Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH:16]([O:29][Si](C(C)(C)C)(C)C)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.C(OC1C=CC(I)=CC=1)(=O)C>>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CC(=O)Oc1ccc(I)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2ccc(O)cc2)o1
Yield: 54 %

Procedure:
4-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)phenyl acetate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (74 mg, 0.112 mmol) and 4-iodophenyl acetate following General Procedure A. Flash chromatography (5-20% EtOAc/hexanes) yielded the title compound as a clear oil (31 mg, 54%): 1H NMR (CDCl3, 600 MHz) δ 7.65 (d, 2H, J=7.8 Hz), 7.27-7.24 (m, 3H), 7.16-7.14 (m, 5H), 4.82 (t, 1H, J=6.0 Hz), 2.58 (t, 2H, J=7.5 Hz), 2.32 (s, 3H), 1.97-1.87 (m, 2H), 1.65-1.60 (m, 2H), 1.45-1.34 (m, 6H), 0.89 (s, 9H), 0.09 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 170.2, 165.8, 151.4, 151.3, 143.7, 129.2, 129.1, 126.7, 126.4, 126.2, 123.1, 122.4, 69.5, 37.3, 36.8, 32.3, 30.0, 26.6, 26.6, 26.0, 22.1, 19.1, −4.1, −4.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:39][C:40]1[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=1)[C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C>[CH3:46][O:45][C:43](=[O:44])[C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([CH2:39][O:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][C@@H:14]3[CH3:31])=[O:30])=[CH:28][CH:27]=2)[CH:41]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(COc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (150 mg, 0.35 mmol) was dissolved in DMF (5 mL) at room temperature. Cs2CO3 (283 mg, 0.87 mmol) was added followed by methyl 3-(bromomethyl)benzoate (119 mg, 0.52 mmol) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (15 mL). The reaction mixture was washed with sat. aq. NaHCO3 (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5/95 ethyl acetate/hexane-50/50 ethyl acetate/hexane gradient) to afford slightly yellow solid product (111 mg, 54%).
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[C:14]#[CH:15]>C1(C)C(C)=CC=CC=1>[O:12]=[C:4]1[N:1]2[N:2]=[C:14]([C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[CH:15]=[C:3]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5]1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CC(=O)OCCCC
Solvent: Cc1ccccc1C
Product: CCCCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
2.0 g (0.126 mole) of 3-diazo-oxindole is taken up in xylene (85 ml), treated with 1.2 equivalents of n-butyl propiolate (1.9 g) and refluxed under a stream of nitrogen for 17 hours in an oil bath. The light coral-colored precipitates that form are cooled and filtered off and washed with ether. Yield: 3.0 g, m.p. 190°-195°; 83.57% crude yield. The crude product is taken up in boiling absolute ethanol (250 ml), treated with activated carbon, filtered and concentrated down on a steam bath to a volume of ~75 ml. After cooling, tan-colored precipitates are filtered off and dried in a vacuum oven at room temperature for 4 hours. Yield: 2.2 g, m.p. 198°-200°.
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[FH:18].F.F.C(N(CC)CC)C>>[F:18][C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2][C@H:1]1[OH:7]
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Reactant: F
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC[C@@H](F)[C@H](O)C1
Temperature: 100 °C
Yield: 56.4 %

Procedure:
Racemic benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (1.00 g, 4.29 mmol) (AMRI, Syracuse, N.Y. E00017 Lot IN-GBG-A-009B) and triethylamine trihydrofluoride (0.699 mL, 4.29 mmol) were combined in a sealed tube and heated to 100° C. overnight. The reaction was cooled and partitioned between water and EtOAc. The aqueous layer was extracted 3×EtOAc, and the organic layer was washed with water once, saturated aqueous NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (80 g column) using 15-50% EtOAc/hexane to give racemic trans-benzyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (0.612 g, 2.42 mmol, 56% yield). MS (ESI, pos. ion) m/z: 254 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:5]=[CH:4][C:3]=1[NH:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.[CH3:30][C:31]1([CH3:39])[C@@H:36]2[C@H:32]1[C:33](=[O:38])[O:34][C:35]2=O.CC(O)=O>C(#N)C>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:20]2[C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[N:11]=4)=[CH:7][C:2]=3[N:1]=[C:35]2[CH:36]2[CH:32]([C:33]([OH:38])=[O:34])[C:31]2([CH3:39])[CH3:30])=[CH:29][CH:28]=1)#[N:27]
Reactant: CC1(C)[C@@H]2C(=O)OC(=O)[C@@H]21
Reactant: N#Cc1ccc(CNc2ccc(OCc3ccc4ccccc4n3)cc2N)cc1
Solvent: CC#N
Solvent: CC(=O)O
Product: CC1(C)C(C(=O)O)C1c1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 49.1 %

Procedure:
To a solution of 4-(((2-amino-4-(quinolin-2-ylmethoxy)phenyl)amino)methyl)benzonitrile (124 mg, 0.33 mmol) in acetonitrile (3 mL) was added cis-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione (49 mg, 0.33 mmol) and the solution heated to 80° C. for 4 h. AcOH (1 mL) was then added and the heating continued at 80° C. for an additional 16 h. The resulting mixture was cooled to RT and the mixture was concentrated to dryness. The residue purified using FCC to provide 81.4 mg of the title compound. MS (ESI): mass calcd. for C31H26N4O3, 502.20; m/z found, 503.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=8.6 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.78-7.73 (m, 1H), 7.70-7.65 (m, 3H), 7.59-7.54 (m, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.19-7.09 (m, 4H), 5.49-5.39 (m, 4H), 2.32 (d, J=8.3 Hz, 1H), 1.99 (d, J=8.3 Hz, 1H), 1.20 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]=[CH2:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[N:22]1(C=CCCC)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:24]([CH2:25][CH2:26][CH3:27])=[CH:23][N:22]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC=CN1CCCCC1
Reactant: C=CC(=O)c1ccc(-c2ccc(CCCCC)cc2)cc1
Product: CCCCCc1ccc(-c2ccc(-c3ccc(CCC)cn3)cc2)cc1

Procedure:
Example 11 is repeated by reacting 1-(4'-pentylbiphenyl-4-yl)-prop-2-en-1-one and 1-piperidinopentene to give the corresponding 2-(4'-pentylbiphenyl-4-yl)-5-propylpyridine having C 171° N 198° I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([C:14]1[CH:26]=[CH:25][C:17]2[N:18]=[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])[S:20][C:16]=2[CH:15]=1)[C:10]([O:12]C)=O.[NH2:28][NH2:29].[OH-].[NH4+].CO.C(Cl)Cl>CC(O)=O.CCO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]=[C:19]([NH:21][CH:22]([CH3:23])[CH3:24])[S:20][C:16]=3[CH:15]=2)=[C:10]([OH:12])[NH:29][N:28]=1
Reactant: NN
Reactant: COC(=O)C(C(=O)c1ccccc1F)c1ccc2nc(NC(C)C)sc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)Nc1nc2ccc(-c3c(-c4ccccc4F)n[nH]c3O)cc2s1
Temperature: 85 °C
Yield: 22.2 %

Procedure:
To a solution of methyl 3-(2-fluorophenyl)-2-(2-(isopropylamino)benzo[d]thiazol-6-yl)-3-oxopropanoate(63% purity, 0.260 g) in glacial AcOH (4 mL) and EtOH (2 mL) was added anhydrous hydrazine (0.18 mL, 5.73 mmol) at 0° C. The resulting mixture was heated at 85° C. for 4 hr. After it cooled to rt, the mixture was diluted with water (40 mL), basified with concentrated ammonium hydroxide to pH 8, and extracted with AcOEt (3×30 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The title compound (55.0 mg, 27% yield over two steps) was isolated by ISCO (8% MeOH/CH2Cl2). (M+H)+=369.21.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[C:11](=O)[CH2:10][CH2:9][C:8]([NH:19][C:20](=[O:22])[OH:21])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1>CCOCC.C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:8]([O:21][C:20](=[O:22])[NH:19][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:10][C:11]2([CH2:2][CH2:1]2)[N:6]([CH3:5])[CH2:7]1)([CH3:13])([CH3:9])[CH3:7]
Reactant: CC[Mg]Br
Reactant: CN1CC(NC(=O)O)(c2ccccc2)CCC1=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1CC(NC(=O)OC(C)(C)C)(c2ccccc2)CCC12CC2
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 11 %

Procedure:
A solution of 333 ul (1.0 mmol) of a 3M ethyl magnesium bromide solution in ether in 4 ml THF was cooled to −70° C. A solution of 124 ul (0.42 mmol) titanium isopropoxide in 0.4 ml THF was added dropwise. The light brown mixture was stirred for 2 minutes. A solution of 122 mg (0.4 mmol) rac-(1-Methyl-6-oxo-3-phenyl-piperidin-3-yl)-carbamic acid ter!-butyl ester (example A.22, step 2) in 2.4 ml THF was added dropwise. The mixture was allowed to warm to room temperature and was stirred for 3 hours. The mixture was cooled in an ice bath and quenched with a 20% ammonium chloride solution. Water and ethyl acetate were added. The white suspension was filtered through a pad of dicalite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 14 mg (11%) of the title compound as a colorless oil. MS (m/e): 317.2 (M+H).
Reaction SMILES: [C:1]1([CH2:19][OH:20])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25]Cl>>[C:1]1([CH2:19][O:20][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[S:2][CH:3]=[C:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[S:7][C:6]1[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=1
Reactant: CN(C)CCCl
Reactant: OCc1scc2c1-c1ccccc1Sc1ccccc1-2
Agent: Cl
Product: CN(C)CCOCc1scc2c1-c1ccccc1Sc1ccccc1-2

Procedure:
Starting from the alcohol 15 (0.67 mmole) and 2-dimethylaminoethylchloride-hydrochloride (6.7 mmoles), an oily product was obtained;
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Br:16][C:17]1[CH:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(N(CC)CC)C>C(#N)C>[Br:16][C:17]1[CH:22]=[C:21]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Br)ncc2[N+](=O)[O-])C1
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 3-(aminomethyl)-1-boc-piperidine (409 mg, 1.91 mmol) in acetonitrile (2.5 mL) was added dropwise to a solution of 2-bromo-4-chloro-5-nitropyridine (431 mg, 1.82 mmol) and triethylamine (0.28 mL, 2.0 mmol) in acetonitrile (10 mL). The solution was stirred for 1 hr then partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (×3) and the combined organic phases were dried (Na2SO4) and concentrated to give tert-butyl 3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate as a yellow-brown solid (718 mg, 95%) which was used without further purification.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22](OC=C)(=[O:24])[CH3:23]>COC(C)(C)C>[C:22]([O:14][C@@H:11]1[CH2:12][CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reactant: C=COC(C)=O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)C1
Yield: 49 %

Procedure:
Combine (+/-)-cis-3-tert-butyldimethylsilyloxycyclopentanol (2.119 g, 9.8 mmol, prepared in example 29), pancreatin (6.2 g, 3 weight equivalents), triethylamine (0.9 mL, 6.5 mmol) and vinyl acetate (4.3 mL) in tert-butyl methyl ether (12 mL) and stir for 27 hours at room temperature. Then filter the reaction through diatomaceous earth and concentrate the filtrate under vacuum (room temperature/ 15 mmHg). Purify the residue by column chromatography [silica gel, 55 g, hexane (300 mL) followed by 5% ethyl acetate/hexane (500 mL)] to provide the (lR,3S)-(+)-3-tert-butyldimethylsilyloxycyclopentanyl acetate (1.23 g, 49% yield, 98% ee as determined from gas chromatography with a chiral column) and (1S,3R)-(-)-3-tert-butyldimethylsilyloxycyclopentanol (771 mg, 37% yield, 92% ee as determined from its acetate derivative followed by GC chiral column analysis, see example 30a).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reactant: Cc1cc(O)c(Br)cc1F
Product: C=CC[C@H](C)Oc1cc(C)c(F)cc1Br
Yield: 59 %

Procedure:
Prepared in 59% yield from 2-bromo-4-fluoro-5-methylphenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=8.8 Hz, 1H), 6.75 (d, J=6.8 Hz, 1H), 5.91 (ddt, J=17.2, 10.2, 7.2 Hz, 1H), 5.20-5.07 (m, 2H), 4.42-4.26 (m, 1H), 2.60-2.48 (m, 1H), 2.45-2.37 (m, 1H), 2.23 (d, J=1.8 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].COS([O-])(=O)=O.[CH2:15]([N+:33]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])([CH3:35])[CH3:34])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[F:1][C:2]([S:3]([O-:6])(=[O:5])=[O:4])([F:8])[F:7].[CH2:36]([N+:33]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH3:35])[CH3:34])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 500 milliliters of water was cautiously added 43 milliliters (72.9 grams, 0.486 mol) of trifluoromethane sulfonic acid, CF3SO3H (3M Corporation, Fluorad FC-24, anhydrous). This solution was cooled to room temperature then added to a suspension of distearyl dimethyl ammonium methyl sulfate (DDAMS) (150 grams, 0.227 mol) in 600 milliliters water. The mixture was heated on a hot plate with stirring (80° to 90° C.) for 4 hours, cooled to room temperature and allowed to stand overnight (16 hours). The mixture had separated into a tan solid layer atop the aqueous layer. The solid layer was broken up and the aqueous phase removed by filtration under reduced pressure. The tan solid was washed with water then air dried for 1 hour. The crude material was recrystallized from acetone to afford 114.7 grams (0.164 mol, 72 percent theory), m.p. 90° C. (soften), 119° C. (liquid) of the above trifluoromethane sulfonate salt (DDATRIF), as an off-white powder. A second crop, 17 grams of a tan-yellow solid, was unacceptable for use without further extensive purification.
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].C1(O)C=CC(C)=C(C)C=1.[N+:14]([C:17]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[CH:19][C:18]=1[OH:25])([O-:16])=[O:15].[N+](C1(C)C=CC(O)=CC1C)([O-])=O>ClCCl>[N+:14]([C:17]1[C:22]([CH3:23])=[C:21]([CH3:24])[CH:20]=[C:19]([N+:1]([O-:3])=[O:2])[C:18]=1[OH:25])([O-:16])=[O:15]
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1C
Reactant: O=[N+]([O-])O
Agent: CC1C=C(O)C=CC1(C)[N+](=O)[O-]
Agent: Cc1ccc(O)cc1C
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of 630 grams (5 moles/ of a 50% aqueous nitric acid and 400 ml dichloromethane were introduced in a two liter flask fitted with a stirrer, a reflex condenser, a dropping funnel and a thermometer. To this stirred mixture was added dropwise a solution of 245 g (2 moles) 3,4-xylenol in 400 ml dichloromethane, during two hours, maintaining the temperature at 20°-25° C. After another hour stirring at the same temperature the reaction mixture was heated to reflux (about 40° C.) until the starting product and the two intermediate products (2-nitro-3,4-xylenol and 4-nitro-3,4-xylenol) have disappeared (followed by GC analysis). This occurs in about three hours. The mixture was cooled to ambient temperature and allowed to separate in two phases. The lower organic phase was separated from the aqueous acidic layer and washed twice with water. Water (400 ml) was added to the organic phase and dichloromethane was removed by distillation. The slurry of the dinitro compound in water was cooled and filtered and dried at 70° C. A product of 93.7%. 2,6-dinitro-3,4-xylenol pure was obtained which was 74.5% of the theoretical yield. After crystallization from ethyl alcohol it has a melting point of 124°-125° C.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[C@H:12]2[CH2:15][CH:16]=[CH:17][CH2:18][C@H:11]2[C:10]1=[O:19])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].CC1C=CC(C)=CC=1>[CH2:1]([N:9]1[C:13](=[O:14])[C@H:12]2[CH2:15][CH2:16][CH:17]=[CH:18][C@H:11]2[C:10]1=[O:19])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1[C@H]2CC=CC[C@H]2C(=O)N1CCc1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccc(C)cc1
Product: O=C1[C@H]2CCC=C[C@H]2C(=O)N1CCc1ccccc1
Yield: 94.4 %

Procedure:
A mixture of 5.0 g of cis-N-phenethyl-1,2,3,6-tetrahydrophthalimide (prepared by the method of Example 1), 0.5 g of chlorotris(triphenylphosphine)rhodium and 50 mL of p-xylene was heated under reflux for 48 hours. Removal of the solvent and short-path distillation of the residue (150° bath temperature, 0.001 mm) gave 4.72 g of cis-N-phenethyl-1,2,3,4-tetrahydrophthalimide containing 12% of unrearranged starting material.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][C:17]#[N:18])[C:6]1=[O:19])=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].Cl>O.CN(C=O)C>[CH3:32][C:31]([O:30][C:28](=[O:29])[CH2:27][C:5]1([C:3]([O:2][CH3:1])=[O:4])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][C:17]#[N:18])[C:6]1=[O:19])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C1C(=O)N(CC#N)C(=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(CC(=O)OC(C)(C)C)C(=O)N(CC#N)C(=O)c2ccccc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
To a suspension of 2-(cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylic acid methyl ester (6.5 g, 25.19 mmol), K2CO3 (6.95 g, 50.38 mmol) and anhydrous DMF (100 mL) was added tert-butyl bromoacetate (6.1 mL, 37.79 mmol). After stirring at 85° C. for 3 hours, the mixture was poured into H2O, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexane/EtOAc 4/1) gave a white solid (8.5 g, 90.7%).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][C:5](=[O:8])[O:6][CH3:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][C:32]#[N:33]>C1COCC1>[C:16]([O:15][C:13]([NH:1][C@@H:2]([CH2:3][CH:4]([CH2:31][C:32]#[N:33])[C:5]([O:6][CH3:7])=[O:8])[C:9]([O:11][CH3:12])=[O:10])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: N#CCBr
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
To a solution of Boc-Glu(OMe)-OMe (20.0 g., 72.6 mmol) in THF (50 mL) was added dropwise a solution of LiHMDS (26.3 g, 157 mmol) in THF (250 mL) at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 1.5 h and bromoacetonitrile (13.0 g, 108 mmol) was added dropwise over 1 h while maintaining the temperature below −70° C. The reaction mixture was stirred at −78° C. for 2 h and quenched with pre-cooled methanol (10 mL) in one portion. The mixture was stirred for 10 min and then treated with a pre-cooled solution of acetic acid (9 mL) in THF (60 mL). The mixture was stirred for 10 min and poured into brine (200 mL). The resulting mixture was extracted with EtOAc (300 mL×2) and the combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=1:1) to afford (2S)-dimethyl 2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate (16.0 g, 70% yield) as a light brown oil.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:6][C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]([C:13]#[N:14])=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1N
Temperature: 120 °C
Yield: 73 %

Procedure:
A suspension of 4-bromo-2-methyl-6-nitroaniline (11.5 g, 50 mmol), Zn(CN)2 (770 mg, 150 mmol), and Pd(PPh3)4 (2.32 g, 2.0 mmol) in DMF (100 mL) was sealed and heated at 120° C. for 70 h. After cooled down to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography with CH2Cl2 to afford the title compound (6.4 g, 73%). ESI-MS m/z 178 (MH+).