Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:23].O>C1(C)C=CC=CC=1>[NH2:23]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)=[O:6]
Reactant: N
Reactant: CCOCCOc1ccc(C=CCOC(=O)CC(C)=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOCCOc1ccc(C=CCOC(=O)/C=C(/C)N)cc1

Procedure:
10 Grams of 4-[(1-ethoxy)ethoxy]cinnamyl acetoactate was dissolved in 20 ml of toluene, then 2 g of ammonia gas was passed through this solution at about 80° C. with stirring condition. The water formed during the reaction was removed by azeotropic distillation with toluene. 2 Hours after the azeotropic distillation, the toluene was removed by distillation under reduced pressure to yield 10 g of 4-[(1-ethoxy)ethoxy]cinnamyl 3-aminocrotonate as in the form of an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH2:9][C:10](=[O:12])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:5]=2[CH:4]=1
Reactant: COc1ccc(CC(=O)O)c(Oc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)Oc1ccccc1C(=O)C2
Reaction time: 2.5 h
Yield: 47.8 %

Procedure:
A solution of 2-(4-methoxy-2-phenoxyphenyl)acetic acid (594 mg, 2.3 mmole) in thionyl chloride (10 mL) was heated at reflux for 30 min, then was concentrated to dryness, and the residue was reconcentrated from toluene. The resulting residue was dissolved in dry CH2Cl2 (3 mL), and the solution was added dropwise at RT to a suspension of AlCl3 (673 mg, 5.06 mmole) in dry CH2Cl2 (4 mL) in a flame-dried flask under argon. After stirring for 2.5 hr, the mixture was diluted with CH2Cl2 (10 mL) and washed sequentially with 1.0 N NaOH and brine. Drying (MgSO4), concentration, and flash chromatography on silica gel (5% EtOAc/hexanes) gave the title compound (264 mg, 48%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ3.80 (s, 3 H), 4.02 (s, 2 H), 6.74-8.08 (m, 7 H).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:7][CH:8]([CH2:21][CH:22]=[CH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:3]([O:5][CH3:6])=[O:4]>C(O)C.[Pd]>[CH3:1][C:2]([CH3:30])([CH2:7][CH:8]([CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)CC(CC=Cc1cccnc1)CCCCO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)(C)CC(CCCCO[Si](C)(C)C(C)(C)C)CCCc1cccnc1
Reaction time: 7.5 h

Procedure:
To a solution of 1.83 g of methyl 2,2-dimethyl-4-[3-(3-pyridyl)-2-propenyl]-8-(t-butyldimethylsilyloxy)-octanoate in 50 ml ethanol is added 0.18 g of 10% palladium on carbon. The mixture is hydrogenated at 3 atmospheres (=3.04 bar) pressure in a Parr apparatus for 7.5 h. The catalyst is filtered off and washed with ethanol. The solvent is evaporated to give methyl 2,2-dimethyl-4-[3-(3-pyridyl)propyl]-8-(t-butyldimethylsilyloxy)-octanoate as an oil, NMR (CDCl3): delta 3.58 (s,3H), 3.55 (t,2H), 2.57 (t,2H), 1.13 (s,6H).
Reaction SMILES: O[Li].O.SCC(O)=O.[CH2:9]([O:16][N:17]([C@H:30]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:33]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:32][CH2:31]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.O>[CH2:9]([O:16][NH:17][C@H:30]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[C@H:33]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:32][CH2:31]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CN1C(=O)OC(C)(C)C
Agent: O=C(O)CS
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
LiOH.H2O (95 g, 2.3 mol) and 2-mercaptoacetic acid (124 g, 1.3 mol) were added to a solution of (2S,5R)-1-tert-butyl 2-ethyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)piperidine-1,2-dicarboxylate (251 g, 0.45 mol) in DMF (1200 mL). The reaction mixture was then stirred at 20° C. overnight. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layer was washed with brine (3×), concentrated in vacuum and purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford (2S,5R)-1-tert-butyl 2-ethyl 5-((benzyloxy)amino)piperidine-1,2-dicarboxylate (122.9 g, 85%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=[N:27][NH:26]C=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.N#N.[NH2:47][C@@H:48]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C@H:49]([OH:64])[CH2:50][C@@:51]1([C:61]([NH2:63])=[O:62])[CH2:55][C@@H:54]([OH:56])[CH2:53][N:52]1[C:57]([CH3:60])([CH3:59])[CH3:58]>ClCCl.CO>[N:26]#[N:27].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:47][C@@H:48]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C@H:49]([OH:64])[CH2:50][C@@:51]1([C:61]([NH2:63])=[O:62])[CH2:55][C@@H:54]([OH:56])[CH2:53][N:52]1[C:57]([CH3:60])([CH3:58])[CH3:59])=[O:19])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)N1C[C@H](O)C[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccccc1)C(N)=O
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)N1C[C@H](O)C[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(N)=O
Yield: 37.7 %

Procedure:
In a manner analogous to that described in Example 92, from 0.133 g of N-(benzyloxycarbonyl)-L-asparagine, 0.068 g of hydroxybenzotriazole, 0.103 g of dicyclohexylcarbodiimide and 0.16 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-4(R)-hydroxy-L-prolinamide, but using dichloromethane in place of ethyl acetate as the partitioning solvent and 20% methanol in dichloromethane for the chromatography and carrying out the re-evaporation with diethyl ether, there was obtained 0.1 g of N2 -[3(S)-[N-(benzyloxycarbonyl)-L-asparaginylamino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-4(R)-hydroxy-L-prolinamide of melting point 115° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
1-(tert-Butoxycarbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (20) (8.17 g; 17.1 mmol) is dissolved in methylene chloride (60 mL) at ambient temperature. Trifluoroacetic acid (40 mL) is added in a slow stream, and the solution is stirred for 2 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (400 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×100 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (5.91 g) as a white solid. ESMS: MH− 379.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:29])[CH:10]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CSc2cc(N)ncc2Br)cc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CSc2cc(NC(=S)NC(=O)c3ccccc3)ncc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
4-(4-methoxybenzylthio)-5-bromopyridin-2-amine (7.45 g, 22.9 mmol) was dissolved in THF (80 mL). Benzoyl isothiocyanate (3.4 ml, 25 mmol) was added, and the reaction was stirred overnight at ambient temperature. The solution was diluted in 9:1 hexanes:EtOAc and stirred for 5 minutes, then filtered and dried to provide the desired product (8.5 g, 76% yield) as a brown solid.
Reaction SMILES: C([O-])(=O)C.[NH4+].[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:14]=1)[CH:10]=O.[N+:19]([CH3:22])([O-:21])=[O:20].O>C(O)(=O)C>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH3:18])[CH:12]=[C:9](/[CH:10]=[CH:22]/[N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: CCCOc1cc(F)cc(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1cc(F)cc(/C=C/[N+](=O)[O-])c1
Temperature: 140 °C
Yield: 69.7 %

Procedure:
Add ammonium acetate (2.63 g, 34.08 mmol) to 3-fluoro-5-propoxy-benzaldehyde (2.25 g, 12.35 mmol) and nitromethane (3.09 g, 50.63 mmol) in acetic acid (41 mL) at room temperature and heat in 140° C. oil bath for 3 hours. Cool to room temperature and pour into water. Extract with ethyl acetate, dry over magnesium sulfate, filter and concentrate to afford 1.94 g (69.8%) of the desired compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]2([CH3:20])OCC[O:16]2)[C:8]1=[O:21])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)[N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH3:20])[C:8]1=[O:21])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCC2(C)OCCO2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C[C@@H](c1cccc(F)c1)N1CCC(CCCC(C)=O)C1=O

Procedure:
A solution of 2-6 (450 mg, 1.10 mmol), p-TSA (50 mg) and acetone (50 mL) was heated at reflux for 4 hr. The cooled reaction mixture was diluted with EtOAc and then washed with sat. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 2-7 as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:73])[NH:11][CH:12]([C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34]#[C:35][C:36]#[C:37][CH2:38][N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]([CH2:48][CH:49]3[CH2:53][CH2:52][CH2:51][N:50]3[C:54](=[O:72])[CH:55]([NH:59][C:60](=[O:71])[CH:61]([NH:63]C(OC(C)(C)C)=O)[CH3:62])[CH:56]([CH3:58])[CH3:57])=[CH:40]2)[CH:25]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:63][CH:61]([CH3:62])[C:60]([NH:59][CH:55]([C:54]([N:50]1[CH2:51][CH2:52][CH2:53][CH:49]1[CH2:48][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:39]([CH2:38][C:37]#[C:36][C:35]#[C:34][CH2:33][N:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]([CH2:23][CH:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16](=[O:17])[CH:12]([NH:11][C:10](=[O:73])[CH:8]([NH2:7])[CH3:9])[CH:13]([CH3:15])[CH3:14])=[CH:25]2)[CH:40]=1)=[O:72])[CH:56]([CH3:57])[CH3:58])=[O:71]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1cn(CC#CC#CCn2cc(CC3CCCN3C(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)C)c3ccccc32)c2ccccc12)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)NC(C(=O)N1CCCC1Cc1cn(CC#CC#CCn2cc(CC3CCCN3C(=O)C(NC(=O)C(C)N)C(C)C)c3ccccc32)c2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 42 (0.030 g, 0.029 mmol) in DCM (5 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature for 30 min. Aqueous NaHCO3 (3 mL) was then added to the reaction mixture. The reaction mixture was concentrated, diluted with water, and the product was extracted with DCM (3×30 mL). The organic extracts were washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed on rotary evaporator and the product was purified by reverse phase HPLC. 1H NMR (DMSO, 300 MHz) δ8.0 (s, 2H), 7.9 (d, J=9.9 Hz, 2H), 7.38 (d, J=9.9 Hz, 2H), 7.3-7.1 (m, 6H), 6.8 (m, 2H), 4.8 (s, 4H), 4.62 (m 2H), 4.5-4.4 (m 2H), 4.4-4.0 (m, 4H), 3.7-3.5 (m, 4H), 3.4 (m, 2H), 2.5 (m, 2H), 2.2-1.8 (m, 8H), 1.35 (d, J=9.9 Hz, 6H), 1.05 (d, J=5.5 Hz, 6H), 0.95 (d, J=5.5 Hz, 6H) ppm.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11]I.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CC(C)=O>[C:13]1(=[O:23])[N:17]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ICCCCC=CCCCCI
Agent: [K]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCC=CCCCCN1C(=O)c2ccccc2C1=O

Procedure:
The 1,10-Diiodo-dec-5-ene (1 equiv.) is dissolved in anhydrous acetone at ambient temperature followed by the addition of potassium phthalimide (4. equiv.). The reaction mixture is stirred until completion, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified via silica gel chromatography to afford 1,10-dipthalimido-dec-5-ene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O.[Br:19][C:20]1[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]2[O:27][C:26]([CH2:29]I)([CH3:28])[CH2:25][C:24]=2[C:31]=1[CH3:32]>C(OCC)(=O)C.O>[Br:19][C:20]1[C:21]([CH3:34])=[C:22]([CH3:33])[C:23]2[O:27][C:26]([CH2:28][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)([CH3:29])[CH2:25][C:24]=2[C:31]=1[CH3:32]
Reactant: C1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CI)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1Br)CC(C)(CN1CCCCC1)O2
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Piperidine (323 mg, 3.80 mmol) and potassium carbonate (525 mg, 3.80 mmol) were added to a solution of DMA (3 mL) containing 5-bromo-2-(iodomethyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran (300 mg, 0.759 mmol) synthesized in Reference Example 133, and the mixture was stirred under microwave irradiation at 150° C. for 10 minutes. The reaction solution was cooled to room temperature, and water and ethyl acetate were added thereto to separate an organic layer. The organic layer was washed with water and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-85:15) to give 170 mg of the title compound (yield: 64%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(=[O:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:28])[CH:19]([N+:25]([O-:27])=[O:26])[CH:20](O)[CH2:21][O:22][CH3:23])[CH3:16]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:15]([O:17][C:18](=[O:28])[CH:19]([N+:25]([O-:27])=[O:26])[CH:20]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[CH2:5][O:4][C:1](=[O:3])[CH3:2])[NH:10][CH:9]=1)[CH2:21][O:22][CH3:23])[CH3:16]
Reactant: CC(=O)OCc1cccc2[nH]ccc12
Reactant: CCOC(=O)C(C(O)COC)[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(COC)c1c[nH]c2cccc(COC(C)=O)c12)[N+](=O)[O-]

Procedure:
4-Acetoxymethylindole (189 g) is dissolved in a mixture of toluene (6 l) and acetic acid (0.7 l). To this solution is added 3-hydroxy-2-nitro-5-oxa-hexanoic acid ethyl ester (570 ml). The flask containing the mixture is evacuated by means of a water jet pump. Then balancing to normal pressure is brought about by argon. Evacuation and pressure balancing are repeated four times. Then the reaction mixture is refluxed for two hours in a water-free argon atmosphere. After concentrating to 2 l the solution is diluted with ethyl acetate and shaken out three times with a liter of 1N hydrochloric acid each. Then it is washed to neutrality with saturated hydrochloric acid solution. The solution, dried over sodium sulfate, is evaporated. The residue is chromatographed on silica gel with dichloromethane. 393 g of the title compound is obtained in oily form.
Reaction SMILES: O=[C:2]1[N:7]([CH2:8][C:9]([N:11]([CH:18]([CH3:20])[CH3:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[C:6]2[CH:21]=[CH:22][CH2:23][CH2:24][C:5]=2[C:4](=[O:25])[O:3]1.[NH2:26][CH2:27]C(O)=O.C(N(CC)CC)C>O>[O:3]=[C:2]1[N:7]([CH2:8][C:9]([N:11]([CH:18]([CH3:20])[CH3:19])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[C:4](=[O:25])[NH:26][CH2:27]1
Reactant: NCC(=O)O
Reactant: CC(C)N(C(=O)Cn1c2c(c(=O)oc1=O)CCC=C2)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)CNC(=O)c2ccccc21)c1ccccc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A suspension of 2-(2,4-dioxo-6H-benzo[d][1,3]oxazin-1-yl)-N-isopropyl-N-phenylacetamide (10 g, 31 mmol), glycine (2.32 g, 31 mmol) and triethylamine (4.32 mL, 31 mmol) in water (50 mL) is stirred at 50° C. for 5 h. The reaction mixture is concentrated to a brown viscous oil, acetic acid (100 mL) is added and the mixture heated at reflux for 6 h. The reaction mixture is concentrated to a brown viscous oil, dissolved in ethyl acetate (300 mL) and washed with water, saturated aqueous sodium bicarbonate and brine. The resulting solution is dried over magnesium sulfate and concentrated to a yellow foam. Recrystallization from ethyl acetate/petroleum ether (4:1, 100 mL) gave the title compound (7.55 g, 21.5 mmol) as an off-white powder. 1H NMR (300M Hz, CDCl3): 1.12 (d, J=6.7 Hz, 6H); 3.6-6.4 (m, 4H); 5.05 (m, J=6.7 Hz, 1H); 6.62 (m, 1H); 7.1-7.6 (m, 7H); 7.84 (d, J=7.5 Hz, 1H). MS (FAB): [M+H]+ =352.
Reaction SMILES: [H-].[Na+].[OH:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](Cl)=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:3][N:4]2[C:5](=[O:14])[C:6]3=[CH:13][CH:12]=[CH:11][CH:10]=[C:7]3[C:8]2=[O:9])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: [H-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
11.5 g of sodium hydride as a 50% oil suspension were admixed at 20° C. with 300 ml of anhydrous diemthylformamide and after cooling the mixture to 5° to 10° C., 36.5 g of N-hydroxy-phthalimide were added thereto. The mixture was stirred at 20° C. for 30 minutes and 50 g of 4-nitro-2-trifluoromethyl-chloro benzene were added over 10 minutes. The suspension was heated at 80°-85° C. for one hour and was cooled to 20° C. and poured over ice. The mixture was stirred for one hour and was filtered. The solid product was washed with water and dried to obtain 60.7 g of N-(4-nitro-2-trifluoromethyl-phenoxy)-phthalimide melting at 190° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][S:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1CSCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
In a 50 mL round-bottomed flask was charged 4-fluoro-2-methoxy-1-nitrobenzene (1.05 g, 6.14 mmol), thiomorpholine (1.164 ml, 12.27 mmol), and Hunig's Base (1.072 ml, 6.14 mmol) in acetonitrile (20.45 ml). The reaction was heated at 85° C. for three days. The mixture was concentrated and the residue was placed on a silica gel column. The product was eluted from the column with dichloromethane to give the title compound. MS (DCI(+)) m/e 255.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:11][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=3)[C:20]([OH:22])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:34][CH2:35]O>O1CCOCC1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([CH:12]([C:17]3[CH:18]=[C:19]([CH:23]=[C:24]([F:26])[CH:25]=3)[C:20]([O:22][CH2:34][CH3:35])=[O:21])[C:13]([F:16])([CH3:15])[CH3:14])[CH2:11]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCO
Reactant: CC(C)(F)C(c1cc(F)cc(C(=O)O)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cc(C(C2CN(C(c3ccccc3)c3ccccc3)C2)C(C)(C)F)c1
Reaction time: 10 h

Procedure:
A mixture of 7.5 g (17.15 mmol) of 3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorobenzoic acid, 25 mL of 4N HCl in dioxane, and 200 mL of EtOH was refluxed. After 10 h, it was concentrated to remove solvents. To the residue was added 150 mL of CH2Cl2 and 30 mL of H2O and pH was adjusted to 7-8 with aq NaHCO3, then extracted with CH2Cl2. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as an white solid; 1H-NMR(CDCl3) δ 1.25(d, 3H, J=22 Hz), 1.30(d, 3H, J=22 Hz), 1.42 (t, 3H, J=7.1 Hz), 2.35 (t, 1H, J=8 Hz), 2.89 (t, 1H, J=8 Hz), 2.97 (m, 1H), 3.12 (m, 1H), 3.24 (m, 1H), 3.68 (t, 1H, J=6 Hz), 4.27 (s, 1H), 4.38 (q, 2H, J1=14, J2=7 Hz), 7.103-7.66 (m, 13H); Mass Spectrum: m/e=464 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[N+:13]([O-:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:19]I>>[CH3:19][N:8]([C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[S:9]([C:12]1[N+:13]([O-:18])=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(Nc1cccnc1Cl)c1cccc[n+]1[O-]
Reactant: CI
Product: CN(c1cccnc1Cl)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
The title compound of Example 5 above is reacted with methyl iodide (0.6 g, 0.26 ml, 4.2 mmol) to give N-methyl-N-(2-chloro-3-pyridyl)-2-pyridinesulfonamide 1-oxide, MS m/e 300.00 (M+ +1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])#[N:11].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20].Cl>O1CCCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]([CH2:18][CH:12]([C:10]#[N:11])[C:13]([O:15][CH3:16])=[O:14])=[O:20])=[CH:22][CH:23]=1
Reactant: COC(=O)CC#N
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C#N)CC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
Diisopropylethyl amine (15.5 g, 0.12 mol) is added to dry tetrahydrofuran (60 mL) followed by a solution of methyl cyanoacetate (5.4 g, 0.055 mol) in tetrahydrofuran (10 mL). Finally, a solution of α-bromo-p-chloroacetophenone (11.0 g, 0.05 mol) in tetrahydrofuran (50 mL) is added. After three hours at room temperature, TLC (75/25 hexanes/ethyl acetate) indicates very little starting material. The reaction mixture is then heated at 50° C. for fifteen minutes, cooled and filtered. The filtrate is concentrated in vacuo to obtain an oil which solidifies when treated with dilute hydrochloric acid. The supernatant is decanted and the residue is taken up in ethyl acetate and dried. Work-up leaves a brown waxy solid (8.0 g, 64% crude yield) which on recrystallization from methanol gives the title compound as a white solid (4.3 g, mp 75°-79° C.).