Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:19][OH:20])[C:8]([NH:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:6][C@@H:7]2[CH2:8][N:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NOCc1ccccc1)[C@@H](CO)CC1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1[C@H](CC2CCCC2)CN1OCc1ccccc1
Temperature: 0 °C
Yield: 80.5 %

Procedure:
To a mixture of (2R)-3-cyclopentyl-2-(hydroxymethyl)-N-[(phenylmethyl)oxy]propanamide (22.5 g, 81 mmol) and triphenylphosphine (22.5 g, 97 mmol) in THF (800 mL) at 0° C. was added dropwise diisopropyl azodicarboxylate (18.9 mL, 97 mmol). The reaction mixture was maintained at 0° C. for 45 min and was then evaporated. Purification by chromatography on silica gel using an eluting system of hexane/EtOAc (95:5) provided (3R)-3-(cyclopentylmethyl)-1-[(phenylmethyl)oxy]-2-azetidinone (16.9 g, 81%). LCMS: (M+H)+: 260.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:16])([F:15])[C:12](O)=O>>[Cl:1][C:2]1[C:7]2[N:8]=[C:12]([C:11]([F:16])([F:15])[F:10])[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccnc(Cl)c1N
Product: FC(F)(F)c1nc2c(Cl)nccc2[nH]1

Procedure:
A mixture of 400 mg (2.79 mmol) of 2-chloropyridine-3,4-diamine [H. Dvorakova et al., Collect. Czech. Chem. Commun., 58, 629 (1993)] and a few mL of trifluoroacetic acid was stirred at reflux overnight. The cooled solution was concentrated and then re-concentrated from ethanol. Flash chromatography of the residue on silica gel [0-10% of (9:1 methanol:concentrated ammonium hydroxide solution) in dichloromethane] yielded the title compound as a foam. LC-MS 222 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](OS(C(F)(F)F)(=O)=O)=[C:9]([C:21]([O:23]CC)=O)[C:8]2=[O:26])=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10]3[N:32]4[CH2:33][CH2:34][NH:29][C:30](=[O:35])[C:31]4=[C:21]([OH:23])[C:9]=3[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(Cc2ccc(F)cc2)C1=O
Reactant: O=C1CNCCN1
Solvent: CO
Product: O=C1NCCn2c3c(c(O)c21)C(=O)N(Cc1ccc(F)cc1)CC3
Temperature: 180 °C

Procedure:
A mixture of ethyl 1-(4-fluorobenzyl)-2-oxo-4-{[(trifluoromethyl)-sulfonyl]oxy}-1,2,5,6-tetrahydropyridine-3-carboxylate (0.67 g, 1.58 mmol) and piperazin-2-one (0.63 g, 6.3 mmol) was heated in a sealed tube at 180° C. in a microwave reactor for 10 minutes with stirring. The resultant solution was diluted with methanol and was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided a semi-purified sample of title compound. Further purification of the product was achieved through formation of the corresponding tosylate. To a solution of the semipurified product (0.1 g, 0.30 mmol) and triethylamine (63 μL, 0.46 mmol) in dichloromethane (2 mL) at room temperature, toluenesulfonyl chloride (58 mg, 0.30 mmol) was added. The resultant solution was stirred at room temperature for two hours. The product was isolated and purified. A solution of the resultant tosylate (30 mg, 0.06 mmol) and sodium methoxide (10 mg, 0.18 mmol) in anhydrous methanol (0.5 mL) was heated at 60° C. for 1 hour. The resultant solution was concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3(C)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:21](Cl)(=[O:23])[CH3:22]>C(O)(=O)C>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][O:19][C:16](=[O:17])[CH3:18])[C@@H:14]([O:15][C:14](=[O:15])[CH2:12][CH3:11])[C@H:12]3[O:13][C:21](=[O:23])[CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)Cl
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Solvent: CC(=O)O
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2ccc3c(N)ncnc32)O[C@@H]1COC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step 3 (1.10 g, 3.92 mmol) in glacial acetic acid (8 mL) was added acetyl chloride (3 mL) and the mixture stirred at room temp overnight. The reaction was concentrated in vacuo and the residue was plated onto silica gel column with dichloromethane and eluded by ramping to 5% methanol in dichloromethane to give 1.5 g (94%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][C:12](=[O:14])[N:11]([C:15](=[O:28])[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-5-oxo-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[NH3:18]>>[NH2:18][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1
Reactant: N
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1Br
Product: Nc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5-amino-2′-deoxyuridine was prepared from 5-bromo-2′-deoxyuridine according to the procedure of Roberts and Visser, J. Am. Chem. Soc. 14:665–669 (1952). 5-bromo-2′-deoxyuridine (2 g, 6.2 mmol) dissolved in liquid ammonia (20 ml) was scaled in a glass tube and heated at 50° for 5 days. The tube was opened, and the ammonia was evaporated. 5-amino-2′-deoxyuridine was recrystallized from 5 ml water and 75 ml hot isopropyl alcohol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][C:15]#[C:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(OCC)(=O)C>CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14]/[CH:15]=[CH:16]/[CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (7.6 g., 0.2 mole) is dissolved in ether (225 ml.) and 1-(2-tetrahydropyranyloxy)-4-hydroxy-5-(4-fluorophenoxy)-2-pentyne (35.2 g., 0.12 mole) is added dropwise with stirring during 1.5 hour. The resulting mixture is stirred at 25° for 21 hours and then heated at reflux for 4 hours. The mixture is cooled and treated dropwise with ethyl acetate to consume excess lithium aluminum hydride. It is then poured into 600 ml. of ice-cold 20% aqueous potassium hydroxide solution. The oily product is taken up in ether, washed with water and brine, and dried over magnesium sulfate. Removal of solvent under vacuum leaves the title compound as a yellow residual oil.
Reaction SMILES: C(OC([N:8]([S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[C@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.Cl>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([S:24]([NH:8][C@H:9]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:10]([OH:12])=[O:11])(=[O:26])=[O:25])[CH2:32][CH2:31]2)=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)N(C(=O)OC(C)(C)C)S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74 %

Procedure:
A solution of tert-butyl 2-(R)-{tert-butoxycarbonyl-[4-(4-chlorophenyl)piperazine-1sulfonyl]amino}-3-phenylpropionate (579 mg, 1.15 mmol), [prepared as described in Step 2 above], in methylene chloride (20 ml) was saturated with dry hydrogen chloride gas at 0° C. The reaction vessel was sealed and the reaction mixture was stirred at RT. After 72 h, the reaction mixture was vented with nitrogen and then concentrated in vacuo. The residue was treated with methylene chloride and the product was filtered to give 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-phenylpropionic acid as a white solid (74%), mp 176.0-178.0 ° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Na].[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CO
Agent: [Na]
Product: COc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4-chloro-3-nitrobenzotrifluoride (112.8 g) in methanol (200 ml) was mixed with a solution of sodium (11.6 g) in methanol (800 ml) and stirred for 2 hours. The mixture was kept overnight and then stirred and heated under reflux for 3 hours. The solution was left overnight, filtered, and the solvent removed. The remaining oil was taken up in ether (500 ml) and washed with water. The ether solution was dried and evaporated to give 4-methoxy-3-nitrobenzotrifluoride (106 g).
Reaction SMILES: [OH-].[K+].C(O)C.[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH:20]C(=O)OC>O>[F:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][C:8]=1[NH2:20]
Reactant: COC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A 4N potassium hydroxide aqueous solution (4.75 liters) was added to an ethanol solution (3 liters) of methyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate (2.25 Kg, 7.85 mol), followed by refluxing under heating for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (5 liters) was added thereto, and the mixture was extracted with toluene (5 liters×2 portions). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the filtrate was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5-cyclopentyloxyaniline as an oily substance (1.75 Kg, 7.62 mol, 98.3% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.[Na+].[I-:18].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:6][C:7]=1[I:18]
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Reactant: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2ccc(O)c(I)c2)ccc1C#N
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 52 %

Procedure:
The product from Example 106B (4.67 g, 22.3 mmol), NaI (3.343 g, 22.3 mmol), and NaOH (892 mg, 22.3 mmol) were combined in methanol (70 mL) at 0° C. and treated with bleach (5.25%, 31.6 g) dropwise over 30 minutes. After being stirred at 0° C. for 80 minutes, the mixture was quenched with 10% aqueous sodium thiosulfate (10 mL). The mixture was acidified with 1M aqueous HCl (25 mL), neutralized with dipotassium hydrogen phosphate, recooled to 0° C., and filtered. The solids were rinsed with water, then mostly dissolved in 50% EtOAc/hexanes and filtered. When this filtrate was mostly concentrated crystals began to form. The solids were slurried with 20% EtOAc/hexanes, collected by filtration, and washed with 10% EtOAc/hexanes followed by hexanes to provide the impure title compound as a light tan powder (52% yield). MS (ESI APCI negative ion detection) m/z 334 (M−H)−; 1HNMR (300 MHz, d6-DMSO) δ 2.52 (s, 3H), 6.98 (d, 1H), 7.58-7.63 (m, 2H), 7.73 (s, 1H), 7.78 (d, 1H), 8.06 (d, 1H), 10.66 (s, 1H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)(=[O:3])[CH3:2].[CH3:16][N:17]([CH:19](OC)OC)[CH3:18]>CN(C=O)C>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:2]/[C:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 140 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of tert-butyl 3-acetylpyrrolidine-1-carboxylate (3.6 g, 16 mmol), DMF (10 mL), and DMF-DMA (20 mL) was stirred at 140° C. for 16 h. The resultant mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and evaporated to afford tert-butyl 3-((E)-3-(dimethylamino)acryloyl)pyrro-lidine-1-carboxylate (4.44 g, 97% yield) as brown oil. LCMS (ESI) m/z: 213.3 [M-56+H+].
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH3:11])=[C:7]([CH:9]=[O:10])[O:8][C:4]=2[CH:3]=1.[CH:14]1([Mg]Br)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[CH:14]1([CH:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([F:1])[CH:13]=[CH:12][C:5]=3[C:6]=2[CH3:11])[OH:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1c(C=O)oc2cc(F)ccc12
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2cc(F)ccc12
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution (20 mL) of 6-fluoro-3-methyl-1-benzofuran-2-carbaldehyde (940 mg) synthesized above in tetrahydrofuran was added a 1.0M solution (7.92 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane) to give the title object compound (931 mg, 67%) as a pale-yellow oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[C:1]([C:5]1[N:10]=[C:9]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[CH:18]=[CH:19]3)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: COC(=O)c1cnc(C(C)(C)C)nc1Cl
Product: COC(=O)c1cnc(C(C)(C)C)nc1-c1ccc2c(ccn2C)c1
Yield: 74.8 %

Procedure:
Using a procedure analogous to Example B32, methyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (0.849 g, 3.71 mmol), N-methylindole-5-boronic acid (1.30 g, 7.43 mmol) and tetrakis-(triphenylphosphine)palladium(0) (86 mg) were combined to give methyl 2-tert-butyl-4-(1-methyl-1 H-indol-5-yl)pyrimidine-5-carboxylate (898 mg, 74% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.40 (s, 9 H), 3.70 (s, 3 H), 3.82 (s, 3 H), 6.57 (s, 1 H), 7.41-7.44 (m, 2 H), 7.53 (d, J=8.6 Hz, 1 H), 7.92 (s, 1 H), 8.94 (s, 1 H); MS (ESI) m/z: 324.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH3:11])[CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].O.O1CCC[CH2:16]1>>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:16])[N:9]=[C:8]([CH3:11])[CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(C)nn1C
Reaction time: 2 h

Procedure:
Dissolve ethyl-3-methylpyrazole-5-carboxylate (1.0893 g, 7.07 mmol) in 10 mL tetrahydrofuran and add it dropwise to a suspension of sodium hydride (60%) (377.6 mg, 9.44 mmol) in 10 mL tetrahydrofuran. After 2 hours, quench the reaction with methyl iodide (excess) and stir for an additional 2 hours. Add water to the reaction and remove the tetrahydrofuran in vacuo. Partition the residue between ethyl acetate and brine. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 950.0 mg of crude 2,5-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester. Dissolve this material (950.0 mg, 5.65 mmol) in 10 mL tetrahydrofuran and add it dropwise to a slurry of lithium aluminum hydride (220.2 mg) in 20 mL tetrahydrofuran at 0° C. After 30 minutes at this temperature, heat the reaction to reflux for 2 hours. Cool the reaction to room temperature and add 20 mL ethyl acetate to the reaction. Add 5N sodium hydroxide to the reaction until a white precipitate appears. Filter the reaction and concentrate the filtrate in vacuo. Partition the residue between ethyl acetate and water. Dry the organic layer with magnesium sulfate. Filter and remove the solvent in vacuo to afford 493.7 mg of crude (2,5-dimethyl-2H-pyrazol-3-yl)-methanol. Dissolve this crude material (493.7 mg, 3.91 mmol) in 20 mL methylene chloride and add MnO2 (1.2939 g, 14.88 mmol) to the reaction mixture. Heat the reaction mixture to reflux and allow it to stir for 16 hours. Cool the reaction and filter it through a pad of celite. Concentrate the filtrate in vacuo to afford 444.5 mg of crude product. Purify via Biotage chromatography (25% ethyl acetate/Hexanes) to afford 138.7 mg of the title compound 1H NMR (CDCl3) δ 9.81 (1H, s), 6.46 (1H, s), 3.82 (3H, s), 2.24 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[CH2:4][N:5]([C@@H:13]1[C:21]2[C:16](=[C:17]([C:22](=[NH:25])[NH:23][OH:24])[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:28]([O:30][C:31]1[CH:32]=[C:33]([CH2:40][C:41](O)=O)[CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH3:29]>>[CH2:28]([O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[CH2:40][C:41]1[O:24][N:23]=[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH2:15][CH2:14][C@@H:13]3[N:5]([CH2:4][C:3]([N:2]([CH3:1])[CH3:27])=[O:26])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[N:25]=1)[CH3:29]
Reactant: CN(C)C(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(C(=N)NO)cccc21
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@@H]4N(CC(=O)N(C)C)C(=O)OC(C)(C)C)no2)cc1OCC

Procedure:
(S)-tert-butyl (4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-(dimethylamino)-2-oxoethyl)carbamate INT-64 was prepared using General Procedure 2, analogously to INT-63, from (S)-tert-butyl (2-(dimethylamino)-2-oxoethyl)(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-62 and 2-(3,4-diethoxyphenyl)acetic acid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:24])([F:23])[F:22])(=[O:3])[CH3:2].[CH3:26][S:27][CH2:28][CH2:29][NH2:30]>>[C:1]([C:4]1[C:5](=[O:25])[NH:6][C:7]2[C:12]([C:13]=1[NH:30][CH2:29][CH2:28][S:27][CH3:26])=[CH:11][C:10]([Cl:20])=[CH:9][C:8]=2[C:21]([F:22])([F:23])[F:24])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(Cl)cc(C(F)(F)F)c2[nH]c1=O
Reactant: CSCCN
Product: CSCCNc1c(C(C)=O)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12
Yield: 75.8 %

Procedure:
3-Acetyl-6-chloro-4-methylsulfoxy-8-trifluoromethyl-2-quinolinone (351 mg, 1 mmol) and methylthioethylamine (91 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (287 mg, yield: 76%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:14][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1ccc2nonc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccc2nonc2c1
Reaction time: 0.08 h
Yield: 86639240 %

Procedure:
A solution of 5-(2-hydroxyethyl)benzofurazan (1.0 g, 6.1 nmol) and carbon tetrabromide (2.6 g, 7.9 nmol) in methylene chloride (10 ml) was cooled to 0° C. A solution of triphenyl phosphine (1.9 g, 7.3 nmol) in methylene chloride (10 ml) was added dropwise and the reaction was stirred for 5 min. Solvent evaporation and flash chromatography (silica gel, ethyl acetate-hexane, 5/95) gave 5-(2 bromoethyl)benzofurazan (1.2 g, 86%); 1H NMR (CDCl3) δ: 3.32 (t, 2H), 3.69 (t, 2H), 7.32 (d, 1H), 7.69 (s, 1H), 7.84 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[CH2:7][NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:15]=1)[CH2:7][N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CNCc1cc(F)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(Cc1cc(F)ccc1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.15 g (3.95 mmol) of ethyl (5-fluoro-2-nitrobenzyl)aminoacetate was dissolved in 20 ml of dichloromethane. 0.61 ml (4.7 mmol) of 4-chlorobenzoyl chloride and 0.82 ml (5.9 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 2 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=O)[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:39]>N1C=CC=CC=1>[CH3:1][N:2]1[C:7](=[S:39])[C:6]2=[C:9]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=[C:5]2[N:4]2[C@H:32]3[CH2:37][CH2:36][CH2:35][C@H:33]3[N:34]=[C:3]12
Reactant: CN1C(=O)c2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CN1C(=S)c2c(nn(Cc3ccc(-c4ccccn4)cc3)c2Nc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 150 °C

Procedure:
(6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-Pyridin-2-yl)-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one (36.1 mg, 0.055 mmol) and P4S10 are placed in a Biotage microwave vial, and then 1 mL of pyridine is added. The reaction mixture is heated in a microwave at 150° C. for 2.5 h. Pyridine is removed under high vacuum. The obtained crude product is purified by a semi-preparative HPLC to give 3.2 mg of pure product as pale yellow solids. MS (ESI) m/z 506.2 [M+H]+.