Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[N+:9]([C:12]1[CH:13]=[C:14]([OH:22])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[N+:9]([C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=1)[O:22][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:11])=[O:10]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCCN2CCCC2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-chloroethyl)pyrrolidine (0.355 g, 2.66 mmol), 3-nitro-5-(trifluoromethyl)phenol (0.500 g, 2.41 nmmol), Cs2CO3 (2.36 g, 7.24 mmol), and DMF (18.69 mL) was allowed to stir at rt until reaction was judged to be complete. The mixture was diluted with EtOAc and washed with water (3×25 mL). The organic solution was dried over Na2SO4, filtered, and concentrated to give 3-(2-pyrrohidin-1-ylethoxy)-5-(trifluoromethyl)anlline as a brown oil (0.49 g, 63%). LCMS: (FA) ES+ 304.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]2[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)=O)=[O:10])=[CH:4][CH:3]=1.CN(C)C=O.O1CCCC1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][CH3:17])[CH2:13][N:12]3[C:18]=2[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=2)=[CH:4][CH:3]=1
Reactant: COC1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)c2ccnc(SC)n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1Cn2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)c(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of 2-(4-fluorophenyl)-1-[4-methoxy-2-(2-methylsulfanyl-pyrimidine-4-carbonyl)pyrazolidine-1-yl]-ethanone, 48, (2.04 g, 5.22 mmol) in 1:1 dimethylformamide/tetrahydrofuran (30 mL) is added dropwise to a 0° C. suspension of sodium hydride (230 mg of a 60% dispersion in mineral oil, 5.75 mmol) in dimethylformamide (60 mL). After 2 hours at 0° C., the bright red solution is quenched by slow addition of a saturated aqueous solution of ammonium chloride (5 mL). The cold bath is removed, and the solution allowed to warm to room temperature. The reaction mixture is concentrated in vacuo and the resultant residue diluted with ethyl acetate (175 mL). The mixture is washed with a saturated aqueous solution of ammonium chloride (150 mL). The aqueous layer is extracted with ethyl acetate (4×75 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is purified over silica gel (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford 1.1 g (57% yield) of the desired product as an orange oil.
Reaction SMILES: Cl.F[C:3](F)([O:15][NH2:16])[C:4]1[C:9]([F:10])=[C:8]([F:11])[C:7]([F:12])=[C:6]([F:13])[C:5]=1[F:14].[N:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([C:21]3=O)[CH2:19]1)[CH2:25]2>C(O)C>[F:10][C:9]1[C:4]([CH2:3][O:15][N:16]=[C:21]2[CH:22]3[CH2:27][N:18]4[CH2:25][CH:24]([CH2:26][CH:20]2[CH2:19]4)[CH2:23]3)=[C:5]([F:14])[C:6]([F:13])=[C:7]([F:12])[C:8]=1[F:11]
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: NOC(F)(F)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: CCO
Product: Fc1c(F)c(F)c(CON=C2C3CC4CC2CN(C4)C3)c(F)c1F
Temperature: 25 °C

Procedure:
Solid O-(perfluorobenzyl)hydroxylamine HCl (167 mg, 0.669 mmol, Aldrich Chemical Co.) was added to a warm solution of 1-azatricyclo[3.3.1.13,7]decan-4-one (102 mg, 0.675 mmol) (prepared as reported in: Becker, D. P. and Flynn, D. L. Synthesis 1992, 1080-1082) in ethanol (1 mL). The mixture was swirled with warming to dissolve all solids. The nearly colorless solution was allowed to cool to room temperature overnight. The solvent was removed under vacuum, and the residue was crystallized from 10% ethanol in ethyl acetate (3 mL) to provide the title compound as hydrochloride salt. 1H NMR (300 MHz, CD3OD) δ 1.87-2.06 (m, 2 H), 2.22 (q, J=3 Hz, 1 H), 2.24-2.37 (m, 2 H), 2.83 (s, 1H), 3.30, (m, 1H), 3.43-3.57 (m, 2 H), 3.64 (s, 2 H), 3.66-3.78 (m, 2 H), 5.15-5.24 ppm (m, 2 H); MS (DCI/NH3) m/z 347 (M+H)+; Anal. C16H15N2OF5—HCl requires C, 50.21; H, 4.21; N, 7.32. Found C, 50.20; H, 3.99; N, 7.22.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18](OC(=O)C)(=O)[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:17])[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[C:18]([CH3:19])[O:1]2)=[CH:4][CH:5]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Yield: 66 %

Procedure:
1-(2,4-Dihydroxy-phenyl)-2-phenyl-ethanone (0.5 g, 3.2 mmol) was refluxed in anhydrous DMF with acetic anhydride (1.5 ml), and anhydrous potassium carbonate (1.4 g 10.1 mmol) for 3 hrs. The solution was then poured into water and the precipitate filtered to give 7-hydroxy-2-methyl-3-phenyl-chromen-4-one as white solid (0.62 g, 66%); Rf 0.75 cf SM 0.9 ethyl acetate/hexane (75/25).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1OB(O)O.C1(C)C=CC=CC=1>C(O)C.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>[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[F:8]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCC[C@H]1CC[C@H](c2ccc(OB(O)O)c(F)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(-c3c(F)cccc3F)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3,5-Difluorobromobenzene (30 g), tetrakis(triphenylphosphine)palladium (0) (1.8 g), ethanol (150 mL), and a 2 mol/L aqueous potassium carbonate solution (155 mL) were mixed with each other and heated to 50° C. A solution prepared by dissolving 2-fluoro-4-(trans-4-propylcyclohexyl)phenylboric acid (49.3 g) in ethanol (300 mL) was added thereto, and stirring was performed at 50° C. for five hours. After the temperature was decreased to room temperature by natural cooling, toluene (300 mL) was added thereto and the mixture was separated. The resulting organic layer was washed with a saturated saline solution (200 mL) twice. Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography and recrystallized using ethanol to obtain 4-[2-fluoro-4-(trans-4-propylcyclohexyl)phenyl]-3,5-difluorobenzene (39.1 g). (2-2) The subsequent processes were performed by the same method as in Example 1 to obtain [3,5-difluoro-4-(2-fluoro-4-(trans-4-propylcyclohexyl)phenyl)phenyl]-(5,6,7-trifluoro-2-naphthyloxy)difluoromethane (20.5 g).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([OH:20])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:21][CH3:22])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19]([O:20][CH3:25])=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:21][CH3:22])[N:11]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CNc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(C(=O)NCc2ccc(F)cc2)c(OC)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of N-(4-fluorobenzyl)-8-hydroxy-5-(methylamino)-1,6-naphthyridine-7-carboxamide (2.65 g, 8.12 mmol) in methanol (50 mL) and CH2Cl2 (20 mL) was added trimethylsilyldiazomethane (12.1 ml of a 2M solution in hexanes, 24.4 mmol) and the mixture was stirred for 16 hr at rt. Additional trimethylsilyldiazomethane (24.0 ml of a 2M solution in hexanes, 48 mmol) was added and the reaction was stirred for 16 hr. The reaction was quenched by the addition of acetic acid (2 mL) and the solvent was evaporated in vacuo. The residue was purified by flash chromatography eluting with MeOH/CH2Cl2 (5-15% gradient elution), to afford the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.[C:15]([O:19][C:20](=O)[O:21]C(C)(C)C)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: OC1CCCNC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of 10.0 g (72.67 mmol) 3-hydroxypiperidine in 100 mL dry THF at 0° C. was added 10.1 mL (72.67 mmol) NEt3 and 15.86 g (72.67 mmol) di-t-butylcarbonate in 100 mL THF and the reaction allowed to warm to rt and stirred overnight. The solvent was removed under reduced pressure, the resulting residue dissolved in 300 mL CH2Cl2 and the solution extracted with H2O (2×200 mL), dried over MgSO4, filtered and rotary evaporated to yield 12.66 g (87%) of N-(t-butoxycarbonyl)-3-piperidinol as an oil which slowly solidified to a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](Cl)=[O:14])[N:12]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13]([N:25]([O:26][CH3:27])[CH3:24])=[O:14])[N:12]=1
Reactant: O=C(Cl)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride (4.71 g, 13.4 mmol, prepared by the method described in Example 13, step 1) in 10 mL dichloromethane was added to a solution of N,O-dimethylhydroxyamine hydrochloride (1.44 g, 14.7 mmol) and triethylamine (5.6 mL, 40.2 mmol) in 60 mL dichloromethane in an ice water bath under argon with stirring. The bath was removed upon completion of addition. Stirring was continued for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated down under reduced pressure. The crude product was purified on silica gel, eluting with ethyl acetate to yield 2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-methoxy-N-methyl-1H-imidazole-4-carboxamide as an off-white solid (4.20 g, 83%): Rf=0.22 (ethyl acetate).
Reaction SMILES: [CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH2:27])[CH:21]=3)=[CH:18][CH:19]=2)=[O:14])[C:8](=[O:11])[NH:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.Cl[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37]>CN(C=O)C>[CH:1]1([C@H:7]([NH:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH2:26][NH:27][C:36](=[O:37])[O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[CH:18][CH:19]=2)=[O:14])[C:8]([NH:9][CH3:10])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(=O)Cl
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CN)c2)o1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CNC(=O)OCC(C)C)c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(3-aminomethyl-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide (37 mg, 0.10 mmol) in DMF (2.0 mL) is added 4-methylmorpholine (44 μL, 0.40 mmol) followed by isobutyl chloroformate (21 mg, 0.15 mmol). After stirring at room temperature for 12 hours, the mixture is evaporated in vacuo and the resulting oil purified on reverse phase HPLC to obtain a white solid, 26 mg, 54%, LC/MS ESI m/z (M+H)+=470.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].I[CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:39][CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(O)cc(Br)c2)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC3CCCC3)c2)c1CCC(=O)OCC
Yield: 71458.6 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-[6-(3-bromo-5-hydroxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (600 mg, 1.03 mmol), iodomethylcyclopentane (260 mg, 1.24 mmol), and potassium carbonate (356 mg, 2.57 mmol) to afford 4-[3-[6-(3-bromo-5-cyclopentylmethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (487 g, 73%) as a colorless viscous oil: EI(+)-LRMS m/e calcd for C35H49BrO7 (M+H)+ 663.45. found 663.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:8])[C:5]([OH:7])=[O:6].[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>[OH-].[Na+].CCOCC>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([NH:1][CH2:2][CH2:3][C@H:4]([OH:8])[C:5]([OH:7])=[O:6])=[O:19])=[CH:21][CH:22]=1)([O-:11])=[O:10]
Reactant: NCC[C@H](O)C(=O)O
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(NCC[C@H](O)C(=O)O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 2.82 g portion of (2S)-4-amino-2-hydroxybutyric acid was dissolved in 15 ml of 2N sodium hydroxide, and to the solution cooled on an ice bath were simultaneously added dropwise 6.13 g of p-nitrobenzyloxycarbonyl chloride dissolved in ether and 7.5 ml of 4N sodium hydroxide. After 2 hours of stirring at the same temperature, the solution was washed with ether, an aqueous layer was adjusted to acidic with concentrated hydrochloric acid, and a precipitated solid material was collected by filtration, washed with water and then dried to yield 4.48 g of (2S)-4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyric acid.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].CCCCC.[CH3:17][C:18]([CH:21]=O)([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>FC(F)(F)S(O)(=O)=O>[C:18]([C@H:21]1[O:10][C:1](=[O:11])[C@@H:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:3]1)([CH3:20])([CH3:19])[CH3:17]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: CC(C)(C)C=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCCCC
Product: CC(C)(C)[C@H]1OC(=O)[C@@H](c2ccccc2)O1
Temperature: 36 °C
Reaction time: 5.5 h
Yield: 83.1 %

Procedure:
(R)-Mandelic acid (20 g, 130 mmol) was dissolved in anhydrous pentane (200 mL, 1.7 mol). Pivaldehyde (13.6 g, 153 mmol) was added followed by trifluoromethanesulfonic acid (488 μL, 5.4 mmol). The reaction was allowed to reflux at 36° C. under nitrogen. After 5.5 hours, the mixture was allowed to cool to room temperature before stirring with 200 mL of an 8 wt % NaHCO3 solution for 10 minutes. Excess pentane was removed by rotary evaporation. The solids were collected by filtration and rinsed (100 mL water) while under vacuum filtration. The solids were dried overnight under high vacuum to yield intermediate (1a) as a white solid (23.8 g, 88% purity).
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[F:25]>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[NH:6][CH:5]=[N:4][C:3]=2[C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)=[CH:18][C:17]=1[F:25]
Reactant: N#Cc1ccnc(-c2nc[nH]c2Br)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: N#Cc1ccnc(-c2nc[nH]c2-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C15H8ClFN4, 300. Found, 299, 301.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][NH2:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:39][CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([F:34])[CH:36]=5)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4ccnc(NCc5cccc(F)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (140 mg, 0.3 mmol) and 3-fluorobenzylamine (148 mg, 1.2 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford (4-{3-[2-(3-fluoro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 110 mg, 69.6%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O)[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14].Cl.[C:32]([O:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])([CH3:35])([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO.O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])=[O:14])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][NH:39][CH:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:44]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)C(Cc1ccccc1C=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(NCc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-formyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (250 mg, 0.590 mmol) in methanol (15 mL) and treat with L-leucine tert-butyl ester hydrochloride (0.66 g, 3.0 mmol). Stir at room temperature for 2 hours with 3A molecular sieves, add sodium cyanoborohydride (0.6 mL of a 1.0M solution in tetrahydrofuran, 0.6 mmol), stir for 0.5 hours, add additional sodium cyanoborohydride (0.3 mL) and stir for 5 hours. Filter through filter aid, evaporate the solvent in vacuo and partition the residue between methylene chloride (100 mL) and saturated sodium hydrogen carbonate (40 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography (5:1 hexane/ethyl acetate followed by 3:1 hexane/ethyl acetate) to give the title compound (221 mg, 63%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22](Cl)(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:27]([OH:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>C1COCC1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[O:19][C:20](=[O:26])[NH:21][S:22]([O:39][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: CCCCCCCCCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOS(=O)(=O)NC(=O)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of [1,1':3',1"-terphenyl]-2'-yl(chlorosulfonyl)carbamate (5.0 g, 12.9 moles) in 75 mL THF was added dropwise to a solution of n-dodecyl alcohol (2.4 g, 12.9 mmoles) and triethylamine (1.3 g, 12.9 mmoles) in 100 mL THF at ~15° C. under an atmosphere of N2. The mixture was allowed to warm to room temperature for 16 hours, then concentrated in vacuo and partitioned between H2O and EtOAc. The EtOAc layer was dried with MgSO4 and evaporated to give a white solid. Chromatography (SiO2, 10% EtOAc/hexanes) gave 2.95 g of the title compound, mp 124°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[NH4+:16]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([S:11]([NH2:16])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 5.00 g 3-fluoro-4-nitrobenzenesulfonyl chloride in 20 mL acetonitrile cooled in an ice bath was added dropwise 4.40 mL of a 30% ammonium hydroxide solution. After removal of the ice bath, stirring was continued for 30 min. at room temperature. Water was added and the mixture was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness to give 4.65 g (99%) of a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 2H), 7.89 (d, J=9.33 Hz, 1H), 7.92 (dd, J=10.23, 1.81 Hz, 1H), 8.14-8.21 (m, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=1)#[CH:34]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:34]#[C:33][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][OH:42])=[CH:37][CH:36]=3)[CH:17]=[C:18]([O:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:19]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: C#Cc1ccc(CO)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C

Procedure:
(4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (270 mg; 0.46 mmol), (4-ethynyl-phenyl)-methanol (296 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110° C. for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 270 mg (83%). HPLC-MS: m/z: 587.1 (M+H)+; Rt: 2.96 min.