then added in portions over 20 min at 0 to 5° C. Stirring is continued at this temperature for 5 min then the ice bath is removed and the yellow suspension is stirred over night at RT. The solid is filtered off, washed with ethanol and ether and re-suspended in 450 ml actonitrile. The mixture is heated for 5 min under reflux, filtered while still hot and then cooled in an ice bath. The title compound is collected by succion and dried. Flash chromatography (dichloromethane/ethyl acetate mixture) of the mother liquors gives an additional crop of the title compound as a yellow solid; m.p. 228-229° C.; MS-ES+: (M+H)+=254.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[O:12])=[CH:6][CH:5]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:30]([C:32]2[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][CH:33]=2)=O)=O)=[CH:24][CH:23]=1.O>C(O)C.ClCCl>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:12])[C:13]([C:14]3[CH:15]=[CH:16][C:17]([Br:20])=[CH:18][CH:19]=3)=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=3)[C:30]=2[C:32]2[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][CH:37]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cc1ccc(Br)cc1)Cc1ccc(Br)cc1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=C1C(c2ccc(Br)cc2)=C(c2ccc(Br)cc2)C(c2ccc(Br)cc2)=C1c1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A solution of potassium hydroxide (230 mg, 4.1 mmol) in ethanol (5 cm3) was added to a solution of (13) (3.01 g, 8.2 mmol) and 4,4′-dibromobenzil (3.01 g, 8.2 mmol) in ethanol (45 cm3) at 70° C., and the reaction was stirred at 70° C. for 4 hours. Water (200 cm3) and dichloromethane (200 cm3) were added, and the layers were separated. The organic layer was washed with brine (200 cm3) and dried over magnesium sulfate. The solvent was removed to leave a dark purple solid. The crude product was passed through a plug of silica, and then recrystallised from a dichloromethane/ethanol mixture to give (14) as a dark purple crystalline solid (3.87 g, 68%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:26](O)(=O)[CH:27]([CH3:29])[CH3:28].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[C:22]([O:21][C:19]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([CH2:2][NH:1][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:4][CH:5]=2)[CH:10]1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CN)cc2C1C1CCCCC1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)CNCc1ccc2c(c1)C(C1CCCCC1)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Tert-butyl 7-(aminomethyl)-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (999 mg) was dissolved in methylene chloride. Isobutyric acid (0.33 mL), triethylamine (1.2 mL), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.32 g) were added thereto, followed by stirring at room temperature for 18 hours. Water was added to the mixture which was then extracted with chloroform. The extract was washed with a 1 M aqueous NaOH solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to obtain tert-butyl-1-cyclohexyl-7-[(isobutylamino)methyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (468 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[C:13]3[NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C(O)(C(F)(F)F)=O>>[NH2:32][C@H:29]1[CH2:30][CH2:31][C@H:26]([NH:25][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:4]4[CH:3]=[C:2]([F:1])[C:7]([OH:8])=[C:6]([F:9])[CH:5]=4)[CH:11]=3)[N:16]=[CH:15][C:14]=2[C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)cc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[6-(3,5-difluoro-4-hydroxyphenyl)-3-isobutyrylquinolin-4-ylamino]cyclohexylcarbamate (64 mg, 0.100 mmol) was reacted with TFA (2 mL) to afford the desired product (10.8 mg, 36%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.97 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.00 (dd, J=8.7, 2.0 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.28 (dd, J=7.8, 1.9 Hz, 2H), 4.26-4.15 (m, 1H), 3.81-3.69 (m, 1H), 3.27-3.18 (m, 1H), 2.38 (d, J=12.6 Hz, 2H), 2.18 (d, J=11.7 Hz, 2H), 1.69 (q, J=10.4 Hz, 2H), 1.61-1.53 (m, 2H), 1.24 (d, J=6.8 Hz, 6H); ESI MS m/s 440 [C25H27F2N3O2+H]+; HPLC 95.0% (AUC), tR=10.50 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][OH:46])[CH2:40][CH2:39]1.O1CCN(CCO)CC1>>[CH:30]1([C:26]2[N:25]=[C:24]([CH2:23][N:18]3[C:19]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[N:5]6[CH:6]=[CH:7][C:2]([O:46][CH2:45][CH2:44][N:41]7[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH2:39][CH2:40]7)=[CH:3][C:4]6=[N:10][CH:9]=5)=[O:12])[CH:22]=[CH:21][CH:20]=4)[C:16]([CH3:33])=[N:17]3)[CH:29]=[CH:28][CH:27]=2)[CH2:31][CH2:32]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: COCCN1CCN(CCO)CC1
Agent: OCCN1CCOCC1
Product: COCCN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4c(C)nn5Cc4cccc(C5CC5)n4)cnc3c2)CC1
Yield: 41 %

Procedure:
Prepared according Example 1, Step B, substituting N-(1-((6-cyclopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (Example 16, Steps A-G) for 7-fluoro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanol for 2-morpholinoethanol to give the title compound (41%). MS (APCI), positive scan, m/z=609.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:6]2.Cl.[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:33][C:19]([F:18])([F:32])[C:20]1[CH:21]=[C:22]([C:26]2[CH2:31][CH2:30][N:29]([C:14](=[O:16])[CH2:13][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=3)[CH2:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Reactant: COc1ccc2cc(CC(=O)O)ccc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cc(CC(=O)N3CC=C(c4cccc(C(F)(F)F)c4)CC3)ccc2c1
Yield: 81 %

Procedure:
A solution of 6-methoxy-2-naphthylacetic acid (1.8 g, 0.009 mol), 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (2.4 g, 0.009 mol), triethylamine (2.4 ml, 0.018 mol), and BOP (3.7 g, 0.009 mol) in methylene chloride (40 ml) is stirred at room temperature for 5 hours. Then it is concentrated to dryness, the obtained residue is dissolved in a mixture ethyl ether/water, the organic phase is separated, and washed sequentially with 1N HCl, water, 5% NaOH, and water. The reaction mixture is then filtered over silica and the filtrate is concentrated to dryness affording 1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1-yl]-1-oxo-2-(6-methoxy-naphth-2-yl)ethane (3.1 g). M.p. 102°-105° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O-:4])=[O:3].C(N(CC)CC)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1>ClCCl>[F:35][C:34]([F:36])([F:37])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][CH:17]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[CH2:14][CH2:13]2)=[CH:28][CH:29]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: O=[N+]([O-])c1cccc(OC2CCNCC2)c1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 20 h
Yield: 70.4 %

Procedure:
To a stirred mixture of 4-(3-nitrophenoxy)piperidine hydrochloride (11.87 mmol, 3.07 g) and triethylamine (35.6 mmol, 4.96 mL, 3.60 g) in dichloromethane was added 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (11.87 mmol, 4.00 g). The reaction was stirred for 20 hours then was filtered. The filtrate was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (4 g). MS (ESI) m/z 479.0 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](O)=[O:35].CCN=C=NCCCN(C)C>>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:35]
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(O)Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccccn4)c3)c2c1
Yield: 10.6 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-pyridylacetic acid hydrochloride (0.12 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 22 mg (10% yield) of the title compound. 1H NMR (DMSOd6) δ 13.4 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.5 (dd, 1H), 8.2 (br s, 1H), 8.1 (s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.45 (m, 2H), 7.35-7.2 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 372 [M+H]+.