Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:4]=13.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[N+:17]([C:9]1[CH:1]=[C:2]2[C:6]3=[C:7]([CH2:10][CH2:11][N:5]3[C:4]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:3]2=3)[CH:8]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])[O-]
Reactant: c1cc2c3c(c1)c1c(n3CC2)CCCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CC2)CCCCC1

Procedure:
Following the procedure of Example 1, step 2, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole (7.5 g, 35 mmol) and potassium nitrate (3.6 g, 35 mmol) in concentrated sulfuric acid (100 mL) provided 2-nitro-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[CH2:12][CH2:13]Br>>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:11]=1[CH2:12][CH2:13][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: Clc1cccc(Cl)c1CCBr
Reactant: CCc1ccncc1
Product: CC(CCc1c(Cl)cccc1Cl)c1ccncc1
Yield: 55.3 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 2,6-dichlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.45 g of the desired compound (yield: 55.3%). The resulting compound was identified as 1-(2,6-dichlorophenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 11) by the following analytical results.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Br:8].[CH3:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11](Cl)=[O:12]>>[Br:8][C:4]1[N:3]([O:2][C:11](=[O:12])[N:10]([CH3:9])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: On1ccnc1Br
Agent: Cl
Product: CN(C(=O)On1ccnc1Br)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-bromoimidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (63%, oil).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11](=O)[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:12][C:11](=[N:20][OH:21])[CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1=NO
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 60.2 %

Procedure:
A solution of 24.7 g (0.1 mole) of 1-benzyl-3-ethoxycarbonyl-4-pyrrolidone in 135 ml of ethanol was added dropwise at room temperature to a solution of 34.7 g (0.5 mole) of hydroxylamine hydrochloride dissolved in 135 ml of water, and then 28.1 g (0.265 mole) of sodium carbonate were added to the mixture. The mixture was then stirred at room temperature for 6.5 hours, after which it was extracted with 300 ml of chloroform. The chloroform extract was washed with water and dried over anhydrous sodium sulfate. It was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 2:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 15.8 g of 1-benzyl-3-ethoxycarbonyl-4-hydroxyiminopyrrolidine as a brown oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52](O)=[O:53])=[CH:47][CH:46]=1>C(#N)C>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:53])=[CH:47][CH:46]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc(Cl)cc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.4 mmol) and 4-chlorophenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminlpropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was filtered. The solid was slurried with hot acetone (15 mL) to afford 2-(4-chloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.8 g, 82%) as a white solid: mp 243-245° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.04 min. (86%); 1H NMR (DMSO-d6) δ 2.02-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.54 (s, 2H), 4.72 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 7.29-7.38 (m, 4H), 7.61-7.67 (m, 1H), 7.71-7.83 (m, 2H), 8.68 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.86, 41.31, 48.83, 121.90, 127.13, 128.14, 130.94, 131.14, 131.52, 133.22, 134.69, 135.11, 139.95, 166.89, 167.42, 169.78, 170.24, 172.73; Anal. Calcd. for C22H18N3O5Cl: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 60.06; H, 3.85; N, 9.67; Cl, 8.07.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:4][CH:3]1[CH2:5][OH:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])O.[Na+]>C1COCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([S:24]([O:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:7])[F:1])(=[O:26])=[O:25])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: OCC1CC1(F)F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CC2(F)F)cc1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (2,2-difluorocyclopropyl)methanol (20.0 g) and triethylamine (32.2 mL) in THF (300 mL) was added 4-nitrobenzenesulfonyl chloride (41.0 g) at 0° C., and the mixture was stirred for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (47.2 g) as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:3])C.[CH2:21](N)CC>>[CH3:12][C:9]([CH3:10])([CH3:11])[C@@H:8]([C:13]([OH:15])=[O:14])[NH:7][C:5]([N:4]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH2:1][CH2:3][CH3:21])=[O:6]
Reactant: CCCN
Reactant: C=CCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C
Product: C=CCCCN(CCC)C(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
3-Methyl-N-{[pent-4-en-1-yl(propyl)amino]carbonyl}-L-valine was prepared according to the procedure described for N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine by using n-propylamine in Step 1. LRMS (ESI) m/z 285 [(M+H)+; calcd for C15H29N2O3: 285.2].
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH2:21])[CH3:20]>O>[CH2:19]([NH:21][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][N:7]=1)[CH3:20]
Reactant: COc1ccc2nc(-c3ccc(F)nc3)sc2c1
Reactant: CCN
Solvent: O
Product: CCNc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Temperature: 100 °C

Procedure:
In a microwave vial were added 2-(6-fluoropyridin-3-yl)-6-methoxy-1,3-benzothiazole (75 mg, 0.289 mmol), water (1.2 mL) and ethylamine in water (70%, 1.2 mL) and the reaction was heated in a microwave oven at 100° C. for 5 min. The precipitated product was filtered off, washed with water and dried in a desicator over P2O5 to yield the product (67 mg) as a white solid. 1H NMR δ ppm 8.62 (d, 1 H) 7.95 (dd, 1 H) 7.82 (d, 1 H) 7.64 (d, 1 H) 7.23 (t, 1 H) 7.07 (dd, 1 H) 6.57 (d, 1 H) 3.83 (s, 3 H) 3.33-3.40 (m, 2 H) 1.16 (t, 3 H); MS m/z (M+H) 286.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH3:30][C@H:31]([NH:40][CH3:41])[C@@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:40]([CH:31]([CH3:30])[CH:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:41])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(O)c1ccccc1)N(C)C(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a dry round-bottomed flask equipped with a magnetic stirrer and an argon inlet was dissolved N (benzyloxycarbonyl)-glycine (5.00 g, 23.9 mmol, 1.0 equiv) in dichloromethane (25 mL). Triethylamine (3.66 mL, 26.3 mmol, 1.1 equiv) was added and the resulting mixture was cooled to 0° C. To the reaction was added dropwise trimethylacetylchloride (2.94 mL, 23.9 mmol, 1.0 equiv). A white precipitate formed and dichloromethane (25 mL) was added to allow efficient stirring. The reaction was stirred for 30 min at 0° C. and then a solution of (+)-pseudoephedrine (4.15 g, 25.1 mmol, 1.05 eq) and triethylamine (3.66 mL, 26.3 mmol, 1.1 eq) in dichloromethane (40 mL) was added via cannula. The reaction was stirred for 30 min at 0° C. Most of the solvent was removed under reduced pressure and water and saturated sodium bicarbonate were added. The product was extracted with two portions of ethyl acetate and the organic extracts were washed with saturated ammonium chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel with ethyl acetate/hexanes as the eluent (30%-80% gradient) gave [S-(R*,R*)-N2-(benzyloxycarbonyl)-N1-(2-hydroxy-1-methyl-2-phenylethyl)-N1-methyl glycinamide (6.67g, 78%) as a white foam (1:1 mixture of rotamers): 1H NMR (CDCl3, 300 MHz) δ7.25-7.40 (m, 10H), 6.04 (m, 1H), 5.09 (28, 4H), 4.67 (m, 0.5H), 4.51 (d, 0.5H, J=4.5 Hz), 4.49 (d, 0.5H, J=4.7 Hz), 4.23 (dd, 0.5H, J1 =16.7 Hz, J2=3.8 Hz), 4.15 (s(br), 1H), 4.04 (dd, 0.5H, J1=16.5 Hz, J2=5.1 Hz), 3.92 (d, 1H, J=4.3 Hz), 3.77 (m, 0.5H), 2.88 (s, 1.5H), 2.77 (s, 1.5H), 0.94 (d, 1.5H, J =6.4 Hz), 0.92 (d, 1.5H, J=6.3 Hz); 13C NMR (CDCl3, 75.5 MHz) δ169.3, 169.0, 156.2, 141.4, 141.1, 136.30, 136.26, 128.4, 128.2, 128.02, 127.95, 127.7, 126.6, 126.5, 75.2, 74.6, 66.5, 57.4, 56.1, 42.9, 42.6, 29.3, 26.8, 14.9, 13.9; FTIR (neat film) cm-1 3405, 3323, 3031, 2980, 1719, 1638.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[N:16][CH:15]=[CH:14][CH:13]=2>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])[C:18]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CC(C)(O)CNc1c(N)cnc2cccnc12
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCc1nc2cnc3cccnc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, ethoxyacetyl chloride (19.1 g, 0.156 mol) was added over a period of 12 minutes to a mixture of 1-[(3-amino[1,5]naphthyridin-4-yl)amino]-2-methylpropan-2-ol (28.95 g, 0.125 mol) in pyridine (300 mL). The reaction mixture was stirred at ambient temperature for 4 hours and then at reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature overnight and then concentrated under high vacuum. The residue was dissolved in 5% potassium carbonate (200 mL) and then extracted with dichloromethane (200 mL). The extract was filtered to remove some insoluble material, dried over magnesium sulfate, filtered, and then concentrated under high vacuum. The residue was dissolved in dichloromethane (150 mL) and eluted through a short column of alumina. The eluent was concentrated under reduced pressure and air dried to provide 31.9 g of 1-(2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-2-methylpropan-2-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].C(O)C>[N:11]1([CH:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C(c2ccccc2)n2ccnc2)cc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Yield: 99.1 %

Procedure:
A solution of 39 parts of intermediate 42, namely 1-[(4-nitrophenyl)phenylmethyl]-1H-imidazole, in 240 parts of ethanol was hydrogenated at 3.105Pa and at room temperature with 20 parts of Raney nickel. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 34.6 parts (99.1%) of 4-[(1H-imidazol-1-yl)phenylmethyl]-benzenamine (interm. 43).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:32])([F:41])[F:42])=[CH:35][CH:36]=1)=[O:14]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a solution of 5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (200 mg, 0.4716 mmol) in methylene chloride (10 ml) were added 4-trifluoromethylaniline (114 mg, 0.7080 mmol), triethylamine (95 mg, 0.9405 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (239 mg, 1.4142 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (166 mg, 0.2932 mmol, 62%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:19])([CH3:18])[CH2:12]OS(C)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:18])[CH2:12][O:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@](O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
(R)-2-Chloro-1-(2-hydroxy-3-methanesulfonyloxy-2-methylpropyl)-4-nitroimidazole prepared in Example 11 (942.6 g, 3 mol) was suspended in ethyl acetate (9426 ml). DBU (494 ml, 3.3 mol) was added to the suspension, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water (5 liters). The water layer was extracted with ethyl acetate (5 liters) twice. The organic phases were combined together, and the mixture was washed with a saturated saline solution (5 liters), dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to afford (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole (600.7 g, yield 92%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[CH:8][CH2:7][CH2:6]2.CN(C)[CH:16]=[O:17].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:13])=[C:8]([CH:16]=[O:17])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC=C2C
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCC(C=O)=C2C
Temperature: 72.5 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of Compound B (0.44 g, 2.5 mmole) in dry dimethylformamide (1.3 ml, 16.8 mmole) at ice cooling and stirring under argon atmosphere, phosphorus oxychloride (0.62 ml, 6.65 mmole) was added drop-by-drop in 2 minutes. The reaction mixture was stirred in an oil bath of 70-75° C. for 3 hours. After cooling in an ice bath, ice (6 g) was added, then sodium acetate (anhydrous, 3.7 g) was added, and the mixture (pH ˜6) was warmed in an oil bath at 70-75° C. for 15 minutes. After cooling, it was extracted with ether (1×10 ml and 3×5 ml), the combined organic solutions were washed with water (3×3 ml), dried (magnesium sulfate), decolorized (with activated carbon), and evaporated. The residue (0.33 g) was recrystallized from cyclohexane (2 ml) and dried over potassium hydroxide in a vacuum giving the pure product 6-Methoxy-1-methyl-3,4-dihydro-2-naphthaldehyde (Compound C, 0.22 g, 44%) as light brown crystals, mp. 70-72° C.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:10]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][NH2+:15]1)#[N:9].C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[C:34]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:10]=1[C:8]#[N:9])(=[O:38])[CH2:35][CH2:36][CH3:37]
Reactant: N#Cc1c(OC[C@H]2CCCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
To a solution of (R)-2-((2-cyano-3-nitrophenoxy)methyl)piperidin-1-ium 2,2,2-trifluoroacetate (Example 16c, 2.26 g, 6.03 mmol) in anhydrous DCM (50 mL) was added triethylamine (4.2 mL, 30.1 mmol) at room temperature. The reaction mixture was cooled down to 0° C. and butyryl chloride (0.95 mL, 9.05 mmol) was added and the solution stirred at room temperature overnight. The solvent was then removed under reduced pressure and the residue was diluted with EtOAc (150 mL), the organic layer was washed successively with water, brine and dried over Na2SO4, filtered and evaporated. The residue was purified by Biotage SP-1 (40s column) eluting with EtOAc/Hexane (10%-70%) to give the desired product (1.5 g, 75%). MS 332 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:8][C:9]1([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:32][CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl[1-[(4-benzyl-1-piperazinyl)methyl]cyclohexyl]methylcarbamate (770 mg/1.92 mmol) in dimethylformamide (10 ml) was added potassium hydride (157 mg/3.84 mmol) at 0° C. and the resulting solution was stirred for 30 minutes at the same temperature. Ethyliodide (0.46 ml/5.76 mmol) was added to the solution and the resulting mixture was stirred for 6 hours at ambient temperature Water (20 ml) was added for quenching and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si/230-400 mesh/20 g/dichloromethane:methanol=100:0-100:2-100:4-100:6) to give a colorless oil (730 mg/89%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]1([C:22]#[C:23][C:2]2[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=Cc1cnc(C#Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a round bottom flask was added 2-bromo-5-formylthiazole (3.83 g, 19.9 mmol, purchased from Frontier Scientific, Inc.), THF (100 mL) and triethylamine (20 mL). To the solution was successively added CuI (228 mg, 1.20 mmol), PdCl2(PPh3)2 (420 mg, 0.60 mmol) and a solution of phenylacetylene (2.24 g, 21.9 mmol) in THF (20 mL) over a period of about 5 minutes. The reaction was then stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure, the residue transferred to a 1.0-L separatory funnel with EtOAc (200 mL) and saturated aqueous sodium bicarbonate (300 mL) and extracted. The layers were separated and the aqueous layer was extracted again with EtOAc (2×100 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient ranging from 5% to 50% EtOAc in hexanes to afford the titled compound, 2-phenylethynyl-thiazole-5-carbaldehyde, (3.94 g, 93%) as an orange solid.
Reaction SMILES: [NH:1]1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[OH-].[K+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1.O>CN(C=O)C>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:1]2[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][C:2]2=[O:8])=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: O=C1CCCC(=O)N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) mixture of commercially available piperidine-2,6-dione (400 mg; 3.46 mmol; 1.0 equiv.) and KOH (213 mg; 3.81 mmol; 1.1 equiv.) in anh. DMF (3.5 ml) was stirred, under nitrogen, for 30 min., and was then treated with a solution of commercially available 1-(bromomethyl)-4-(trifluoromethoxy)benzene (956 mg; 3.63 mmol; 1.05 equiv.) in anh. DMF (1 ml). The resulting mixture was further stirred at rt, under nitrogen, for 3 days. Water was added, and the mixture was extracted with Et2O (3×). The mixed organic layers were washed successively with 2 M aq. NaOH, aq. sat. NH4Cl, and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 1-(4-(trifluoromethoxy)benzyl)piperidine-2,6-dione as a colorless oil. LC-MS (conditions E): tR=0.67 min.; no ionisation.