Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3C(N)=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.N1C=CC=CC=1C.B.FC(F)(F)C(O)=O.[CH3:45][N:46]([CH3:49])[CH:47]=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:47]([N:46]([CH3:49])[CH3:45])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Agent: B
Agent: C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: Cc1ccccn1
Product: CN(C)c1ncccc1-c1cc(Cc2ccc(OCc3ccccc3)cc2)no1
Reaction time: 8 h
Yield: 21 %

Procedure:
To a mixture of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (50 mg, 0.14 mmol) described in Example 1 and N,N-dimethylformamide (0.5 mL) were added a formaldehyde aqueous solution (34 mg, 0.42 mmol, content: 37%), α-picoline-borane (37 mg, 0.35 mmol), and acetic acid (50 μL), which was stirred overnight at the same temperature. Trifluoroacetic acid (50 μL) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The solvent was evaporated under a reduced pressure, and the residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (15 mg, 21%) as a trifluoroacetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[OH:10][C:11]1[CH:20]=[CH:19][C:14]2[S:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1.O>CN(C)C=O>[CH2:7]([O:10][C:11]1[CH:20]=[CH:19][C:14]2[S:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1)[CH3:8]
Reactant: O=c1oc2cc(O)ccc2s1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2sc(=O)oc2c1
Reaction time: 4 h

Procedure:
Potassium carbonate (533 mg) and ethyl iodide (160 μL) were added to a solution of 6-hydroxy-1,3-benzoxathiol-2-one (336 mg) in N,N-dimethylformamide (10 mL) to form a reaction solution. This reaction solution was stirred for 4 hours at normal temperature. Water was added to the reaction solution. The precipitated crystals were filtered off, thoroughly washed with water and diisopropyl ether, and then dried under reduced pressure to obtain the target product (245 mg) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[Na].[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([S:25][CH2:2][C:3]([CH3:16])=[CH:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCc1ccccc1
Reactant: CC(=O)c1ccc(OCC=C(C)CBr)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC=C(C)CSCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
14.15 g (0.05 mol) of 4'-(4-bromo-3-methyl-2-butenyloxy)- acetophenone are added at 10°-15° during the course of 1 hour to 7.3 g (0.05 mol) of sodium salt of benzylmercaptan which is dissolved in 120 cc of dimethylformamide. The mixture is stirred at 20°-25° for 20 hours, is subsequently filtered and the filtrate is evaporated at reduced pressure. The residue is dissolved in ether, is extracted with saturated salt solution and the ether solution is evaporated. The remaining yellowish oil is chromatographed on silica gel with hexane/ethyl acetate 2:1. After recrystallization from ether/hexane the 4'-(4-benzylthio-3-methyl-2-butenyloxy)-acetophenone is obtained as colourless crystals. M.P. 75°-76.5°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C.[F-].[K+].CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:14]1([S:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:20]=[CH2:21])[CH:3]=3)[NH:7][CH:6]=2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ccc(Br)cc12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1ccc2[nH]cc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
5-bromo-3-(phenylsulfonyl)-1H-indole (505 mg, 1.50 mmol) and dichlorobis(tri-o-tolylphosphine)-palladium(II) (118 mg, 0.09 mmol) were dissolved in toluene (5 mL) and stirred for 10 minutes at room temperature under a nitrogen atmosphere. Tributyl(vinyl)tin (619 mg, 1.95 mmol) was added and the mixture was refluxed for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), 1 M KF (5 mL) and stirred for 12 hours. The resultant tin salt precipitate is removed by suction filtration and the organic layer was washed with water (5 mL), then brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (40% ethyl acetate/petroleum ether) gave the title compound as a white solid (313 mg, 74%). Mp: 140-145° C. MS (ES+): 284 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+]([O-])=O.[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.[ClH:23].Cl.CN1CCN(N)CC1.CCN(C(C)C)C(C)C.CN(C)CCN(C)C>>[Cl:23][C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Cl
Reactant: NCC1CCOCC1
Agent: CN(C)CCN(C)C
Agent: CN1CCN(N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NCC2CCOCC2)c(Cl)c1

Procedure:
The title compound was prepared by substituting 4-fluoro-3-chlorobenzenesulfonamide for 4-chloro-3-nitrobenzenesulfonamide, (tetrahydro-2H-pyran-4-yl)methanamine for 4-methylpiperazin-1-amine dihydrochloride and Hunig's base for N1,N1,N2,N2-tetramethylethane-1,2-diamine in EXAMPLE 6A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.C([Li])(C)(C)C.C([S@@]([N:22]=[CH:23][CH2:24][CH2:25][C:26]([CH3:38])([CH3:37])[C:27](OCC1C=CC=CC=1)=[O:28])=O)(C)(C)C>C1COCC1.CCCCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]([CH:23]2[NH:22][C:27](=[O:28])[C:26]([CH3:38])([CH3:37])[CH2:25][CH2:24]2)=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CC(C)(CCC=N[S@@](=O)C(C)(C)C)C(=O)OCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: CC1(C)CCC(c2c(Br)cc(F)c(F)c2F)NC1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-bromo-3,4,5-trifluorobenzene (313 mg, 1.48 mmol) in THF (3 mL) at −78° C. was added tert-butyllithium (1.74 mL of a 1.7 M solution in pentane, 2.96 mmol) dropwise. The reaction mixture was stirred for 1 h at −78° C., 3 h at 0° C., and then cooled back down to −78° C. A solution of benzyl (SS)-5-[(tert-butylsulfinyl)imino]-2,2-dimethylpentanoate (250 mg, 0.741 mmol, described in Intermediate 3) in toluene (5 mL) was added. The reaction mixture was stirred for 20 min at −78° C., 16 h at ambient temperature, and 1 h at reflux. The solvent was removed in vacuo and the crude solid dissolved in DMSO (5 mL). The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=337 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11]C.B(Br)(Br)Br.CO.[OH-].[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(O)c1
Temperature: -20 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
To a stirred solution of 1-chloro-2-methoxy-4-nitrobenzene (20 g, 106.6 mmol) in dichloromethane (500 mL) at −78° C. under a flow of Nitrogen gas, a solution of BBr3 (747 mmol) in dichloromethane was added dropwise. The reaction was stirred overnight at −20° C., then for 1 h at 4° C. To the reaction, 10 mL of MeOH and 100 mL of water were added dropwise. The resulting mixture was made basic with 10% NaOH solution. The aqueous layer was then made acidic and was extracted with chloroform. The combined organic layers were dried with Na2SO4, filtered and concentrated in vacuo to afford the yellow solid 2-chloro-5-nitrophenol (12.5 g, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(O)no1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
Methyl 3-hydroxyisoxazole-5-carboxylate (5.18 g, 36.2 mmol) was dissolved in acetone (90 mL) and treated with potassium carbonate (10.21 g, 73.8 mmol) at reflux for 1 hour. At that time, benzyl bromide (6.5 mL, 54.3 mmol) was added, and the mixture was heated at reflux for an additional 3 hours. The reaction mixture was removed from the oil bath and stirred at room temperature for 18 hours. The mixture was filtered and concentrated in vacuo leaving a yellow oil. The oil was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) which gave the title compound as a light yellow solid (5.0 g, 59%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH2:23][NH2:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][CH2:32][CH2:33]Br)C.C(N(CC)CC)C>CC(C)CCO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH2:23][N:24]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:29])=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(CN)cc(OC)c21
Reactant: CCOC(=O)CCCBr
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(CN3CCCC3=O)cc(OC)c21
Yield: 33.2 %

Procedure:
A solution of 50 mg (0.143 mmol) C-[2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-methylamine, 28 mg (0.143 mmol) ethyl-4-bromobutyrate and 28 μl (0.2 mmol) triethylamine in 4 ml 3-methyl-1-butanol is stirred at reflux temperature for 8 h. Then the reaction mixture is poured on water and extracted (3×) with EtOAc. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (EtOAc:MeOH=98:2) to afford 20 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8](=O)[C:7]=2[CH:16]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][C:7]=2[CH:16]=1
Reactant: COc1ccc2oc(C(=O)O)cc(=O)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(C(=O)O)O2
Yield: 84.2 %

Procedure:
A mixture of 61 parts of 6-methoxy-4-oxo-4H-1-benzopyran-2-carboxylic acid and 500 parts of acetic acid was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in petroleumether. The product was filtered off and dried in vacuo at about 65° C., yielding 49.1 parts (84.2%) of 3,4-dihydro-6-methoxy-2H-1-benzopyran-2-carboxylic acid; mp. 140° C. (intermediate 13).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:27](OC)=[O:28])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]21.O1CC[CH2:33][CH2:32]1>>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([C:27]([OH:28])([CH2:1][CH3:2])[CH2:32][CH3:33])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Product: CCC(O)(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 2.9 mL, 8.7 mmol) was added to a stirred solution of methyl 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (720 mg, 1.75 mmol) in tetrahydrofuran (7.0 mL), and the mixture was stirred at 60° C. for 2 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol to give the title compound as a colorless crystal (378 mg, 0.861 mmol, 49%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[OH:12][C:13]1[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:6]([N:5]([CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[F:1])[C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:7]
Reactant: CCNCc1ccccc1F
Reactant: O=C(O)COc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(Cc1ccccc1F)C(=O)COc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
N-(2-Fluorobenzyl)ethanamine (0.248 g, 0.993) was dissolved in DMF (10 ml), (4-hydroxyphenoxy)acetic acid (0.150 g, 0.903 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.319 g, 0.993 mmol) and N-ethyl-N,N-diisopropylamine (0.245 g, 1.896 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.177 g of N-ethyl-N-(2-fluorobenzyl)-2-(4-hydroxyphenoxy)acetamide (yield 64.6%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:9]([F:8])([F:18])[F:19])=[CH:12][CH:13]=1)=[O:4]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Br)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 4.02 g (23.4 mmol) of 2-bromopropionyl chloride in 10 ml of methylene chloride was added to an ice-cooled solution of 5.0 g (23.4 mmol) of 4-(trifluoromethoxy)aniline hydrochloride, 4.65 g (59 mmol) of pyridine and 30 ml of methylene chloride. The mixture was stirred at ambient temperature for a period of 2.5 hours and then washed with two portions of dilute aqueous HCl and two portions of saturated aqueous sodium bicarbonate, dried over MgSO4, treated with charcoal, filtered and the filtrates evaporated to dryness. The residue was recrystallized from methylcyclohexane to give 5.43 g 74 percent of theoretical) of the above-named product as colorless crystals, m.p. 111°-112° C.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:18](=[O:28])[C:4]=2[N:5]2[CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([O:15][CH3:16])[C:9]([F:17])=[CH:8][C:7]=3[C:6]=12.C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([N:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:3]2[C:2]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[C:6]3[C:7]4[CH:8]=[C:9]([F:17])[C:10]([O:15][CH3:16])=[CH:11][C:12]=4[CH2:13][CH2:14][N:5]3[C:4]=2[C:18]1=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1cc2c(cc1F)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1F)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Yield: 75.5 %

Procedure:
To a degassed solution of 50 mg 27b and 62.3 mg 2-(tributylstannyl)thiophene in 3 mL toluene was added 12.9 mg tetrakis(triphenylphosphine)palladium(0). The mixture was stirred at reflux for 16 h. The crude reaction mixture purified by column chromatography over silica and was then triturated with diisopropyl ethyl ether/pentane (1:1) to give 38 mg 27c as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[C:37]([F:40])([F:39])[F:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[C:37]([F:38])([F:40])[F:39])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: OC(c1ccccc1Cl)C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(c1ccccc1Cl)C(F)(F)F

Procedure:
In a similar manner as described for example B31, 1.53 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.0 g of 1-(2-chlorophenyl)-2,2,2-trifluoroethanol, 2.43 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 1.68 g of di-tert-butyl azodicarboxylate in 40 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Zn+2:10].[C:11]([O-:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[NH4+]>>[CH:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=1.[CH:15]1[CH:16]=[CH:17][C:12]([C:11]([OH:19])=[O:18])=[CH:13][CH:14]=1.[Zn:10]
Reactant: [Zn+2]
Reactant: O=C([O-])c1ccccc1
Agent: O=C([O-])O
Agent: [NH4+]
Product: O=C(O)c1ccccc1
Product: [Zn]
Yield: 742.8 %

Procedure:
To the resin obtained in the above step (i), a mixture of 3.2 g (0.01 mole) of zinc benzoate and 2.4 g (0.03 mole) of ammonium bicarbonate was slowly added at 150°-160° C. The resultant mixture was then stirred for 1 hour at 155°-165° C. to complete the reaction. After completion of the reaction, the resultant molten resin was taken out, cooled and ground to obtain 23 g of a zinc-benzoate-modified salicylic acid resin as powder. The softening point of the zinc-modified resin was 108° C. It will be designated as Resin (C)-4.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([OH:10])(=[O:9])C=C.[CH2:11]1COC[CH2:12]1>>[CH:2]12[CH2:1][CH:5]([CH:11]=[CH:12]1)[CH2:4][CH:3]2[C:6]([OH:10])=[O:9]
Reactant: C1CCOC1
Reactant: C1=CCC=C1
Reactant: C=CC(=O)O
Product: O=C(O)C1CC2C=CC1C2
Yield: 79.7 %

Procedure:
Cyclopentadiene (66 g) and 86 g of acrylic acid were dissolved in 500 g of THF solvent. After the reaction at 30° C. for 24 hours, the solvent and excess acrylic acid were removed by rotary evaporator. The residue was distilled under reduced pressure to obtain 110 g of 5-norbornene-2-carboxylic acid as a mixture of endo and exo (yield: 71%). NMR spectral data of the resulting compound (20) is shown in FIG. 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].BrN1C(=O)CCC1=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
2-Fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl4 (50 mL). The mixture was heated at reflux, and irradiated with light (100 W bulb) for 4 hours. The reaction mixture was then filtered and concentrated. The residue was dissolved in THF (50 mL). Morpholine (1.91 g, 22 mmol) was added to it. The mixture was stirred at ambient temperature for 1 hour and then filtered. The filtrate was evaporated. The bright orange residue was purified by column chromatography eluted with hexane:ethyl acetate, 10:1 to provide 4-(2-fluoro-4-nitrobenzyl)morpholine (1.32 g, 5.5 mmol, yield 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1.FC(F)(F)C(O)=O>C(O)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([C:25]5[NH:26][CH:27]=[CH:28][N:24]=5)[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Nc1cccc(-c2ncc[nH]2)c1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Temperature: 80 °C

Procedure:
Into a sealed tube were added 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (368 mg, 1.0 mmol), 3-(1H-imidazol-2-yl)-phenylamine (210 mg, 1.32 mmol), trifluoroacetic acid (847 μL, 11.0 mmol) and 1-butanol (10 mL). The above mixture was heated at 80° C. for 24 h. After that time, the mixture was concentrated in vacuo, and the residue was dissolved in DMSO for submission for MS-directed purification to obtain brown oil, which was purified again to give the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.52 (s, 9H), 2.58 (brs, 2H), 3.68 (brs, 2H), 4.14 (brs, 2H), 6.30 (brs, 1H), 6.68 (s, 1H), 7.16 (s, 2H), 7,45 (t, 1H, J=8.0 Hz), 7.57-7.60 (m, 1H), 7.76-7.79 (m, 1H), 8.21 (t, 1H, J=1.6 Hz), 9.26 (s, 1H). MS (ES+): m/z 458.06 (100) [MH+]. HPLC: tR=2.17 min (ZQ2000, polar—5 min).