Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:15]=[C:14](Cl)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:17]C)[CH:12]=2)[N:7]=1)=[O:5])C.[CH2:19]([S-:21])[CH3:20].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.CCOC(C)=O>[CH2:19]([S:21][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:17])[CH:12]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[N:15]=1)[CH3:20]
Reactant: CC[S-]
Reactant: CCOC(=O)c1nc(Cl)c2cc(OC)ccc2n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc(C(=O)O)nc2ccc(O)cc12
Temperature: 140 °C
Yield: 67.3 %

Procedure:
To a solution of 4-chloro-6-methoxy-quinazoline-2-carboxylic acid ethyl ester (1.22 g, 4.574 mmol) in anhydrous DMF (4.0 mL) was added sodium ethanethiolate (3.07 g, 36.59 mmol) and the reaction mixture was heated at 140° C. for 3 h. Water and EtOAc was added . The pH of the aq. layer was adjusted to 6 with citric acid. The organic layer was separated and the aq. layer was extracted with EtOAc. The combined organic layer was washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure to give 0.770 g of 4-ethylsulfanyl-6-hydroxy-quinazoline-2-carboxylic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]=[CH:17][C:16]=2[CH:26]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.[CH3:35][CH2:36][OH:37]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:15]3[C:16](=[CH:17][N:18]=[C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][C:24]4=3)[CH:26]=[CH:35][C:36]2=[O:37])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnc2ccc(Cl)cc2c1Nc1ccc(Cc2ccccc2)cc1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=c1ccc2cnc3ccc(Cl)cc3c2n1-c1ccc(Cc2ccccc2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4-(4-benzylphenylamino)-6-chloroquinoline-3-carbaldehyde (750 mg, 2.0 mmol) in EtOH (18 mL) was added triethyl phosphonoacetate (1.1 mL, 5.6 mmol) and K2CO3 (1.3 g, 9.3 mmol). The reaction mixture was stirred at 85° C. for 8 hours and then removed solvent. The reaction mixture was treated with 10 mL of water. It was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 97:3 v/v CH2Cl2:EtOH as solvent to afford title compound (510 mg, 64% yield) as a yellow solid.
Reaction SMILES: C12CC(CC1)C=C2B(O)O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=2)=[N:16][C:17]=1[CH2:18][NH:19][C@H:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22]>[Pd]>[N:16]1[CH:17]=[CH:12][CH:13]=[CH:14][C:15]=1[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O-:34])=[O:33])[CH2:28][CH:27]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]2)=[N:16][C:17]=1[CH2:18][NH:19][C@H:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22]
Reactant: CC(C)[C@H](CO)NCc1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Agent: [Pd]
Agent: OB(O)C1=CC2CCC1C2
Product: CC(C)[C@H](CO)NCc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Product: O=C([O-])N1CC=C(c2ccccn2)CC1

Procedure:
(R)-tert-butyl 5-fluoro-6-4(1-hydroxy-3-methylbutan-2-yl)amino)methyl)-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate was prepared according to Example 199, substituting tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate for bicyclo[2.2.1]hept-2-en-2-ylboronic acid. (R)-tert-butyl 5-fluoro-6-(((1-hydroxy-3-methylbutan-2-yl)amino)methyl)-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate was subjected to hydrogenation (H2 atmosphere, Pd/C catalyst) to provide the title compound. MS (ESI+) m/z 396 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1[N:21]=[C:20]([SH:22])[NH:19][N:18]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([CH2:12][S:22][C:20]2[NH:19][N:18]=[C:17]([NH2:16])[N:21]=2)=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2
Reactant: Nc1n[nH]c(S)n1
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1n[nH]c(SCc2nc3cc(Cl)c(Cl)cc3nc2Cl)n1
Reaction time: 8 h

Procedure:
2,6,7-Trichloro-3-chloromethylquinoxaline (105 mg, 0.37 mmol) and 3-amino-5-mercapto-1,2,4-triazole (48 mg, 0.41 mmol) were dissolved in DMF (3 ml). Triethylamine (0.2 ml, 1.1 mmol) was added and the dark brown solution was allowed to stand at room temperature overnight. After evaporation of the solvent under reduced pressure, the residue was taken up in ethyl acetate and water. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were concentrated in vacuo, and the residue was purified by flash column chromatography using ethyl acetate to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1O)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].CI.[C:16](=O)([O-])[O-].[K+].[K+].CN([CH:25]=[O:26])C>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:26][CH3:25])[C:7]([O:9][CH3:16])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Agent: [K+]
Solvent: CI
Product: COC(=O)c1ccc(OC)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Acetyl-4-hydroxybenzoic acid (3.60 g, 20 mmol) and methyl iodide (5.68 g, 40 mmol) were dissolved in 60 ml of DMF, followed by the addition of 11.06 g (80 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 2 hours. The DMF was distilled off under reduced pressure, followed by the addition of water. The resulting mixture was extracted with chloroform. The organic layer was dried over MgSO4, the solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone-hexane, whereby 1.42 g of the title compound were obtained as brown powder (yield: 34%).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH:6]([NH2:9])([CH3:8])[CH3:7]>>[CH:6]([NH:9][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])([CH3:8])[CH3:7]
Reactant: OCC1CO1
Reactant: CC(C)N
Product: CC(C)NCC(O)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 37 g (0.5 mole) of glycidol and 35.4 g (0.6 mole) of isopropylamine was stirred at 25° C. overnight. Excess isopropylamine was evaporated in vacuo and the mixture was distilled to give 53 g of product: b.p. 80° C./0.1 mm Hg. The NMR and IR spectra were consistent with the assigned structure and the elemental analysis was consistent with the empirical formula C6H15O2N.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.CI.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:12]1[C:6]2[CH:5]=[C:4]([O:21][CH3:22])[C:3]([O:2][CH3:1])=[CH:20][C:7]=2[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][CH2:10][C:11]1=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Reactant: BrCc1ccccc1
Solvent: CI
Product: COc1cc2c(cc1OC)N(Cc1ccccc1)C(=O)CN=C2c1ccccc1
Yield: 64 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 7,8-dimethoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaa), and MeI by benzyl bromide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 64%. M: 148–149° C. 1H-NMR (CDCl3, 200 MHz): d 3.67 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.38 (AB system, ? d=0.96, JAB=10.0 2H, CH2), 5.15 (AB system, ? d=0.70, JAB=15.4, 2H, —NCH2), 6.56 (s, 1H Ar), 6.81 (s, 1H Ar), 7.07–7.46 (m, 10H Ar).
Reaction SMILES: [H-].[Na+].[N:3]1([C:9](N)=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl.[O:24]1CC[CH2:26][CH2:25]1>>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:24][C@H:25]([CH3:26])[C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: NC(=O)N1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2CCOCC2)cc1
Yield: 58 %

Procedure:
Subsequently, to a suspension of 60% sodium hydride (8.41 g, 210 mmol) in tetrahydrofuran (120 mL) is added dropwise a solution of the above lactic morpholinamide (32.1 g) in tetrahydrofuran (150 mL) under nitrogen atmosphere with stirring under ice-cooling, and the mixture is heated with stirring at 50° C. for 30 minutes. After cooling with ice, to the mixture is added dropwise a solution of p-toluene-sulfonyl chloride (45.8 g, 234 mmol) in tetrahydrofuran (180 mL), and the mixture is stirred at room temperature for 4 hours. To the mixture is added 1N aqueous hydrochloric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and a saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. To the resulting oily residue is added diethyl ether, and the precipitated crystals are collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (36.1 g, yield: 58%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16](CC)[CH2:17]C)C.ClC(OCC)=O.C(NCC)C>O1CCCC1>[CH3:14][N:16]([CH3:17])[C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCNCC
Product: CN(C)C(=O)CCNC(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 90 %

Procedure:
N-(t-Butyloxycarbonyl)-β-alanine, 3.8 g (20 mmol) was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to 0° C. and stirred. To this mixture, 2.4 g (24 mmol) of triethylamine was added and 2.16 g (20 mmol) of ethyl chloroformate was slowly added. After stirring the reaction mixture for an hour at 0° C., 4 ml of 40% diethylamine aqueous solution was slowly added and stirred vigorously for an hour. The mixture was extracted by adding 100 ml of dichloromethane and 50 ml of water. The organic layer was washed with 1 N HCl aqueous solution and subsequently with saturated sodium bicarbonate aqueous solution. The washed mixture was dried to obtain 3.9 g (90%) of N-(t-butyloxy-carbonyl)-β-alanine dimethylamide.
Reaction SMILES: [Cl:1][C:2]1[N:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)C(OCC)=O)=[O:5]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:4](=[O:5])[CH3:6])=[CH:17][CH:18]=[CH:19][N:20]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cccnc1Cl
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1cccnc1Cl
Temperature: 130 °C
Yield: 52 %

Procedure:
A solution of diethyl 2-(2-chloronicotinoyl)malonate (267 mmol) in dimethylsulfoxide (100 ml) was added dropwise over 1.5 h to a 130° C. solution of water (10 mL) in dimethylsulfoxide (260 mL). The reaction mixture was maintained at 130° C. for an additional 2 h and was allowed to cool to rt. The reaction mixture was diluted with cold (0° C.) water (500 mL) and was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (5×200 mL), dried (sodium sulfate), and concentrated. The residue was purified by chromatography (10/1 petroleum ether/ethyl acetate) to provide 1-(2-chloropyridin-3-yl)ethanone 52% yield as yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C)C(=O)C>[CH2:17]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCCCCn1c2ccccc2c2ccccc21
Temperature: 0 °C

Procedure:
20 g of carbazole was dissolved in 100 mL dry N,N-dimethyl acetamide (DMAc) in a 500 mL round bottomed flask. NaH (60% in mineral oil) was added into the flask slowly in nitrogen to form a mixture. The mixture was stirred for 20 minutes in ice/water bath. 30 g of 1-bromohexane was then added slowly to the flask and stirred for 6 hours in ice/water bath. The resulting solution was poured into 2L deionized water and extracted with ethyl acetate several times. The extract was re-extracted by deionized water. The final extract was concentrated by a rotary evaporator and further purified by column chromatography. A product of the following structure was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH3:5].Cl[CH2:27][C:28]1([CH3:32])[CH2:31][O:30][CH2:29]1.CN(C)C=[O:36]>>[F:3][C:4]([F:25])([C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH2:5][O:36][CH2:27][C:28]1([CH3:32])[CH2:31][O:30][CH2:29]1
Reactant: CN(C)C=O
Reactant: CC1(CCl)COC1
Reactant: CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CC1(COCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A dispersion of 50 weight percent sodium hydride (4.0 g, 83 mmol) in mineral oil was washed with hexanes and suspended in 200 milliliters of dimethylformamide. A solution of 30 grams of 2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctan, 1-ol (75 mmol) in 50 milliliters of dimethylformamide was added over a period of 3 hours, and the resulting mixture was stirred at room temperature for one hour. Next, a solution of 9.3 grams (77 mmol) of 3-chloromethyl-3-methyloxetane in 20 milliliters of dimethylformamide was added and the resulting mixture was heated at 75° C. for 16 hours. The mixture was cooled to room temperature and slowly poured into 1 liter of ice/water and extracted with two volumes of Freon 113. The combined organic extracts were washed twice with water, once with 2 weight percent aqueous hydrochloric acid and once with brine, dried over magnesium sulfate, filtered, and evaporated to give 32 grams of crude product. The crude product was distilled under reduced pressure to give 26.5 grams (73%) of analytically pure 3-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctoxymethy)-3-methyloxetane (i.e., 15-FOX), an oil with a boiling point of 68° to 70° C./1.6mm-Hg. The experimental analyses were: 1H NMR (CDCl3 /Freon 113) δ4.49 and 4.37 (AB, J=5.5 Hz, 4H), 4.00 (triplet, J=13.2 Hz, 2H), 3.70 (singlet, 2H), and 1.32 (singlet, 3H); 13C NMR δ21.02, 40.33, 68.77 (triplet, J=146.2 Hz), 78.60, and 79.87 (signals from carbon bearing fluorine are not included due to complex splitting patterns and low peak intensities); 19F NMR δ-81.3 (3F), -119.9 (2F), -122.6 (2F), -123.3 (2F), -123.5 (2F), -123.9 (2F) and -126.8 (2F). The elemental analysis was: Calculated for C13H11F15O2 : C, 32.2; H, 2.3; F, 58.9. Found: C, 32.2; H, 2.2; F, 58.3.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:28][C:27]3[CH:29]=[CH:30][C:24]([Cl:23])=[CH:25][C:26]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Yield: 70.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (1.2 g, 3.6 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoroaniline (444 μl, 4 mmol) in isopropanol (40 ml) was heated at reflux for 1.5 hours. The mixture was allowed to cool, the precipitate was collected by filtration, washed with isopropanol then ether and dried under vacuum to give 7-benzyloxy4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (1.13 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][CH2:54][C:55]1[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:17]([NH:53][CH2:54][C:55]2[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=2[CH3:61])=[O:19])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[N:8]([CH3:15])[CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CN(c1cc(Cl)nc(C(=O)O)c1Cl)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2nc(Cl)cc(N(C)C3CCOCC3)c2Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirred solution of 3,6-dichloro-4-[methyl(oxan-4-yl)amino]pyridine-2-carboxylic acid (85 mg, 0.28 mmol) in DMF (2 ml) was added DIPEA (73 μl, 0.42 mmol) and HATU (127 mg, 0.33 mmol). The reaction was stirred at room temperature for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 52 mg, 0.31 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction mixture was then poured onto 50 ml of water and the aqueous phase was extracted with EtOAc (3×50 ml), washed with brine (50 ml) dried (Na2SO4) and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 5% MeOH in DCM and evaporated to give a glassy solid which was triturated with diethyl ether and filtered to afford the title compound as a white powder (50 mg, 41%). LC-MS 95%, m/z=439.0/440.8, 1H NMR (500 MHz, Chloroform-d) δ 11.33 (br. s, 1H), 8.20 (br. s, 1H), 6.79 (s, 1H), 5.93 (s, 1H), 4.51 (s, 2H), 4.02 (dd, J=11.4, 3.8 Hz, 2H), 3.92-3.72 (m, 1H), 3.39 (t, J=11.3 Hz, 2H), 2.78 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H), 1.89 (tt, J=12.0, 6.2 Hz, 2H), 1.83-1.52 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1.CO.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)c1cn(-c2ccc(Br)cn2)nn1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc(Br)cn2)nn1
Temperature: 70 °C
Yield: 97.5 %

Procedure:
To a solution of methyl 1-(5-bromopyridin-2-yl)-1H-1,2,3-triazole-4-carboxylate (240 mg, 0.85 mmol) in a mixture of tetrahydrofuran (2.4 ml), methanol (2.4 ml) and water (2.4 ml) lithium hydroxide hydrate (107 mg, 2.54 mmol) was added. The solution was heated to 70° C. for 3 h. Most of the organic solvent was removed under reduced pressure. Water was added and the solution was extracted once with ether. Then 4 N hydrochloric acid was added to reach acidic pH. The product precipitated and the mixture was extracted three times with ethyl acetate. The organic layers were combined, dried (MgSO4) and evaporated to yield a light brown solid (223 mg, 98%). MS (ISP): 269.4 ({79Br} [M+H]+), 271.4 ({81Br} [M+H]+).
Reaction SMILES: [NH2:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:1][CH:2]([CH3:18])[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A solution of tert-butyl 4-(3-aminobutyl)piperidine-1-carboxylate (3.58 g) and acetic anhydride (4.13 g) in ethyl acetate (100 mL) was heated under reflux for 3 hr. The reaction mixture was allowed to cool to room temperature, washed with aqueous citric acid solution and 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 (hexane/ethyl acetate) to give the title compound (2.65 g).
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([O-:5])=O.CCN(CC)CC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1>C1COCC1.ClC(OCC)=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:3](=[O:5])[C:2]([F:1])([F:17])[C:6]2([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)[CH:33]=1
Reactant: COc1ccc(OCc2cc([C@@H]3CCCN3)no2)cc1OC
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)[O-])C1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)no2)cc1OC
Reaction time: 0.5 h
Yield: 217 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (87.83 g) and Et3N (122 mL) in THF (2000 mL), ethyl chloroformate (30.8 mL) was added at room temperature and the mixture was stirred for 30 minutes. To the reaction mixture, a THF (500 mL) solution of the compound (89.00 g) obtained in Example 1-(1) was added dropwise at room temperature over an hour and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and AcOEt (2 L) and a saturated aqueous solution of NH4Cl (2 L) were added; after filtering the insoluble matter, the organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 L), dried (MgSO4), filtered and concentrated to give a crude product (165.0 g). A similar method was applied using 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (34.64 g) and (S)-5-((3,4-dimethoxyphenoxy)methyl)-3-(pyrrolidin-2-yl)isoxazole (35.10 g) to give a crude product (60.10 g), which was combined with the first crude product and further purified by silica gel chromatography (AcOEt/hexane) and NH-form silica gel chromatography (AcOEt/hexane); the purified product was recrystallized (Et2O/pentane) to give the titled compound (134.30 g, colorless powder.)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[CH3:9][C:10]([S:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[N:15]/[S:13]([C:10]([CH3:12])([CH3:11])[CH3:9])=[O:14]
Reactant: CC(C)(C)S(N)=O
Reactant: Cn1ccnc1C=O
Solvent: ClCCl
Product: Cn1ccnc1/C=N/S(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
In a 25 mL vial, cupric sulfate (1.96 g, 12.3 mmol), 1-methyl-1H-imidazole-2-carbaldehyde (450 mg, 4.09 mmol) and 2-methylpropane-2-sulfinamide (594 mg, 4.9 mmol) were combined with dichloromethane (2 ml) to give a light blue suspension. The reaction mixture was stirred at 25° C. for 15 h then filtered through Celite. The reaction mixture was filtered again through silica gel eluting with ethyl acetate. The crude reaction mixture was concentrated in vacuo to provide 670 mg (76%) of 2-methyl-propane-2-sulfinic acid 1-(1-methyl-1H-imidazol-2-yl)-meth-(E)-ylideneamide as an oil. 1H NMR (300 MHz, CDCl3): δ 8.62 (s, 1H), 7.27 (bs, 1H), 7.08 (bs, 1H), 4.02 (s, 1H), 1.26 (s, 9H).