Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(O[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=O)CCCCCCCC.[H][H]>[C].[Pd].C(O)(=O)C>[CH2:17]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)[CH2:18][CH2:13][CH2:14][CH2:15][CH2:16][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: [H][H]
Reactant: CCCCCCCCCC(=O)Oc1ccc(-c2ccc(OC)cc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCc1ccc(-c2ccc(OC)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 38 g of 4-phenylphenol, 9 g of sodium hydroxide, 200 ml of methanol and 20 ml of water was heated. 28 g of dimethyl sulfate was dropped in the mixture with stirring at 50° C. After one hour, 20 ml of 10N-sodium hydroxide was dropped in the solution and continued stirring for 2 hours. The crystals were obtained after the solution was cooled to room temperature. After washing with water and methanol for several times, 30 g of 4-methoxybiphenyl (O) was obtained. 154 g of (O) was dissolved with mixed solution of 200 ml of chloroform and 75 ml of carbon tetrachloride, and then 11 g of aluminum chloride powder was added to the solution. 14 g of octanic acid chloride was added to the solution with stirring after changing colour of the solution to greenish blue. 150 ml of ice-water and 5 ml of conc. hydrochloric acid was added, after refluxing 5 hours. The water layer was removed, then the organic layer was washed with 0.1N hydrochloric acid and dehydrated with magnesium sulfate anhydride, and then evaporated after filtration to obtain crude crystals of 4'-nonylcarbonyloxy-4-methoxybiphenyl (P). 13 g of (P), 1 g of 10% palladium-carbon, 130 ml of acetic acid were put into an autoclave and then gave the pressure to 25 kg/cm2 by using hydrogen. (P) was reduced by heating for 3 hours at 80° C. After substituting nitrogen for hydrogen, palladium-carbon was separated by filtrating the reacted solution. 4'-decyl-4-methoxybiphenyl (Q) was obtained after cooling and drying. 8 g of (Q), 90 ml of acetic acid 30 ml of hydrogen bromide water solution were mixed and refluxed for 5 hours to obtain crude crystals. After cooling, the crude crystals were washed with methanol to crystallize 5.5 g of 4-(4'-octylphenyl)phenol.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:17]=[C:18]([O:21]C)[S:19][CH:20]=3)=[CH:14][C:13]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]3[N:17]=[C:18]([OH:21])[S:19][CH:20]=3)=[CH:14][C:13]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3csc(OC)n3)c2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3csc(O)n3)c2s1
Temperature: 50 °C
Yield: 7.3 %

Procedure:
To a solution of 1-ethyl-3-[7-(2-methoxy-thiazol-4-yl)-5-pyridin-3-yl-benzothiazol-2-yl]-urea (0.05 g, 0.12 mmol) in dry DCM (5 mL) was added BBr3 (0.20 mL) under nitrogen atmosphere at 0° C. The reaction mixture was then heated at 50° C. for 24 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C. and then quenched with ice-cold water followed by extraction with DCM. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified over silica gel (230-400 M) using DCM-MeOH (96:4) to provide the title compound as light greenish solid (3.5 mg, 7%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:37])[C:24]=2[CH:23]=1>>[CH:23]1[C:24]2[C:25](=[O:37])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32](=[O:36])[C:33]=2[CH:34]=[CH:35][C:22]=1[CH2:21][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c(=O)[nH]c1=O
Yield: 36.3 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (175 mg, yield: 36.3%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([CH2:8][C:9](=O)[C:10]([O:12]CC)=[O:11])=O.[CH3:21][NH:22][NH2:23].O>C(O)C>[CH3:21][N:22]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:6]([C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:4]=2)=[N:23]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2cccc(C(F)(F)F)c2)cc1C(=O)O
Reaction time: 2 h

Procedure:
Following the procedure of Example 1, 5.8 g. of ethyl 3-trifluoromethylbenzoylpyruvate and 0.92 g. of methyl hydrazine were heated in ethanol solution for about one hour at about 80° C. The reaction mixture was cooled and water added. The aqueous mixture was extracted with two 100 ml. portions of ether followed by one 100 ml. portion of chloroform. The combined extracts were dried with phase separation paper. The solvents were removed from the filtrate. NMR indicated that the residue comprised the isomeric pair ethyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate and ethyl 1-methyl-5-(3-trifluoromethylphenyl)pyrazole-3-carboxylate in about a 60-40 mixture. Following the procedure of Example 2, the isomers were separated by chromatography over silica gel using dichloromethane. The faster moving fraction, comprising the desired ethyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate, was collected and the solvent removed therefrom; weight=2.0 g. The desired ethyl ester was hydrolyzed without further purification according to the following procedure. A solution of 2.0 g. of ethyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate in 40 ml. of ethanol was refluxed with a solution of 0.3 g. of sodium hydroxide in 120 ml. of water for about 2 hours. The hydrolysis mixture was cooled and then acidified with 1N aqueous hydrochloric acid. The free acid, being insoluble in the acidic aqueous solution, precipitated and was collected by filtration. Recrystallization of the filer cake yielded 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylic acid melting at 198°-9° C. after recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[N:7][C:8]([CH:11]=[CH:12][C:13]3[CH:14]=[C:15]([C@H:19]([S:32][CH2:33][C:34]4([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:36][CH2:35]4)[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([OH:31])([CH3:30])[CH3:29])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:6]2=[N:7][C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[C:15]([C@H:19]([S:32][CH2:33][C:34]4([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH2:36][CH2:35]4)[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([OH:31])([CH3:30])[CH3:29])[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(C=Cc3ccc4scc(Cl)c4n3)c2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2C(C)(C)O)c2cccc(CCc3ccc4scc(Cl)c4n3)c2)CC1
Reaction time: 5 h
Yield: 39.7 %

Procedure:
To a solution of the olefin of Step 18 of Example 1 (270 mg, 0.456 mmol) in THF at 0° C. was added BH3 in THF (1M) (1.36 mL, 1.37 mmol). The mixture was stirred for 5 hr. at room temperature. Addition of 25% aq. NH4OAc and extraction with EtOAc followed by purification by flash chromatography (15% EtOAc in toluene) afforded 110 mg (41%)of the saturated compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[NH:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1.[OH-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:10]1[C:6]([NH2:5])=[N:7][C:8]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1nc(SCc2ccccc2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1nc(SCc2ccccc2)nc1N
Reaction time: 0.5 h

Procedure:
Acetyl chloride (12.57 g) in methylene chloride (30 ml) was added to the product of stage (a) (30 g) in triethylamine (25 ml) and methylene chloride (300 ml) at 0° C., and the mixture was stirred for 30 minutes. Then 1N sodium hydroxide was added, and the solution was extracted with methylene chloride. On drying, and recrystallisation from ethyl acetate, 33 g of the desired product, mp 146° C., were obtained.
Reaction SMILES: [CH:1]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[C:19](OCC)=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([C:6]2[O:10][N:9]=[C:8]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])[C:7]=2[CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCCC1
Temperature: 0 °C
Yield: 96.5 %

Procedure:
To a solution of ethyl 5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (3.0 g, 8.6 mmol) in tetrahydrofuran (35 mL) at 0° C. was added a 1.5 M solution of diisobutylaluminum hydride in toluene (8.6 mL, 13 mmol) dropwise. The solution was allowed to stir while warming slowly for approximately 3.5 hours and was re-cooled to 0° C. An additional portion of diisobutylaluminum hydride (4.3 mL, 6.5 mmol) was added and the solution was allowed to stir for an additional 35 minutes. Then Rochelle's salt (40 mL) was added slowly at 0° C. followed by some ethyl acetate. The mixture was allowed to warm to ambient temperature and stirred overnight. The layers were separated and the ethyl acetate was washed with brine, dried over magnesium sulfate and concentrated to afford [5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (2.59 g, 82%). 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.85 (t, J=5 Hz, 1H), 4.14 (d, J=5 Hz, 2H), 3.46-3.48 (m, 1H), 2.07-1.99 (m, 2H), 1.81-1.60 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (4-benzyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (876 mg, 2.7 mmol) in methanol (20 mL) was added 10% palladium on carbon (132 mg). The resulting mixture was stirred vigorously under a hydrogen atmosphere (balloon) overnight and then filtered. The filtrate was concentrated in vacuo to give (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (601 mg, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.69-7.76 (m, 2H), 7.30 (s, 1H), 7.22-7.26 (m, 1H), 6.82 (s, 1H), 3.74 (s, 3H), 3.72 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:27])[N:11]([C@H:22]2[CH2:25][C@@H:24]([OH:26])[CH2:23]2)[C:12]2[N:13]([N:18]=[C:19]([CH3:21])[N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[C:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C(Cl)Cl>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:27])[N:11]([C@@H:22]3[CH2:25][C@H:24]([O:26][CH:38]([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:23]3)[C:12]3[N:13]([N:18]=[C:19]([CH3:21])[N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:35]
Reactant: CCOC(=O)C(C)=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](O)C2)c2nc(C)nn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OC(C)C(=O)OCC)C2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3′-fluoro-4′-{[4-(cis-3-hydroxycyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (659 mg), rhodium(II) acetate (dimer) (31 mg) and methylene chloride (5 mL) was added dropwise ethyl 2-diazopropanoate (359 mg) under an argon atmosphere at 70° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=90/10→70/30 (volume ratio)] to give the title compound as a colorless amorphous compound (553 mg, 69%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18]1[CH:19]=[C:20](O)[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.CCN(CC)CC>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([O:17][CH3:16])[CH:19]=1)(=[O:5])=[O:4]
Reactant: COc1cc(O)c2ccccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2c1
Yield: 74.2 %

Procedure:
Trifluoromethanesulfonic anhydride (9.35 g, 32.8 mmol) was added dropwise to a solution of 3-methoxy-1-naphthol (5.77 g, 32.8 mmol) and Et3N (10 ml) in dichloromethane (100 ml) at 0° C. with stirring. After 1 h the resulting solution was washed with HCl (50 ml, 1 M) and saturated Na2CO3 (50 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using EtOAc (7% in hexanes) to give the title compound (7.45 g, 74%) as a colourless oil.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[C:7]([C:10]#[N:11])[N:6]=[CH:5][C:4]=2[NH:3][CH:2]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:20][C:21]1(C)[C:25](C)(C)OB(C(C)=C)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:20]=[C:21]([C:2]1[NH:3][C:4]2[CH:5]=[N:6][C:7]([C:10]#[N:11])=[CH:8][C:9]=2[N:1]=1)[CH3:25]
Reactant: N#Cc1cc2nc[nH]c2cn1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Product: C=C(C)c1nc2cc(C#N)ncc2[nH]1
Temperature: 50 °C

Procedure:
A vial was charged with the faster eluting enantiomer (enantiomer 1) of 2-bromo-4-(5-chloropyridin-3-yl)-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 4.1, Step 3; 150 mg, 0.33 mmol), potassium phosphate (208 mg, 0.98 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (23.9 mg, 0.033 mmol). The tube was evacuated and backfilled with argon (3×). Fully degassed dioxane (1.5 mL) and water (0.15 mL) were added, followed by 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.078 mL, 0.392 mmol). The vial was sealed and heated to 50° C. for 16 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C24H26ClN5 [M+H]+ 420. found 420.
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:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[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:21](=[O:22])[CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1)[CH3:7]
Reactant: CCNCc1ccccc1F
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1F)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
N-(2-Fluorobenzyl)ethanamine (0.554 g, 3.615 mmol) was dissolved in DMF (10 ml). 3-(4-hydroxyphenyl)propanoic acid (0.546 g, 3.286 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)-methylene]-N-methylmethanaminium tetrafluoroborate (1.161 g, 3.615 mmol) and N-ethyl-N,N-diisopropylamine (0.892 g, 6.901 mmol) was 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 (starting 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 then solvent was removed by evaporation to give 0.803 g of N-ethyl-N-(2-fluorobenzyl)-3-(4-hydroxyphenyl)propanamide (yield 81.1%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.CC(O)=O.C(O[C:37]1(O[Si](C)(C)C)[CH2:39][CH2:38]1)C.[NH4+].[Cl-]>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH:37]4[CH2:39][CH2:38]4)[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CC5)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (30 mg, 0.072 mmol) in MeOH (0.7 mL) was added AcOH (35 mg, 0.58 mmol), (1-ethoxycyclopropoxy)trimethylsilane (37 mg, 0.216 mmol) and a small amount of 4 Å molecular sieves. The mixture was stirred at room temperature for 1 h before the addition of Na(CN)BH3 (14 mg, 0.216 mmol). The resulting mixture was then stirred at 60° C. for 14 h and cooled to room temperature. Saturated aqueous NH4Cl (2 mL) was added and the mixture was extracted with EtOAc (3×3 mL). The combined organic layers were concentrated and purified by preparative RP-HPLC to provide 5-chloro-N2-(4-(1-cyclopropylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 1H NMR (400 MHz, MeOD-d4) δ 7.97 (s, 1H), 7.84 (d, 1H), 7.50 (s, 1H), 6.93 (d, 1H), 6.29 (s, 1H), 5.33 (s, 1H), 2.80 (m, 1H), 2.58 (s, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.96 (m, 1H), 1.80-1.85 (m, 2H), 1.65-1.75 (m, 2H), 0.2-0.7 (m, 6H); ESMS m/z 456.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([C:16]1[CH:26]=[C:25]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20](Cl)=[O:21])([CH2:14][CH3:15])([CH3:13])[CH3:12]>N1C=CC=CC=1>[C:11]([C:16]1[CH:26]=[C:25]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1)=[O:21])([CH2:14][CH3:15])([CH3:13])[CH3:12]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Cl)c(C(C)(C)CC)c1
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(C)=O)c2)c(C(C)(C)CC)c1

Procedure:
40 grams (0.1 mol) of N-α -(2,4-di-tert-amylphenoxy)acetyl-m-aminoacetophenone (m.p.:135° C), obtained by the reaction between m-aminoacetophenone and α-(2,4-di-tert-amylphenoxy)acetyl chloride in pyridine, was dissolved in 200 ml of anhydrous ethyl ether (placed in a three-necked flask), and 0.5 g of anhydrous aluminum chloride powder was added to this solution followed by ice-cooling (about 0°-5° C.) under stirring. 16 grams (0.1 mol) of bromine was added dropwise to this mixture. After the completion of the dropwise addition, the temperature was allowed to rise to room temperature (about 20°-35° C.). Stirring was continued until the generation of hydrogen bromide stopped. Thus, white crystals were precipitated.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:26]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)=[CH:33][CH:32]=3)=[N:28][N:27]=2)=[N:11][C:12]([N:15]2[CH2:20][C@H:19]3[C@H:17]([CH:18]3[C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH2:16]2)=[CH:13][N:14]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:20][C@H:19]3[C@H:17]([CH:18]3[C:21]([N:22]([CH3:23])[CH3:24])=[O:25])[CH2:16]2)=[N:11][C:10]=1[C:26]1[O:30][C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][NH:38][CH3:39])=[CH:35][CH:36]=2)=[N:28][N:27]=1
Reactant: CN(C)C(=O)C1[C@H]2CN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2nnc(-c3nc(N4C[C@@H]5C(C(=O)N(C)C)[C@@H]5C4)cnc3N)o2)cc1

Procedure:
A solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[(1R,5S)-6-(dimethylcarbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (75 mg, 0.1 mmol) in 0.8 mL of 50% TFA-DCM mixture was stirred under an atmosphere of nitrogen at room temperature for 1 h. The solvents were evaporated and the crude material was purified via reverse phase HPLC using 10 to 99% methanol in water (TFA modifier) to obtain (1R,5S)-3-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-6-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 2H), 8.16 (d, J=8.2 Hz, 2H), 7.91 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 6.76 (s, 2H), 4.26 (t, J=5.7 Hz, 2H), 3.86 (d, J=10.2 Hz, 2H), 3.49-3.46 (m, 2H), 3.10 (s, 3H), 2.84 (s, 3H), 2.63 (t, J=5.2 Hz, 3H), 2.09 (s, 2H), 1.90 (t, J=3.1 Hz, 1H). LC/MS m/z 435.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]([O-])([O-])=O.[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[C:10]([Cl:11])[C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)O)c(N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(OC)c(Cl)c1N
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a stirred solution of compound 247d (1.9 g, 9.6 mmol) in dry DMF (25 mL) was added K2CO3 (1.32 g, 9.6 mmol) at room temperature. The reaction mixture was stirred for 30 min and methyl iodide (0.77 mL, 12.4 mmol) was added. After 2 hrs at room temperature, 5% aqueous citric acid was added. The mixture was extracted with EtOAc. Organics were washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 248d as beige solid in 50% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 3.79 (s, 3H), 3.86 (s, 3H), 6.23 (d, J=9.03 Hz, 1H), 7.75 (d, J=9.03 Hz, 1H).