Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([OH:14])=[C:10]([C:12]#[N:13])[N:11]=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Na].[CH2:16](I)[CH3:17]>C(O)C>[CH2:16]([O:14][C:9]1[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]2=[N:11][C:10]=1[C:12]#[N:13])[CH3:17]
Reactant: CCI
Reactant: CCn1ncc2nc(C#N)c(O)nc21
Agent: [Na]
Solvent: CCO
Product: CCOc1nc2c(cnn2CC)nc1C#N

Procedure:
18.9 g. of 1-ethyl-6-hydroxy-1H-pyrazolo[3,4-b]-pyrazine-5-carbonitrile (0.1 mol.) are added to a solution of 2.3 g. of sodium (0.1 mol.) in 500 ml. of absolute ethanol and the mixture is stirred for 30 minutes at room temperature. Then the alcohol is distilled off in vacuo and the sodium salt is dissolved in dry dimethylformamide. Then 23.5 g. of ethyl iodide (0.15 mol.) are added and the solution is heated in an autoclave at 120° for 5 hours. After the dimethylformamide is removed in vacuo, the residual 6-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carbonitrile (19.1 g.) is recrystallized from hexane, yield 17 g. (78%), m.p. 73°-74°.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[C:5]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([O:16]C)=[O:15])=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+]>CO.O>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]1[C:5]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[CH:9][CH:8]=2)[CH3:26]
Reactant: CCN(CC)c1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of methyl 3-(diethylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (95.0 mg, 0.27 mmol,) in methanol (20 mL) was added a solution of NaOH (20 mg, 0.50 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (5 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(diethylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (50 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.Cl[C:9]1[N:10]=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:12]2[N:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:16]=[CH:15][C:13]=2[N:14]=1>>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:9]2[N:10]=[C:11]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:12]3[N:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: Cc1cc(Nc2nc(N3CCOCC3)c3nc(CN4CCC(C(C)(C)O)CC4)ccc3n2)n[nH]1

Procedure:
Following General Procedure C, 5-methyl-1H-pyrazol-3-amine and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 106. LCMS (MH+)=467.3. 1H-NMR (DMSO-d6): δ 11.8 (s, 1H), 8.91 (s, 1H), 7.78 (s, 1H), 7.62 (d, 1H), 6.48 (s, 1H), 4.39 (s, 4H), 3.99 (s, 1H), 3.76 (m, 4H), 3.59 (s, 2H), 2.90, (m, 2H), 2.19 (s, 3H), 1.93 (m, 2H), 1.63 (m, 2H), 1.24 (m, 2H), 1.16 (m, 1H), 1.03 (s, 6H)
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].O.[Cl-].[NH4+]>CN(C)C=O>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][S:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(CCl)OC
Reactant: Oc1cccc(S)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CSc1cccc(O)c1)OC
Reaction time: 3 h

Procedure:
The S-sodium salt of 3-mercaptophenol prepared in Example 7 was dissolved in dimethylformamide (25 ml) and charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The solution was heated to a temperature of 45 to 50° C., and 1-chloro-2,2-dimethoxyethane (3.15 grams) was added with stirring. After the addition was completed, stirring was continued for a period of about 3 hours. After this time the reaction mixture was poured into water (150 ml), and the resulting mixture was carefully neutralized with ammonium chloride. The mixture was then extracted with chloroform and the organic phase was separated. The organic portion was washed with water and then dried with phase separation paper. The dried solution was then stripped of solvent, leaving an oil. This oil was distilled, and the fraction boiling at 138° to 144° C. at 0.04 mm of Hg pressure was collected to yield the desired product 3-(2,2-dimethoxyethylthio)phenol.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[Cl:21][C:22]1[C:23](OS(C(F)(F)F)(=O)=O)=[CH:24][C:25]([CH3:34])=[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>COCCOC.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>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:23]3[CH:24]=[C:25]([CH3:34])[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:22]=3[Cl:21])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]
Reactant: CCOC(=O)Cc1cc(Cl)c(OS(=O)(=O)C(F)(F)F)cc1C
Reactant: Cc1nc(C)c(-c2ccc(B(O)O)cc2)nc1C(N)=O
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: [Cl-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)Cc1cc(Cl)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)cc1C
Temperature: 85 °C
Reaction time: 17 h
Yield: 70.7 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 284 mg, 1.05 mmol) and ethyl 2-(5-chloro-2-methyl-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 3-2; 336 mg, 0.93 mmol) and 2M sodium carbonate (0.757 mL, 1.51 mmol), tetrakis(triphenylphosphine)palladium(0) (66.7 mg, 0.06 mmol) and lithium chloride (69.1 mg, 1.63 mmol) in DME (20 mL) and ethanol (5 mL) was degassed and then stirred at 85° C. After 4 hours further tetrakis(triphenylphosphine)palladium(0) (100 mg) and 2M sodium carbonate (0.5 mL) were added and heating was continued for a further 17 hours (overnight). The reaction mixture was allowed to cool, evaporated and partitioned between EtOAc (100 mL), water (50 mL) and 2M HCl (10 mL). The aqueous phase was re-extracted with EtOAc (100 mL), the combined organic extracts were dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-5-methylbiphenyl-4-yl)acetate (288 mg, 70.6%) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[C:14]([C:19]([NH2:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:23][CH3:24])C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:22][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:23][CH3:24])[CH:11]=2)[N:16]=[CH:15][C:14]=1[C:19]([NH2:21])=[O:20]
Reactant: COc1cc2c(Cl)c(C(N)=O)cnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Cl)c(C(N)=O)cnc2cc1O
Yield: 71 %

Procedure:
A mixture of 7-Benzyloxy-4-chloro-6-methoxy-3-quinolinecarboxamide (1.0 g, 2.9 mmol) prepared analogous to the method described in Example 1 and thioanisole (1.75 ml, 14.1 mmol) in TFA (15 ml) was refluxed for three hours. After cooling, the solvents were removed at reduced pressure and the residue was poured on water and alkalized with aqueous ammonia. The precipitate was filtered, washed with water and dried affording 0.52 g (72% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14].N1C=CC=CC=1.CN1CCCC1=O>CC(OC)(C)C.[Cu]=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]2[O:9][C:13]([CH2:12][CH2:11][OH:15])=[CH:14][C:6]=2[CH:7]=1
Reactant: C#CCCO
Reactant: Oc1c(Cl)cc(Br)cc1I
Agent: O=[Cu]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: COC(C)(C)C
Product: OCCc1cc2cc(Br)cc(Cl)c2o1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 66.2 %

Procedure:
The product of step A (14.0 g, 42.76 mmol) was added to a mixture of but-3-yn-1-ol (3.24 mL, 42.79 mmol), copper(II)oxide (3.67 g, 25.67 mmol), pyridine (21.3 mL) and N-methylpyrrolidone (85.0 mL). The reaction mixture was heated to 70° C. for 12 h then 100° C. for a further 2.5 h. The mixture was diluted with MTBE (200 mL), washed successively with 5% aq NH4OH (200 mL), 0.5 M NaOH (200 mL) and saturated brine solution (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing 2-(5-bromo-7-chlorobenzofuran-2-yl)ethanol (7.8 g, 66%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.52 (d, J=1.6 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 6.52-6.51 (m, 1H), 4.02 (q, J=6.0 Hz, 2H), 3.09 (t, J=6.2 Hz, 2H), 1.65 (t, J=5.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:25]#[N:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>N.CO.[Ni]>[NH2:26][CH2:25][C:10]1[CH:9]=[C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])[CH:24]=[CH:23][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2CN)cc1
Reaction time: 12 h
Yield: 74 %

Procedure:
The product of step A (2.5 g, 6.80 mmol) was diluted with 7N ammonia/methanol (30 mL) followed by the addition of Raney Nickel (0.0583 g, 0.680 mmol). The reaction mixture was purged three times with hydrogen and stirred for 12 hours. The reaction mixture was then filtered through a GF/F filter and concentrated. The residue was purified using a biotage 40M column eluting with methylene chloride:MeOH:NH4OH (90:9:1) to yield methyl 4-(2-(aminomethyl)-4-(2-tert-butoxy-2-oxoethyl)phenoxy)benzoate (1.87 g, 74.0% yield) as a clear oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:24]1[CH2:29][CH2:28][N:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:30]([N:27]1[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)N1CCOCC1)OCc1ccccc1

Procedure:
Analogously to Example 7b), 7.69 g (22.8 mmol) of glycine-benzyl ester 4-toluenesulfonate and 2.8 g (19 mmol) of (morpholinocarbonyl)chloride in 118 ml of methylene chloride and 9 ml (53 mmol) of N-ethyldiisopropylamine are reacted for 18 h. The title compound is obtained in pure form after extraction with methylene chloride and digestion with hexane: tRet (I)=11.6 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([C:11]2[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][C:16]([O:23][CH2:24][O:25][CH3:26])=[CH:15][C:12]=2[CH:13]=[O:14])=[CH:8][CH:7]=1.[CH2:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(OCC)C.C1([Li])C=CC=CC=1.O>C(OCC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([C:11]2[C:18]([O:19][CH2:20][O:21][CH3:22])=[CH:17][C:16]([O:23][CH2:24][O:25][CH3:26])=[CH:15][C:12]=2[CH:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[OH:14])=[CH:8][CH:7]=1
Reactant: C1CCCCC1
Reactant: COCOc1cc(C=O)c(-c2ccc(C3OCCO3)o2)c(OCOC)c1
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: O
Product: COCOc1cc(OCOC)c(-c2ccc(C3OCCO3)o2)c(C(O)c2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
2-[5-(1,3-Dioxolan-2-yl)furan-2-yl]-3,5-bis(methoxymethoxy)benzaldehyde (135 mg, 0.374 mmol) was dissolved in diethyl ether (10 mL), and the solution was cooled to −78° C., and then cyclohexane/diethyl ether solution of 1.06 mol/L phenyllithium (0.54 mL, 0.57 mmol) was added thereto and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was extracted out under reduced pressure. The resulting residue was purified through preparative thin-layer chromatography (chloroform/methanol=50/1) to obtain 1-{2-[5-(1,3-dioxolan-2-yl)furan-2-yl]-3,5-bis(methoxymethoxy)phenyl}-1-phenylmethanol (93.9 mg, 57%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[N+:15]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21](Cl)=[N:22][OH:23])([O-:17])=[O:16]>O1CCOCC1>[NH2:7][C:4]1[N:5]([C:21](=[N:22][OH:23])[C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(C(Cl)=NO)c1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(N)n(C(=NO)c2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
4.85 g (0.05 mol) of 3(5)-amino-5(3)-methyl-pyrazole in 50 ml of absolute dioxan are treated with 8.3 ml (0,06 mol) of triethylamine and then, under stirring at room temperature, are treated dropwise with a solution of 10 g (0.05 mol) of 3-nitro-benzohydroximoyl chloride in 50 ml of absolute dioxan. Stirring is continued for 3 hours and then the mixture is evaporated to dryness. The residue is treated with water and ethyl acetate. The organic phase is dried over magnesium sulphate, evaporated under vacuum and the residue obtained in this way is recrystallised from dioxan. 9.8 g (48%) of 5-amino-1-(3-nitro-benzohydroximoyl)-3-methyl-pyrazole with a m. pt. of 224° to 226° C. are obtained.
Reaction SMILES: COC(=O)[CH2:4][CH2:5][N:6]([C@H:18]([CH3:32])[CH2:19][N:20]([C:25](OC(C)(C)C)=[O:26])[CH2:21][CH2:22][CH2:23][OH:24])[C:7](=[O:17])/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1>Cl.CO>[Cl:16][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:7]([N:6]2[CH2:5][CH2:4][C:25](=[O:26])[N:20]([CH2:21][CH2:22][CH2:23][OH:24])[CH2:19][C@H:18]2[CH3:32])=[O:17])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CCN(C(=O)/C=C/c1cccc(Cl)c1)[C@H](C)CN(CCCO)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@@H]1CN(CCCO)C(=O)CCN1C(=O)/C=C/c1cccc(Cl)c1
Reaction time: 4 h
Yield: 62 %

Procedure:
63.1 g (0.13 mol) of 3-{{(R)-2-[tert-butoxycarbonyl-(3-hydroxy-propyl)-amino]-1-methyl-ethyl}-[(E)-3-(3-chloro-phenyl)-acryloyl]-amino}-propionic acid methyl ester was dissolved in 130 ml of 4 N HCl in MeOH. The reaction was stirred for 4 h after which time it was evaporated to dryness and the residue redissolved in CH2Cl2, washed with sat. aq. NaHCO3, dried (Na2SO4) and the mixture concentrated to 300 ml. 3.6 g (0.03 mol) of 1,5,7-triazabucyclodec-5-ene was then added and the mixture stirred for 16 h after which time the solvent was evaporated. The residue was redissolved in 100 ml of MeOH and 6N NaOH was added until the pH was basic and the mixture stirred for 1 h. The solvent was evaporated, the residue redissolved in CH2Cl2, washed with 10% citric acid solution, washed with sat. aq. NaHCO3, dried (Na2SO4) and concentrated. This afforded the titled compound in 62% yield as a colorless foam. MS: 351.2 (MH+, Cl).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C:23]4([F:36])[F:35])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:37].O1CCOCC1.CCOCC>CO>[ClH:37].[ClH:37].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]4([F:36])[F:35])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)C(F)(F)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1cc(OC2CCNCC2(F)F)c2nc(-c3nnc4ccccn34)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-yloxy)-3,3-difluoropiperidine-1-carboxylate (0.072 g, 0.144 mmol) was dissolved in MeOH (0.72 mL) and treated with 4.0 M HCl in dioxane (0.360 mL, 1.44 mmol), then stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in MeOH and concentrated three times. The residue was chromatographed on SiO2 eluting with a gradient of 2% NH4OH in isopropanol/methylene chloride. The desired product was dissolved in MeOH (2 mL), treated with 2.0 M HCl in ether (0.809 mL, 1.62 mmol) and concentrated in vacuo. The residue was again dissolve in MeOH and concentrated in vacuo several times, then placed under vacuum to give the desired product as a white solid (27.8 mg). MS APCI (+) m/z 400.3 (M+1) detected.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][CH2:33][CH:34](O)[CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH:34]([CH3:35])[CH2:33][NH2:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH:34]([CH3:35])[CH2:33][NH2:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC(O)CN
Solvent: CCO
Product: CC(CN)OB(c1ccccc1)C(OC(B(OC(C)CN)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (42 mg) was obtained by allowing 41 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 17 mg of 1-amino-2-propanol to act in 1 mL of ethanol.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:21][C:3]1[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=1
Reactant: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)cccc1-c1cccc(OC(F)(F)F)c1

Procedure:
In analogy to the procedure described for example 1, (3-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 2) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as dark brown amorphous solid. MS: 433.3 (MH+).
Reaction SMILES: [BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[CH2:6]([C:10]1[N:11]=[C:12]([CH3:47])[N:13]([C:32]2[CH:46]=[CH:45][C:35]([O:36][C:37]([CH3:44])([CH3:43])[C:38](OCC)=[O:39])=[CH:34][CH:33]=2)[C:14](=[O:31])[C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]#[N:30])=[CH:19][CH:18]=1)[CH2:7][CH2:8][CH3:9]>O1CCCC1.C(O)C.C(OCC)(=O)C>[CH2:6]([C:10]1[N:11]=[C:12]([CH3:47])[N:13]([C:32]2[CH:33]=[CH:34][C:35]([O:36][C:37]([CH3:44])([CH3:43])[CH2:38][OH:39])=[CH:45][CH:46]=2)[C:14](=[O:31])[C:15]=1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:22]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
Sodium borohydride (0.85 g) was dissolved in tetrahydrofuran (20 mL) and ethanol (20 mL), and calcium chloride (1.2 g) was added at 0° C. The reaction solution was stirred at 0° C. for 1 hr, ethyl 2-{4-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate (2.1 g) was added, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.2 g, 60%) as a pale-yellow liquid.
Reaction SMILES: [H-].[Na+].[CH3:3][C@H:4]1[C@@H:8]([C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)[O:7][C:6](=[O:15])[NH:5]1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[C:31]([F:37])=[CH:30][C:29]=1[O:38][CH3:39].[NH4+].[Cl-]>C1COCC1>[F:37][C:31]1[C:32]([CH:34]([CH3:36])[CH3:35])=[CH:33][C:28]([C:19]2[CH:20]=[CH:21][C:22]([C:24]([F:26])([F:27])[F:25])=[CH:23][C:18]=2[CH2:17][N:5]2[C@@H:4]([CH3:3])[C@@H:8]([C:9]3[S:10][CH:11]=[C:12]([CH3:14])[N:13]=3)[O:7][C:6]2=[O:15])=[C:29]([O:38][CH3:39])[CH:30]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Reactant: Cc1csc([C@H]2OC(=O)N[C@H]2C)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2nc(C)cs2)[C@@H]1C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 8.1 mg, 0.202 mmol) was added to a stirred solution of (4S,5S)-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one (33.4 mg, 0.168 mmol) in dry THF (1 mL) at room temperature under N2. The reaction was stirred for 15 min then a solution of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (81.0 mg, 0.202 mmol) in dry THF (2 mL) was added by cannula. The reaction was stirred at room temperature overnight. Saturated NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-70% EtOAc in hexanes gradient) and chiral HPLC (IA column, 20×250 mm, 5% i-PrOH in heptane) to afford (4S,5S)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(4-methyl-1,3-thiazol-2-yl)-1,3-oxazolidin-2-one. Rf=0.18 (20% EtOAc in hexanes). LCMS calc.=523.2; found=523.1 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.68 (s, 0.5H), 7.63 (s, 0.5H), 7.59 (d, J=8.0 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 6.99 (d, J=8.5 Hz, 0.5H), 6.95 (d, J=8.5 Hz, 0.5H), 6.88 (s, 1H), 6.68 (d, J=5.0 Hz, 0.5H), 6.66 (d, J=4.9 Hz, 0.5H), 5.70 (d, J=8.3 Hz, 0.5H), 5.55 (d, J=8.2 Hz, 0.5H), 4.72 (d, J=15.9 Hz, 0.5H), 4.64 (d, J=15.9 Hz, 0.5H), 4.20 (d, J=15.9 Hz, 0.5H), 3.95 (d, J=15.9 Hz, 0.5H), 3.91-3.83 (m, 1H), 3.75 (s, 1.5H), 3.74 (s, 1.5H), 3.23-3.15 (m, 1H), 2.40 (s, 3H), 1.26-1.18 (m, 6H), 0.65 (d, J=6.5 Hz, 1.5H), 0.55 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:16].O1CCOCC1>CCOC(C)=O>[ClH:16].[F:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CCNCC1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a hazy solution of tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (52.66 g, 242 mmol) in EtOAc (1 L) was added 4M HCl/dioxane (303 mL, 1212 mmol). The mixture was allowed to stir at ambient temperature for 16 hours. The resulting precipitate was collected by filtration, washed with EtOAc and dried in vacuo to afford 37 g (99%) of desired product as a solid.