Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:24])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>COCCO>[CH2:17]([O:16][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])[C:6](=[O:24])[O:7]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2c(OCc3ccccc3)cccc2oc1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2c(OCc3ccccc3)cccc2oc1=O
Yield: 71.7 %

Procedure:
A mixture of 5-benzyloxy-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (54 mg, 0.17 mmol) and sodium glycinate (241 mg, 2.48 mmol) in 2-methoxyethanol was refluxed for 18 h and then concentrated. Residue was dissolved in water (60 mL) and acidified using 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo. Crude product was triturated with hexanes. Solid was collected and dried to provide the title compound (45 mg). MS ESI(+) m/e: 370.13 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:9][CH2:8][C:7]=2[C:6]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[N:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([O-:36])[C:6]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:9][CH2:8]2
Reactant: COc1ccc(CN2CCc3c(C(=O)N(C)C)ncc(OC)c3C2=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(c(OC)c[n+]([O-])c3C(=O)N(C)C)C2=O)cc1
Temperature: 25 °C

Procedure:
A 100 ml CH2Cl2 solution of 12 g 4-methoxy-6-(4-methoxybenzyl)-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide and 16.8 g mCPBA (maximum 77% purity) was allowed to stir at room temperature until the starting material was consumed (5 hours). The reaction was washed four times with 100 mL sat aqueous NaHCO3 then the organic layer was concentrated. The crude reaction was dissolved in 250 mL CH2Cl2 and the excess mCPBA was then quenched by vigorous stirring with a sat aq sodium sulfite solution for 30 minutes (both organic and aqueous layers were cloudy initially but then turned transparent). The layers were separated and the organic washed twice with sat aqueous NaHCO3. The organic layer was dried over sodium sulfate and concentrated to pure product by HPLC/MS and NMR.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The crude extract was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were filtered and dried on phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 539.5 mg.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:15]=1[NH:16][C:17]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:18]=1[C:19]([OH:21])=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>C1COCC1>[CH2:34]([O:41][NH:42][C:19](=[O:21])[C:18]1[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:17]=1[NH:16][C:15]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:14]=1[F:13])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
Carbonyldiimidazole (3.1 g, 19.1 mmol) was added to a suspension of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid (Example H-4, 4.54 g, 15.9 mmol) in 120 mL of THF, and the mixture was stirred for 24 hours at 25° C. O-Benzylhydroxylamine hydrochloride (2.54 g, 15.9 mmol) and triethylamine (2.66 mL, 19.1 mmol) were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated and washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 5.66 g of the title compound as an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH2:19][CH3:20])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:7]=1)[CH3:2].[N+:25]([O-])([OH:27])=[O:26].O>C(Cl)(Cl)Cl>[CH2:19]([CH:14]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:13][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][C:10]=1[N+:25]([O-:27])=[O:26])[CH3:20]
Reactant: CCCCC(CC)COc1ccc(OCC(CC)CCCC)cc1
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCC(CC)COc1ccc(OCC(CC)CCCC)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
1,4-Bis(2-ethylhexyloxy)benzene (50.2 g, 0.150 mol) is dissolved in chloroform (150 ml) and cooled to 0° C. Nitric acid (70%, 17.0 g, 0.190 mol) is added dropwise at 0-3° C. and the reaction stirred whilst monitoring progress by HPLC. After 60 minutes, water (50 ml) is added and the organic layer separated, dried (MgSO4) and evaporated to give the title compound as a yellow oil (56.9 g, 100%). The material is used without further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([C:26]([OH:28])=O)[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:33]1([NH:35][C:26]([C:21]2[N:20]=[N:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:11])=[CH:17][CH:16]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:32]1
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 61 h
Yield: 126.6 %

Procedure:
1-(4-{[(2-Piperidin-1-ylethyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (650 mg, 1.52 mmol) obtained in Example 62b), HOBt (104 mg, 0.759 mmol, 0.5 eq.) and cyclopropylamine (0.152 ml, 2.12 mmol, 1.4 eq.) were dissolved in acetonitrile-DMF (1:1, 10 ml), WSC (386 mg, 1.97 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 61 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed sequentially with 2% aqueous sodium carbonate solution-saturated brine (1:1, 40 ml×2, 1:4, 40 ml×1). The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated, the residue was dissolved in toluene, and the solution was subjected to column chromatography on NH silica gel (Fuji Silysia Chemical Ltd., 100-200 mesh, DM1020, 6 g). The flow-through solution and the fraction obtained by elution with ethyl acetate-hexane (1:1-2:1) were concentrated, and ethyl acetate and diethyl ether were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (408 mg, 0.961 mmol, 63.2%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[O:27][C:19]3=[C:20]([O:25][CH3:26])[N:21]=[CH:22][C:23]([Br:24])=[C:18]3[CH:17]=2)([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>[OH-].[Na+]>[Br:24][C:23]1[CH:22]=[N:21][C:20]([O:25][CH3:26])=[C:19]2[O:27][C:16]([C:11]3([O:14][CH3:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:17][C:18]=12
Reactant: COc1ncc(Br)c2cc(C3(OC)CCN(C(=O)OC(C)(C)C)CC3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Br)c2cc(C3(OC)CCNCC3)oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.5 %

Procedure:
4-(4-Bromo-7-methoxyfuro[2,3-c]pyridin-2-yl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester (1.5 g), dichloromethane (50 ml) and trifluoroacetic acid (5 ml ) were combined and stirred at room temperature for 3 hours. The reaction mixture was then diluted with 1N sodium hydroxide solution (100 ml) and extracted with dichloromethane (3×50 ml). The combined extracts were then dried over magnesium sulphate and evaporated in vacuo to give the title compound (1.2 g) as a pale yellow oil.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[O:7]=[C:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:9][C:10]([O:12][CH3:13])=[O:11].CI>CC(C)=O>[CH3:1][CH:9]([C:8](=[O:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCCCCC(=O)CC(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCCCC(=O)C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
K2CO3 (2.67 g) was added to a solution of methyl 3-oxononanoate (3.01 g) and methyl iodide (2.77 g) in acetone (100 ml) and the mixture was stirred at room temperature for 24 hours. The reaction solution was celite filtered, and then the mother liquor was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/AcOEt=13/1) to obtain methyl 2-methyl-3-oxononanoate.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1SCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (200.0 mg, 0.96 mmol) and Et3N (195.5 mg, 1.93 mmol) in DMF (2.0 mL) at 0° C. was added (S)-3-methylmorpholine (97.7 mg) dropwise. The mixture was stirred overnight at rt then was partitioned between H2O and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered, evaporated and then the crude product which was purified by column chromatography on silica gel (eluent: PE/EA=20:1-2/1) to provide (S)-2-chloro-4-(3-methylmorpholino)-6,7-dihydrothieno[3,2-d]pyrimidine as a light yellow solid (120 mg, 46%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][O:13]C2=O)=[CH:7][C:6]=1[N+:17]([O-:19])=[O:18]>CO.O>[OH:13][CH2:14][CH2:15][NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=1
Reactant: COc1ccc(N2CCOC2=O)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(NCCO)cc1[N+](=O)[O-]

Procedure:
Solid potassium hydroxide (3.5 g) is dissolved in methanol (100 ml). To the obtained solution the 3-(4-methoxy-3-nitrophenyl)-1,3-oxazolidin-2-one of step 1.1 (5 g) is added whereupon a yellow suspension is formed. Then the reaction mixture is heated under reflux for 5 hours and a red solution is obtained. With stirring, diluted acetc acid (3.7 g in 20 ml water) is added dropwise to the warm solution and the reaction mixture is cooled down to from about 0° C. to about 5° C. An orange suspension is obtained, which is filtered. The resulting solid is dried.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH3:19]O>>[N+:6]([C:9]1[CH:17]=[C:13]([C:14]([O:16][CH3:19])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reaction time: 8 h

Procedure:
80 ml of methanol and 10 g of concentrated sulfuric acid were added to 5 g of 5-nitrosalicylic acid. The resultant mixture was heated under stirring for 8 hours while distilling methanol off. The solvent was then distilled off under reduced pressure and the residue was dissolved in chloroform. The resultant chloroform solution was washed with water and then concentrated to dryness. The resultant residue was purified by chromatography on a silica gel column (eluent: chloroform), followed by recrystallization from chloroform-ether to obtain 5.1 g of methyl 5-nitrosalicylate as crystals.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][CH3:17])[S:15][C:9]=2[NH:8][C:7]1=[O:18].[F:25][C:26]1[CH:27]=[C:28]([C:40]#[N:41])[C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=2)=[CH:30][CH:31]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[CH2:16]([C:14]1[S:15][C:9]2[N:8]([CH2:38][C:35]3[CH:36]=[CH:37][C:32]([C:29]4[C:28]([C:40]#[N:41])=[CH:27][C:26]([F:25])=[CH:31][CH:30]=4)=[CH:33][CH:34]=3)[C:7](=[O:18])[NH:6][C:11](=[O:12])[C:10]=2[CH:13]=1)[CH3:17]
Reactant: N#Cc1cc(F)ccc1-c1ccc(CO)cc1
Reactant: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccc(F)cc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of 3-(2,4-dimethoxybenzyl)-6-ethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (2 g), 4-fluoro-4′-(hydroxymethyl)biphenyl-2-carbonitrile (1.4 g), 1,1′-(azodicarbonyl)dipiperidine (2.2 g), tributylphosphine (2.2 mL) and tetrahydrofuran (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (15 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and insoluble material was filtered off. The filtrate was concentrated and recrystallized from diethyl ether to give the title compound as a colorless solid (2 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21](O)=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH:24]([NH:27][NH:28][C:29]([CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30])([CH3:26])[CH3:25].C(NC(C)C)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]([N:27]([CH:24]([CH3:26])[CH3:25])[NH:28][C:29]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:30])=[O:22])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:15]([F:18])([F:16])[F:17])[CH:7]=1
Reactant: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Reactant: CC(C)NNC(=O)C1CCOCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)N(NC(=O)C1CCOCC1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 61.8 %

Procedure:
A solution of (5-fluoro-2′-trifluoromethoxy-biphenyl-2-yloxy)-acetic acid (280 mg, 0.85 mmol) and tetrahydro-pyran-4-carboxylic acid N′-isopropyl-hydrazide (1.2 eq. 190 mg, 1.02 mmol) in DMF (3 ml) was treated with diisopropyl amine (0.370 ml, 2.12 mmol) and PyBroP (595 mg, 1.275 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 50-100% ethyl acetate/hexanes gradient to afford the product as a white solid (262 mg, 62%). MS m/e 499.23 (M+H+)
Reaction SMILES: C1(S([C:10](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])(=O)=O)C=CC=CC=1.COCCO.[N-:36]=[N+:37]=[N-:38].[Na+]>O>[CH3:30][C:27]([C:18]1[CH:17]=[C:16]([C:15]2[NH:36][N:37]=[N:38][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]=1[OH:26])([CH3:28])[CH3:29]
Reactant: CNC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)S(=O)(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: CNC(=O)c1nn[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A 250 mL 3-neck round-bottom flask immersed in an oil bath, equipped with a mechanical stirrer, thermometer, reflux condenser and nitrogen bubbler, was charged with 42.96 g (0.100 mol) of 2-(benzenesulfonyl)-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methylacrylamide (II), 100 mL of 2-methoxyethanol and 6.83 g (0.105 mol) of sodium azide. The yellow mixture was heated at 105° C. for 30 h. The cooled orange solution was poured onto a mixture of 150 g of ice and 150 mL of deionized water. The yellow suspension was agitated for 1 h at 5° C. The resulting solid precipitate was filtered off and washed with 5×50 mL of cold deionized water. The recovered solids were dried in vacuo over potassium hydroxide flakes to afford yellow solids, 30.2 g of crude product (I), 98.7% purity by HPLC.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:29]1[C:34]2[CH:35]=[CH:36][C:37]([CH:39]=O)=[CH:38][C:33]=2[O:32][CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:39][C:37]3[CH:36]=[CH:35][C:34]4[O:29][CH2:30][CH2:31][O:32][C:33]=4[CH:38]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5c(c4)OCCO5)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 1,4-benzodioxan-6-carboxaldehyde according to the procedure of step 1, Example 66. MS (ESI) m/z 527.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C-:20]#[N:21].[Na+]>O.C(O)C>[C:20]([CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:21]
Reactant: FC(F)(F)c1ccc(Cc2ccc(CCl)cc2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 80 °C

Procedure:
In a 50 ml round-bottom two-necked flask, 2.0 g were suspended in 2.0 ml of water and heated to 80° C. A 9.2 g amount of 4-(4'-chloromethylbenzyl)benzotrifluoride was dissolved in 7.1 ml of ethanol. This solution was added dropwise into the NaCN suspension. The proportion of undissolved substances increased. The reaction mixture turned brown. The feedstock was boiled under reflux for 5 hours. After the reaction mixture had cooled down to room temperature, the solid substance was removed by filtration and washed with 30 ml ethanol. The filtration was concentrated in a rotary evaporator (bath temp. 30° C., water-jet vacuum). The oily residue was dissolved in 50 ml of diethyl ether and washed to neutrality four times with 30 ml of water each time. The organic phase was dried over sodium sulfate. The drying agent was removed by filtration and the ether was removed by distillation in a rotary evaporator (bath temp. 30° C., water-jet vacuum). The raw product (8.0 g) was chromatographed on silica gel 60 (0.63-0.200) with ether/pentane (1/4) and the 4-(4'-cyanomethylbenzyl)benzotrifluoride (5.8 g) thus obtained was recrystallized from 44 ml of solvent blend (petroleum benzin 60°-80°C0-diethyl ether 5:1 v/v). The precipitated crystallizate was removed by filtration via a D-4 glass suction funnel and washed with 25 ml of ice-cold petroleum benzin. The product was dried in a vacuum drying oven (oil pump) at room temperature for 5 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:55]=[CH:54][CH:53]=[CH:52][C:5]=1[CH2:6][O:7][C:8]([NH:10][CH:11]1[CH:14]([CH2:15][CH2:16][OH:17])[N:13]([P:18]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])=[O:39])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]1=[O:51])=[O:9])([O-:3])=[O:2].CC(C)=[O:58].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:55]=[CH:54][CH:53]=[CH:52][C:5]=1[CH2:6][O:7][C:8]([NH:10][CH:11]1[CH:14]([CH2:15][C:16]([OH:58])=[O:17])[N:13]([P:18]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])=[O:39])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]1=[O:51])=[O:9])([O-:3])=[O:2]
Reactant: O=C(CP(c1ccccc1)(c1ccccc1)(c1ccccc1)N1C(=O)C(NC(=O)OCc2ccccc2[N+](=O)[O-])C1CCO)OCc1ccccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(O)CC1C(NC(=O)OCc2ccccc2[N+](=O)[O-])C(=O)N1P(CC(=O)OCc1ccccc1[N+](=O)[O-])(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
One gram of 3-(o-nitrobenzyloxycarbonylamino)-1-(o-nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4-(2-hydroxyethyl)-2-azetidinone is dissolved in 20 ml. acetone and cooled to 0° C. Jones Reagent (1 ml., 4 N solution) is added dropwise over 5 min. and the resulting solution is stirred at 0° C. for 10 min. Isopropanol (0.1 ml.) is added. The mixture is stirred for another 2 min. The reaction mixture is diluted with CH2Cl2 and filtered. The filtrate is washed with saturated NaCl solutin, dried and evaporated to give the title compound which is used without further purification in the next step.