Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]2[CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:33]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH:11]1([C:4]2[S:3][C:2]3[NH:1][C:15](=[O:17])[N:41]([CH2:40][CH2:39][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[C:7](=[O:9])[C:6]=3[CH:5]=2)[CH2:13][CH2:12]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(C2CC2)sc1N
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2sc(C3CC3)cc2c(=O)n1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution (15 mL) of methyl 2-amino-5-cyclopropylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.98 g) and triethylamine (1.7 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-morpholin-4-ylethanamine (0.99 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), sodium methoxide (0.5 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.76 g, 84%).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[NH:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:12]1.[OH-].[Na+]>O.ClCCl>[CH:3]([C:12]1[NH:11][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:4]
Reactant: O=C(O)CCc1c[nH]c2c1CCCC2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Temperature: -9 °C
Yield: 84 %

Procedure:
A mixture of 24 g of dimethylformamide and 300 mL of dichloromethane was cooled to −9° C. Phosphorus oxychloride (50 g) was rapidly added via an addition funnel. 3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (54.9 g) was added in portions with vigorous stirring. The mixture was warmed to room temperature and then refluxed for 10 minutes. It was then cooled to 5° C. and diluted with 300 mL of water. The pH was adjusted to 10 using 10N sodium hydroxide. The layers were separated. The aqueous layer was cooled to 10° C. and the pH adjusted to 2-3 with about 130 mL of 10 N hydrochloric acid. The oil which formed solidified and was collected by vacuum filtration, washed three times with water and dried under vacuum at 50° C. to give 52.8 g (93% yield) of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid as a dark brown solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][CH:45]=1)[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[C:24]([NH:23][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=5)=[O:10])[CH:45]=[CH:44][CH:43]=4)=[CH:33][N:32]3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: CCn1nc(C)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 84.1 %

Procedure:
In the same manner as in Example 18-4 and using 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (180 mg, 1.17 mmol), tetrahydrofuran (7 mL), oxalyl chloride (152 μL, 1.74 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (242 mg, 84%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][CH2:26][CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:28][CH3:29]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:33]3[CH2:34][CH2:35][N:30]([CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])[CH2:31][CH2:32]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CCC(CC)N1CCNCC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCC(CC)N1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(pentan-3-yl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 6 H) 1.29 (dt, J=14.08, 6.98 Hz, 2 H) 1.47 (dt, J=14.08, 6.98 Hz, 2 H) 2.26 (t, J=6.57 Hz, 1 H) 2.43 (s, 3 H) 2.56 (br. s., 4 H) 3.37-3.48 (m, 2 H) 3.62 (br. s., 2 H) 7.64 (dd, J=8.08, 1.52 Hz, 1 H) 7.71 (s, 1 H) 7.82 (d, J=8.08 Hz, 1 H) 8.05 (dd, J=8.59, 2.27 Hz, 1 H) 8.12 (s, 1 H) 8.39 (d, J=8.59 Hz, 1 H) 8.53 (d, J=2.27 Hz, 1 H) 12.82 (br. s., 1 H); ESI-MS m/z [M+H]+ 459.3.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[F:16].O>C1COCC1>[F:13][C:11]1[CH:12]=[C:7]([CH2:6][CH2:5][OH:4])[C:8]([F:16])=[CH:9][C:10]=1[C:14]#[N:15]
Reactant: COC(=O)Cc1cc(F)c(C#N)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(CCO)cc1F
Reaction time: 12 h

Procedure:
LiBH4 (1.45 mL, 2.9 mmol, 2 M in THF) was added to a stirred solution of methyl(4-cyano-2,5-difluorophenyl)acetate (0.47 g, 2.2 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the product after purification on silica gel (eluted with 5-30% ethyl acetate-hexanes) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.32 (dd, J=5.3, J=5.0 Hz, 1H), 7.23 (dd, J=5.8, J=5.7 Hz, 1H), 3.95 (t, J=6.2, J=6.4 Hz, 2H), 2.98 (t, J=6.4, J=6.2 Hz, 2H). LC-MS (IE, m/z): 184 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClCCl.CN(C1C=CC=[CH:15][N:14]=1)C.C1(=O)OC(=[O:23])C2=CC=CC=C12>C(#N)C>[N:1]1([C:15]([NH2:14])=[O:23])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C1CNCCN1
Reactant: CN(C)c1ccccn1
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)N1CCNCC1

Procedure:
Into a 3 liter, four necked round bottom flask fitted with mechanical stirring, dry nitrogen and a reflux condenser were charged 129.2 grams piperazine, 750 ml dichloromethane, 750 ml acetonitrile, and 6.1 grams dimethylaminopyridine. To this mixture was added portion-wise 222.2 g phthalic anhydride. Following the addition, the mixture was refluxed for 3 hours, at the end of which period no residual anhydride was present by infrared analysis. The solvent was decanted from the solid product precipitate.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10](F)[C:9]=1[CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C1C[O:34]CC1>>[CH2:1]([C:8]1[CH:13]=[CH:12][NH:11][C:10](=[O:34])[C:9]=1[CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COc1ccc2c(OCCc3c(Cc4ccccc4)ccnc3F)ccnc2c1
Agent: Cl
Product: COc1ccc2c(OCCc3c(Cc4ccccc4)cc[nH]c3=O)ccnc2c1
Temperature: 70 °C

Procedure:
An NMR tube was charged with 4-(2-(4-benzyl-2-fluoropyridin-3-yl)ethoxy)-7-methoxyquinoline (0.0061 g, 0.016 mmol), 0.5 mL THF and 0.2 mL 35% HCl. The tube was heated to 70° C. for 40 h, and cooled. The solvent was removed under a stream of nitrogen, and the residue was diluted to 0.6 mL with MeOH, and treated with Si-carbonate (0.022 g, 0.016 mmol). The solution was filtered and concentrated in vacuo. A sample was scouted for prep purification using a 2.1×50 mm Xterra MS C18 column with a 3.5 μm particle size (PN 186000400); A=11 mM NH4HCO3 in water, pH adjusted to 8.5 with concentrated NH4OH; B=Acetonitrile; gradient: initial@1 mL/min, 10% B; 0→5 min@1 mL/min, linear gradient to 100% B; 5→6.9 min@1 mL/min, isocratic at 100% B; 6.9→6.95 min@1 mL/min, linear gradient to 110% B, 8 min end. A major peak was observed at 3.07. The sample was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 25% B; 5.0→35 min@20 mL/min, linear gradient to 55% B; 35→45@20 mL/min, isocratic at 55% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 25% B; 60 min end). A=11 mM NH4HCO3 in water, pH adjusted to 8.5 with concentrated NH4OH; B=Acetonitrile. A band that eluted from 20.9-21.9 minutes was isolated. The solvent was removed in vacuo to afford 4-benzyl-3-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1 H)-one. 1H NMR (400 MHz, CDCl3) δ ppm 3.28 (t, J=6.75 Hz, 2 H) 3.93 (s, 3 H) 4.07 (s, 2 H) 4.36 (t, J=6.65 Hz, 2 H) 6.09 (d, J=6.75 Hz, 1 H) 6.66 (d, J=5.38 Hz, 1 H) 7.08 (dd, J=9.15, 2.49 Hz, 1 H) 7.13-7.17 (m, 2 H) 7.19-7.25 (m, 2 H) 7.26-7.32 (m, 2 H) 7.34 (d, J=2.54 Hz, 1 H) 8.03 (d, J=9.19 Hz, 1 H) 8.62 (d, J=5.18 Hz, 1 H) 11.96 (br. s., 1H). 13C NMR (101 MHz, CDCl3) δ ppm 26.72 (s, 1 C) 38.97 (s, 1 C) 55.43 (s, 1 C) 66.50 (s, 1 C) 99.65 (s, 1 C) 107.20 (s, 1 C) 109.62 (s, 1 C) 116.02 (s, 1 C) 118.12 (s, 1 C) 123.11 (s, 1 C) 126.28 (s, 1 C) 126.79 (s, 1 C) 128.73 (s, 2 C) 128.81 (s, 2 C) 131.53 (s, 1 C) 138.24 (s, 1 C) 151.17 (s, 1 C) 151.82 (s, 1 C) 152.21 (s, 1 C) 160.85 (s, 1 C) 161.60 (s, 1 C) 164.55 (s, 1 C). MS (ESI pos. ion) m/z (MH+): 387.2, calcd for C24H22N2O3+H+=387.2.
Reaction SMILES: [O-]O.[B].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C([O:16]O)(C)(C)C>B#[W]>[CH2:11]1[O:16][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C=CCCCCCC
Reactant: CC(C)(C)OO
Agent: B#[W]
Agent: [B]
Agent: [O-]O
Product: CCCCCCC1CO1
Temperature: 90 °C
Yield: 36 %

Procedure:
In this example, the liquid phase epoxidation of an olefinic compound with an organic hydroperoxide was carried out in the presence of a catalytic amount of a boron containing substance in accordance with the instant invention. A 250 ml. flask equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 84 g. octene-1 and 1 g. tungsten boride (WB). The charged mixture was heated to 90° C. and 90% tertiary butyl hydroperoxide was added dropwise until a total of 25 g. had been added. The reaction mixture was then heated at reflux (108°-110° C.) for 220 minutes with stirring. The heated mixture was allowed to cool and then the crude reaction product was analyzed. The analysis indicated a 36% yield of octene oxide based on the amount of charged hydroperoxide. The crude reaction product was filtered by conventional methods and the resulting filtrate was analyzed for metal content by atomic absorption analysis. No metals were detected in the filtrate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.O.[NH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl.O>[CH3:16][S:17]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 72 h
Yield: 87.1 %

Procedure:
Potassium carbonate (324 g, 2340 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in chloroform (300 mL) and water (:300 mL). The slurry was cooled to 0° C. and treated with methylsulfonyl chloride (136 mL, 1760 mmol) by dropwise addition over a 1 h period (gas evolution was observed). The reaction mixture was allowed to shake for 72 h and was partitioned between CH2Cl2 (500 mL) and saturated aqueous NaHCO3 (500 mL). The aqueous layer was extracted with CH2Cl2 (3×200 mL). The organic layer was washed with 1% KHSO4 (250 mL), dried (Na2SO4), and concentrated to afford 90.5 g (87%) of a white solid. MS (electrospray): exact mass calculated for C6H11NO3S, 177.1; m/z found, 178.1 [M+H]+. HPLC (reverse phase conditions): tR=2.19 min. 1H NMR (400 MHz, CDCl3): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59 (t, J=6.3 Hz, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10][C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14]>C(C1C=CC=CC=1)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:11]([S:10][CH3:9])=[CH:12][N+:13]([O-:15])=[O:14])=[CH:3][CH:4]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1ccc(Cl)nc1
Solvent: CCc1ccccc1
Product: CSC(=C[N+](=O)[O-])Nc1ccc(Cl)nc1
Temperature: 130 °C
Yield: 6.7 %

Procedure:
A mixture of 3.9 g (0.0303 mole) of 5-amino-2-chloropyridine, 5.0 g of 1,1-bis(methylthio)-2-nitroethylene and 80 ml of ethylbenzene was heated at 130° C. for 2 hours. The ethylbenzene was distilled off under reduced pressure and the crystalline residue was washed with AcOEt and subjected to silica gel column chromatography using EtOH--CHCl3 (1:30) as the eluent to recover crude crystals. These crystals were recrystallized from AcOEt, washed with ether and dried. The procedure gave 0.5 g of 1-(6-chloro-3-pyridyl)amino-1-methylthio-2-nitroethylene as pale yellow crystals.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]1[NH:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:35]=1.C(O)(C(F)(F)F)=O.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]1[NH:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:35]=1)=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CCOC(=O)c1n[nH]c(CN)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1n[nH]c(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)n1
Reaction time: 1 h
Yield: 20.77 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 120 mg, 0.278 mmol), ethyl 5-(aminomethyl)-1H-1,2,4-triazole-3-carboxylate, TFA (Int-XIV, 95 mg, 0.334 mmol), 4-methylmorpholine (113 mg, 1.113 mmol), and HATU (138 mg, 0.362 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.1 min) to provide ethyl 5-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)-1H-1,2,4-triazole-3-carboxylate (40 mg, 0.058 mmol, 20.77% yield) as a single enantiomer. LCMS=584.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.08-8.22 (2 H, m), 7.50-7.78 (7 H, m), 5.22 (1 H, s), 4.48-4.72 (2 H, m), 4.42 (2 H, q, J=7.04 Hz), 1.39 (3 H, t, J=7.04 Hz); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1.[CH3:24]I>C1COCC1.O>[CH3:3][O:4][C:5]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:6]=1[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][C:10]([CH3:24])([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1
Reactant: CI
Reactant: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C)CC(=O)N(Cc2ccc(OC)cc2OC)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (327 mg, 13.6 mmol) ws added to a solution of methyl 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (2.0 g, 6.8 mmol) in THF (50 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. Then the mixture was added methyl iodide (4.8 g, 34 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 16 hours and then was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give methyl 1-(2,4-dimethoxybenzyl)-3-methyl-5-oxopyrrolidine-3-carboxylate. MS ESI calc'd. for C16H22NO5 [M+H]+ 308. found 308. 1H NMR (400 MHz, CD3OD): δ 7.11 (d, J=8.8 Hz, 1H), 6.56 (s, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.39 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.68 (s, 3H), 3.64 (d, J=16.8 Hz, 1H), 3.10 (d, J=16.8 Hz, 1H), 2.93 (d, J=16.8 Hz, 1H), 2.32 (d, J=16.8 Hz, 1H), 1.33 (s, 3H).
Reaction SMILES: CC1C=CC=C(C)N=1.[Cl:9][C:10](=[N:19][OH:20])[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18].[Cl:21][CH2:22][CH2:23][CH2:24]S(Cl)(=O)=O>C1C=CC=CC=1>[Cl:21][CH2:22][CH2:23][CH2:24][O:20][N:19]=[C:10]([Cl:9])[C:11]1[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1cccc(C)n1
Solvent: c1ccccc1
Product: ClCCCON=C(Cl)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A 3.6 g (0.034 mol) sample of 2,6-dimethylpyridine was added dropwise to a cooled solution (ice bath) of 7.4 g (0.033 mol) alpha-chloro-2,6-dichlorobenzaldoxime and 5.9 g (0.03 mol) 3-chloropropylsulfonyl chloride in 75 ml benzene. The reaction mixture was allowed to warm to 25° C., stirred for 2 hours (a red solid formed) and allowed to stand overnight. The reaction mixture was evaporated under reduced pressure and the residue was chromatographed through a silica gel column with dichloromethane. A semi-crystalline yellow product was eluted from the column. The product was recrystallized from ether/hexane to give 4.3 g of O-(3-chloropropyl)-alpha-chloro-2,6-dichlorobenzaldoxime as a white solid, m.p. 69°-71° C. Elemental analysis for C10H9Cl4NO3S showed: %S, calc. 8.8, found 9.2; %Cl, calc. 38.8, found 37.9.
Reaction SMILES: CS([CH2:5][C:6]([F:10])([F:9])[CH:7]=[CH2:8])(=O)=O.[C:11]1([C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][O:13]1)=[O:12].[K].C[N:23](C)C=O>>[C:14]1(=[O:13])[N:23]([CH2:5][C:6]([F:10])([F:9])[CH:7]=[CH2:8])[C:11](=[O:12])[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:15]12
Reactant: C=CC(F)(F)CS(C)(=O)=O
Reactant: CN(C)C=O
Reactant: O=C1OCc2ccccc21
Agent: [K]
Product: C=CC(F)(F)CN1C(=O)c2ccccc2C1=O
Temperature: 110 °C

Procedure:
The compound 1-methanesulfonyl-2,2-difluoro-3-butene (11.2 g, 60.2 mM), potassium phthalide (12.3 g, 66.4 mM) and dry dimethylformamide (30 mL) are strirred and heated (bath temperature 110° C.) under nitrogen for 120 hours. After cooling to room temperature, the crude reaction product is precipitated by the addition of water (approximately 300 mL), filtered and dissolved in dichloromethane. The dichloromethane solution is washed with 1N potassium hydroxide (twice), water (twice), dried (Na2SO4) and evaporated to yield 1-phthalimido-2,2-difluoro-3-butene as beige-colored crystals: 11.9 g (83%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH:8]1([Mg]C)[CH2:12][CH2:11][CH2:10][CH2:9]1.[Br-].O1CCC[CH2:17]1>[Cu]I>[CH3:3][C:2]([CH3:5])([C:1](=[O:6])[CH2:17][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:4]
Reactant: C1CCOC1
Reactant: C[Mg]C1CCCC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cu]I
Agent: [Br-]
Product: CC(C)(C)C(=O)CC1CCCC1
Reaction time: 16 h

Procedure:
To a stirred mixture of pivaloyl chloride (11.09 g) and copper (I) iodide (10.0 g) in dry tetrahydrofuran (120 mls) at -75° C. under nitrogen was added dropwise cyclopentyl methylmagnesium bromide [prepared from magnesium turnings (3.313 g) and cyclopentylmethylbromide (15.0 g) in dry tetrahydrofuran (95 mls)]. The cooling bath was removed and the reaction mixture stirred for 16 hours then hydrolysed with cold aqueous ammonium chloride (10%). After filtration and extraction of the filtrates with ether, the combined ethereal extracts were washed with aqueous sodium hydroxide (10%) and brine and were dried over anhydrous magnesium sulphate. Concentration in vacuo gave the crude ketone as a yellow oil which was used without further purification. ##STR26##
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][NH2:7])([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.C(O)(=O)C>O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][N:7]1[CH:14]=[CH:18][CH:17]=[CH:16]1)([O-:3])=[O:2]
Reactant: NCc1ccccc1[N+](=O)[O-]
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1Cn1cccc1

Procedure:
The starting material is prepared as follows: The mixture of 3,078 g of o-nitrobenzylamine and 2,670 g of 2,5-dimethoxytetrahydrofuran is added rapidly to 10,000 ml of glacial acetic acid at 86° while stirring under nitrogen. The mixture is stirred at 95° for 1.25 hours, cooled to 25° and combined with 30,000 ml of water. It is extracted with ethyl acetate, the extract is washed with 10% aqueous sodium hydroxide and 10% aqueous sodium chloride, filtered and evaporated to yield the 1-(o-nitrobenzyl)-pyrrole.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O.ClP(Cl)[CH2:21][CH2:22][P:23](Cl)Cl.[CH2:27]1[CH2:31]O[CH2:29][CH2:28]1>>[CH2:1]([P:23]([CH:22]([P:23]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:22][CH2:21][CH2:31][CH2:27][CH2:28][CH2:29][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:21])[CH2:29][CH2:28][CH2:27][CH2:31][CH2:31][CH2:27][CH2:28][CH2:29][CH2:31][CH2:27][CH2:28][CH2:29][CH2:12][CH2:11][CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCC[Mg]Br
Reactant: ClP(Cl)CCP(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCP(CCCCCCCCCCCCCCC)C(C)P(CCCCCCCCCCCCCCC)CCCCCCCCCCCCCCC
Temperature: -30 °C
Reaction time: 2 h

Procedure:
250 ml of pentadecylmagnesium bromide (15% in tetrahydroluran (THF); 119 mmol) are initially charged in a 1|4-neck flask with internal thermometer, argon blanketing, metal/water condenser and stirrer, and cooled to −30° C. Subsequently, a solution of 5.5 g (23.8 mmol) of 1,2-bis(dichlorophosphino)-ethane in 100 ml of THF is added dropwise within 30 minutes, in the course of which a large amount of solids precipitates. The mixture is then warmed to room temperature within one hour and subsequently stirred at internal temperature 50° C. for a further 2 hours, which gives rise to a grayish-white suspension. This is admixed gradually, and while cooling with ice, with 95 ml of saturated and degassed NH4Cl solution to obtain a white suspension. Another 65 ml of degassed water are added thereto and the precipitate is filtered off with suction through a G2 frit under argon. The product is washed once with water and twice with 20 ml of THF, and dried under reduced pressure. This gives 22.2 g (93.5%) of the product in the form of a white powder. 31P NMR (CDCl3): −26.8 ppm (s); elemental analysis: calc. C 79.6%, H 13.8%, P 6.6%; exp. C 79.5%, H 14.0%, P 6.3%, Br 0.04%, Cl 0.06%, O<0.5%.