Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[C:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:11](=[C:18]2[CH2:23][CH2:22][N:21]([CH3:27])[CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)[CH3:26]
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)C(=O)c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCN(CC)C(=O)c1ccc(C(=C2CCN(C)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.2 %

Procedure:
N,N-Diethyl-4-[(piperidin-4-ylidene)-phenyl-methyl]-benzamide (0.34 g, 1.0 mmol) was disolved in acetonitrile (5 mL). Potassium carbonate (0.14 g, 1.0 mmol) and methyl iodide (63 μL, 1.0 mmol) was added with stirring at 25° C. After 30 min., the reaction mixture was evaporated and put onto silica gel for purification by chromatography using 0 to 10% MeOH(10% Ni40H) in CH2Cl2 to give 48 mg of the final product (28% of converted starting material), which was converted to the hydrochloride salt by treatment with HCl in ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:14][C:15](=[O:17])[CH3:16])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH2:23]([O:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a mixture of N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine (3.0 g) in dimethylformamide (60 ml) was added NaHCO3 (2.05 g) at −2° C., and a solution of benzyl bromide in dimethylformamide (60 ml) was added by using a dropping funnel under stirring. The mixture was stirred overnight around 26° C., then poured into a mixture of ice-water (300 ml) and hexane-ethyl acetate (8:2, 500 ml). After the organic layer was separated, the aqueous layer was extracted again with hexane-ethyl acetate (8:2, 300 ml). The combined organic layer was washed with water (300 ml×2), brine (300 ml) and dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with hexane-ethyl acetate (8:2) to give N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine benzyl ester (3.68 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccc(Cl)cc2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-chloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (95 mg, 0.249 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (43 mg, 1.02 mmol). The reaction was heated to 60° C. for 4 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 45 as yellow solid (49 mg, 56%). ESI-MS m/z: 354 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.34 (d, J=7.2 Hz, 1H), 8.27 (s, 1H), 7.68-7.56 (m, 5H), 2.84 (s, 3H), 2.55-2.52 (m, 1H), 2.39 (s, 3H), 1.08-1.05 (m, 2H), 0.80-0.78 (m, 2H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])[CH2:15][CH2:14]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])[CH2:15][CH2:14]1
Reactant: CCCC[C@H](NC(=O)C1CCC(CNC(=O)OCc2ccccc2)CC1)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](NC(=O)C1CCC(CN)CC1)C(=O)OC
Reaction time: 4 h

Procedure:
A mixture of methyl N-{[4-({[(benzyloxy)carbonyl]amino}methyl)cyclohexyl]carbonyl}-L-norleucinate (830 mg, 1.98 mmol), 10% palladium on C (0.056 g) in methanol (10 mL) was stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the filter cake washed with methanol (2×15 mL). The combined methanol was concentrated under reduced pressure to provide the titled compound as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10])=[O:2].[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>C(O)C.O>[OH:2][CH2:1][C:3]1[C:8]([Cl:9])=[CH:7][N:6]=[CH:5][C:4]=1[Cl:10]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CCO
Product: OCc1c(Cl)cncc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65.9 %

Procedure:
A cold (0° C.) solution of 4-formyl-3,5-dichloro-pyridine (3.0 g) in ethanol (50 mL) is treated with sodium borohydride (0.7 g), portionwise, during 5 minutes. The resulting mixture is stirred at 0° C. for 10 minutes, and then treated with aqueous hydrochloric acid (5 mL; 2 M), followed by basification to pH 7 by treatment with saturated aqueous sodium hydrogen carbonate solution. The mixture is diluted with water (500 mL) and extracted with ethyl acetate (4×150 mL). The combined organic washings are dried over magnesium sulfate, and the solvent removed under reduced pressure. The resulting residue is recrystallised from t-butyl methyl ether to give 4-hydroxymethyl-3,5-dichloropyridine (2.0 g), in the form of a white solid, m.p. 87-88° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:28])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:21])[C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:8]2)=[O:4].[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:16]1([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:28])[C:5]([C:3]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCC2)c1O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A mixture of 1-cyclopentylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.093 mmol), β-alanine (660 mg, 7.4 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 20 mg of the title compound as a yellow solid. MS: (+) m/z 436.38 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:29]1[N:34]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:3][CH:2]([OH:1])[CH2:5]3)=[O:7])[CH2:9]2)[O:26][N:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: CC(C)(C)C(N)=NO
Product: CC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
100 mg (0.269 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 34.3 mg (0.295 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 45 mg (37% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([N:11]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](=[O:36])[NH:28][O:29]C3CCCCO3)=[CH:21][N:20]=2)C(=O)OC(C)(C)C)[CH2:7]1.CO.[ClH:42]>CO>[ClH:42].[ClH:42].[F:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:19]2[N:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[C:27]([NH:28][OH:29])=[O:36])=[CH:23][CH:24]=2)[CH2:7]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(/C=C/C(=O)NOC2CCCCO2)cn1)[C@@H]1CCN(Cc2cccc(F)c2)C1
Agent: Cl
Solvent: CO
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(Cc3cccc(F)c3)C2)nc1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl](5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)carbamate [(251 g) in MeOH (37 mL) was added hydrogen chloride methanol reagent 10 (9.28 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in dioxane (12 mL). To the reaction mixture was added 4N HCl in dioxane and stirred for 1 hour at ambient temperature. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(6-{[(3R)-1-(3-fluorobenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (1.87 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][NH:30][CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(CC)CC.[C:41](Cl)(=[O:43])[CH3:42]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][N:30]([C:41](=[O:43])[CH3:42])[CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CNCC21
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CN(C(C)=O)CC21
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a mixture of N-(3-chloro-4-fluorophenyl)-6-(3-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)propoxy)-7-methoxyquinazolin-4-amine (0.10 g) and Et3N (0.072 g) at 0° C. was added acetyl chloride (0.019 g) dropwise and the reaction was continued to stir for 2 h at same temperature. Then the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent of the filtrate was removed by reduce vacuum pressure, and the residue was recrystallized from DCM/PE to give the title compound (0.04 g, 40.00%), HPLC: 96.24%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 514.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.50-1.53 (m, 2H), 1.83-1.87 (m, 2H), 2.25-2.29 (m, 3H), 2.30 (s, 3H), 2.44 (t, J=4.2 Hz, 2H), 2.90-2.93 (m, 1H), 3.50-3.61 (m, 4H), 4.03 (s, 3H), 4.08 (t, J=4.8 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57-7.60 (m, 1H), 7.91-7.95 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[OH:37][CH2:38][CH2:39][NH2:40]>>[OH:37][CH2:38][CH2:39][NH:40][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: NCCO
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCCO)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-hydroxyethylamine according to Procedure K: mp>230° C.; Anal. Calcd for C17H17N5O5S: C, 50.61; H, 4.25; N, 17.36. Found: C, 50.53; H, 4.28; N, 17.27.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH:11]([CH3:12])[C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH3:32])[CH:25]=[CH:24][C:23]([S:26]([N:29]=[C:30]=[O:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH:11]([CH3:12])[C:10](=[O:13])[N:9]2[C:30]([NH:29][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:32])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1C(=O)NN1C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)N2C(=O)C(C)N2C(c2ccccc2)c2ccccc2)cc1
Yield: 64 %

Procedure:
Following the procedure of Example 2 and using 1-(diphenylmethyl)-4-methyl-1,2-diazetidin-3-one (prepared according to Example 1B.) and p-toluenesulfonylisocyanate there is obtained 1.15 g (64%) of the title compound having a melting point of 155°-159° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]=O)([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[CH3:14][O:15][C:16]([C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:20][CH2:19]1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Reactant: O=CCc1ccccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of (2-Nitro-phenyl)-acetaldehyde (1 g, 5.98 mmol), trans-4-Aminomethyl cyclohexanecarboxylic acid methyl ester hydrogen chloride salt (1.37 g, 6.58 mmol) and TEA (0.92 mL, 6.58 mmol) in dry DCM was stirred at room temperature for 2.5 h. Sodium triacetoxy borohydride (2.53 g, 11.96 mmol) was added and the mixture stirred at room temperature for 25 min. Then (2N) HCl was added until acidic pH and the aqueous layer extracted with DCM. The organic layer was washed with a saturated solution of NaHCO3 and dried over Na2SO4 anhydrous and then evaporated to afford crude product. Finally, the crude product was purified by flash chromatography on silica (ETP/EtOAc 9/1→0/1) to obtain the titled compound (0.51 g, yield: 27%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][N:45]=[C:46]=[S:47]>>[CH3:44][NH:45][C:46]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[S:47]
Reactant: CN=C=S
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=S)NC)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and methyl isothiocyanate in Step B, the title compound was prepared.
Reaction SMILES: [CH3:1][C@@:2]([S:26]([CH3:29])(=[O:28])=[O:27])([CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:17]=[N:16]1)[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl>CCO>[OH:6][NH:5][C:3](=[O:4])[C@:2]([CH3:1])([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[CH:17]=[N:16]1
Reactant: C[C@@](CCn1cc(-c2cnccn2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: C[C@@](CCn1cc(-c2cnccn2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.182 g, 0.430 mmol) in EtOH (8 mL) was added 1M HCl (15 mL). The reaction mixture was allowed to stir at RT overnight. The reaction mixture was concentrated, and azeotroped with methanol to remove water to give (2R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]butanamide (142 mg, 97% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.49 (s, 3H) 2.21-2.33 (m, 1H) 2.68-2.80 (m, 1H) 3.06 (s, 3H) 4.05-4.15 (m, 1H) 4.22-4.32 (m, 1H) 8.12 (s, 1H) 8.40 (d, J=2.54 Hz, 1H) 8.50 (s, 1H) 8.54 (dd, J=2.54, 1.56 Hz, 1H) 8.96 (d, J=1.56 Hz, 1H) 10.93 (br. s., 1H) 11.14 (s, 1H) LC-MS M+H+340.1.
Reaction SMILES: [C:1]1([S@@:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[NH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[C:22]([NH:24][C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37]([CH:41]=2)[C:38](O)=[O:39])[CH:28]=[CH:29][CH:30]=1)=[O:23].Cl.CN(C)CCCN=C=NCC.Cl>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[C:22]([NH:24][C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:33]2[CH:41]=[C:37]([C:38]([N:9]=[S@:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])=[O:39])[CH:36]=[N:35][CH:34]=2)[CH:28]=[CH:29][CH:30]=1)=[O:23]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)O)c2)c1
Reactant: CCOC(=O)C[S@](=N)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of ethyl (S)—(S-phenylsulfonimidoyl)acetate (139 mg, 0.61 mmol) in anhydrous DMF (3 mL) at room temperature was added 5-{3-[(3-Methyl-furan-2-carbonyl)-amino]-phenylethynyl}-nicotinic acid (233 mg), catalytic amount of 4-(dimethylamino)pyridine, and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (141 mg). The reaction mixture was stirred at room temperature for 30 min. The reaction was then poured into aqueous HCl (0.5%) and extracted with EtOAc. After the aqueous layer was separated, solid sodium chloride was added and the resulting aqueous mixture was extracted again with EtOAc. The organic layers were combined, washed with brine (1×), saturated aqueous NaHCO3 (1×), then brine (1×), and finally dried with sodium sulfate. The upper solution was decanted, concentrated, and the yellow oily residue was subject to a column chromatography (silica gel, gradient elution EtOAc-Hex from 1:5 to 1:1.5) to give the title compound as a white foam (147 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:21]=[CH:20][N:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cccc(F)c1
Solvent: O
Solvent: COCCOC
Product: Fc1cccc(-c2cc(Cl)ncn2)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 24.7 %

Procedure:
A reaction vessel was charged with 0.303 g of tetrakistriphenylphosphine palladium, 1.344 g of 3-fluorophenylboronic acid, and 3.707 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.301 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 7 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.45 g of 4-chloro-6-(3-fluorophenyl)pyrimidine.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.BrBr.[Br:12][C:13]1[CH:14]=[C:15]([Cl:20])[N:16]=[N:17][C:18]=1[NH2:19].O>C(Cl)(Cl)Cl>[Br:12][C:13]1[C:18]2[N:17]([CH:5]=[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=2)[N:16]=[C:15]([Cl:20])[CH:14]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: CCOC(=O)CC(C)=O
Agent: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cn2nc(Cl)cc(Br)c2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetoacetate (2.55 mL, 20.0 mmol) was dissolved in CHCl3 (5 mL) and then the solution was cooled to 0° C. Bromine (1.03 mL, 20.0 mmol) in CHCl3 (6 mL) was added dropwise and then the reaction was stirred at 0° C. for 2 h. The reaction was warmed to rt and stirred for 16 h. The headspace of the reaction vessel was purged with air to remove HBr, and then the reaction was stirred an additional 2 h open to air. The reaction was washed with ice-cold water (20 mL) and then the aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with brine and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was placed in a 100 mL round bottom flask equipped with a stir bar and then dry DMF (10 mL) was added. 5-Bromo-3-chloro-6-aminopyridazine (2.08 g, 10.0 mmol) was added and then the reaction was stirred at rt for 4 d. The reaction was poured into water (50 mL) and then the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on an 80 g SiO2 pre-packed column eluting with 0-20% EtOAc/DCM to afford the title compound 28a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.05 (s, 1H), 7.35 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.95 (s, 2H), 1.30 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C10H9BrClN3O2: 318.0 (M+H). Found: 318.0.