Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:6]([CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8])#[CH:5]
Reactant: C[Si](C)(C)C#CC(O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Place a mixture of α-[(trimethylsilyl)ethynyl]-benzene-methanol (1.87 g, 9.13mmol) and tetrahydrofuran (11 mL) under argon atmosphere. Add, by dropwise addition, tetra-n-butylammonium fluoride (11 mL of a 1M solution in tetrahydrofuran, 11 mmol). Stir for 1 hour at room temperature and partition between ethyl ether and water. Separate the organic phase, wash with saturated aqueous sodium chloride, dry (MgSO4), filter, and concentrate in vacuo to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)=O.[K+].[OH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15].[O-]S(C(F)(F)F)(=O)=O.ClC1C=CC=CC=1[I+:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1>C(OC(=O)C)(=O)C.C(Cl)Cl.O>[F:18][C:17]([F:20])([F:19])[S:14]([O-:16])(=[O:15])=[O:13].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I+:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc([I+]c2ccccc2Cl)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: Clc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [K+]
Agent: [O-][I+2]([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Clc1ccc([I+]c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 8.6 %

Procedure:
To a mixture of 20.0 grams (178 mmol, 1 eq) of chlorobenzene in 30 mL of acetic anhydride and 19.0 grams (88.8 mmol, 0.5 eq) of potassium iodate cooled to 0° C. was added 26.7 grams (15.7 mL, 178 mmol, 1.0 eq) of triflic acid at such a rate that the reaction temperature did not exceed 0° C. The mixture was allowed to warm to room temperature slowly and stirred for 14 hours. Approximately 45 mL of water was added to the reaction mixture at 0°-20° C. followed by methylene chloride. The precipitate dissolved in the methylene chloride and the organic phase was washed with water, aqueous sodium bicarbonate, and water, and concentrated in vacuo. This material was recrystallized from a mixture of 20 mL of isopropanol and 35 mL of hexane to give 7.62 grams (8.6% yield). A second crop was obtained from the mother liquor, 2.5 grams (total yield 11.4%). The product contains less than 7% of the isomeric 2-chlorophenyl-4-chlorophenyliodonium triflate and a small amount of uncharacterized impurity.
Reaction SMILES: [CH2:1]([N:8]1[C:16](O)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:36])=O>CN(C=O)C>[CH2:1]([N:8]1[C:16]([Cl:36])([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:19][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCOc1ccc(C2(O)c3ccccc3C(=O)N2Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCOc1ccc(C2(Cl)c3ccccc3C(=O)N2Cc2ccccc2)cc1
Yield: 100 %

Procedure:
2-Benzyl-3-hydroxy-3-[4-(2-trimethylsilanylethoxymethoxy)phenyl]-2,3-dihydroiso-indol-1-one (125 mg, 0.27 mmol) was reacted with thionyl chloride (0.019 mL, 0.27 mmol) and a catalytic amount of DMF (3 drops) as for general procedure G. Removal of the solvent gave 2-benzyl-3-chloro-3-[4-(2 trimethylsilanylethoxymethoxy)phenyl]-2,3-dihydroiso-indol-1-one as a colourless oil (129 mg, 0.27 mmol, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].[CH3:11][N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][C:16]([C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH2:14]1>>[ClH:6].[ClH:6].[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([C:16]2[CH2:17][CH2:18][CH:13]([N:12]([CH3:26])[CH3:11])[CH2:14][CH:15]=2)[N:24]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccccc3Br)n2)CC1
Product: Cl
Yield: 34 %

Procedure:
Using a method similar to example 1, using 2-bromobenzoyl chloride (151 mg, 0.69 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 2 (preparation 11, 100 mg, 0.46 mmol) provides the free amine of the title compound as an oil (63 mg, 34%): MS (ES): m/z=400 (M+H)+, 403 (M+3); 1H NMR (CD3OD): δ 8.30 (t, 1H), 7.69 (d, 2H), 7.67 (d, 1H), 7.49 (m, 3H), 6.78 (m, 1H), 3.55 (m, 1H), 2.87 (s, 6H), 2.73 (m, 4H), 2.37 (m, 1H), 1.87 (m, 1H). Using a salt formation method similar to that in example 1 gives the dihydrochloride salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:18][S:19]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCC(=O)N1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN1C(=O)CCC1=O

Procedure:
The N-(2-hydroxyethyl)succinimide (Aldrich, 0.19 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH2:11]([NH2:15])[CH:12]([CH3:14])[CH3:13]>C1COCC1>[CH2:11]([NH:15][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4])[CH:12]([CH3:14])[CH3:13]
Reactant: O=C(CBr)N1CCOCC1
Reactant: CC(C)CN
Solvent: C1CCOC1
Product: CC(C)CNCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.7 %

Procedure:
N-Bromoacetyl-morpholine (3.73 g, 18 mmol) was dissolved in 20 mL of THF. Isobutylamine (5.40 mL, 54.0 mmol) was added. The reaction mixture was stirred at room temperature for 24 h. Solvent and excess reagent were removed in vacuo. The residue was treated with ether. The resulting solid was removed by filtration and washed with ether. The filtrate was concentrated under reduced pressure to give 2-isobutylamino-1-morpholin-4-yl-ethanone (1.43 g, 40%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].O>CN(C)C=O>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]([NH:11][CH2:10][CH2:9][Cl:8])=[O:13])=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: O=C=NCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCl)Nc1ccncc1
Reaction time: 2 h

Procedure:
To the solution of 1.6 g of 4-aminopyridine in 7 ml of dimethylformamide 2 g of 2-chloroethylisocyanate are added while stirring and keeping the temperature below 40°. After 2 hours 28 ml of water are added and stirring is continued for 2 hours at room temperature. The precipitate formed is filtered off, washed with water, dried and recrystallized from aqueous ethanol, to yield the 1-(4-pyridyl)-3-(2-chloroethyl)-urea melting at 120°-122°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[C:21](Cl)[N:20]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[NH2:28][NH2:29]>CC(O)C.O>[NH2:26][C:25]1[C:22]2[C:21](=[N:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][S:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=4[Cl:1])(=[O:10])=[O:11])=[CH:18][CH:17]=3)=[CH:24][N:23]=2)[NH:29][N:28]=1
Reactant: N#Cc1ncc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)nc1Cl
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Nc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)cnc12
Temperature: 120 °C

Procedure:
2,3-Dichloro-N-[4-(6-chloro-5-cyano-pyrazin-2yl)-phenyl]-benzenesulfonamide (1.0 g) was suspended in a mixture of 5 ml iPrOH and 5 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT. The precipitate was filtered off and washed with water to give the title compound as a yellow solid after drying under vacuum. Yield: 536 mg (54%).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[O:5][N:4]=1.[NH3:20].[CH3:21][OH:22]>>[NH:20]=[CH:21][O:22][CH2:2][C:3]1[N:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[O:5][N:4]=1
Reactant: CO
Reactant: Clc1ccc(OCc2nc(C(Cl)(Cl)Cl)no2)c(Cl)c1
Reactant: N
Product: N=COCc1noc(COc2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
2.17 g of 3-(trichloromethyl)-5-[(2,4-dichlorophenoxy)methyl]-1,2,4-oxadiazole was added to 50 ml of methanol. An excess of ammonia gas was added with formation of bubble at 0° C. and then the mixture was stirred at room temperature for 4 hours. After evaporation of methanol, water was added to the residue. The aqueous solution was extracted with ethylacetate. After evaporation of ethylacetate, the residue was purified by column chromatography(hexane:ethylacetate) to provide 0.92 g of the desired product(yield: 50.9%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[C@@H:10]([CH2:12][O:13][CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[CH3:26][C:25]([NH:11][C@@H:10]([C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH2:12][O:13][CH3:14])=[O:27]
Reactant: CC(=O)OC(C)=O
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
N-benzyl-O-methyl-D-serinamide (5 g), was mixed with DCM (25 ml) at ambient temperature and stirred for 10 minutes to get a clear solution. To this solution, dimethylaminopyridine (0.025 g) was added at ambient temperature. Acetic anhydride (2.695 g) was slowly added over 10-12 minutes at ambient temperature. The solution was stirred for 30 minutes at room temperature. The reaction mixture was washed with 5% sodium bicarbonate (15 ml) solution, deionized water (15 ml), and brine (10 ml). The layers were separated and solvent was completely recovered under vacuum at 35° C. to 40° C. to get crude product. Yield=5.9 gm.
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH2:31][OH:32])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2]>CCCCCC.CCOC(C)=O>[CH:1]([C:4]1[C:5]([CH:31]=[O:32])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]([CH2:13][CH2:14][CH3:15])=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:2])[CH3:3]
Reactant: CCCc1c(C(C)C)cc(C(C)C)c(CO)c1-c1ccc(F)cc1OCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(C(C)C)cc(C(C)C)c(C=O)c1-c1ccc(F)cc1OCc1ccccc1
Yield: 88 %

Procedure:
Prepared from the intermediate obtained in Step A by the procedure described in Example 218, Step A. Silica gel chromatography (95:5 hexane/EtOAc) provided a colorless crystalline solid (0.323 g, 88%). 1H NMR (CDCl3, 300 MHz): δ 9.74 (s, 1H), 7.41 (s, 1H), 7.22-7.28 (m, 3H), 7.06-7.13 (m, 3H), 6.72-6.80 (m, 2H), 5.00 (s, 2H), 3.91 (sept, 6.8 Hz, 1H), 3.23 (sept, 6.7 Hz, 1H), 2.37-2.46 (m, 1H), 2.17-2.27 (m, 1H), 1.20-1.36 (m, 14H), 0.73 (t, 7.4 Hz, 3H). FAB-MS: calculated for C29H33FO2 432; found 433 (M+H).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.C([C:11]1[C:12]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])C)=[N:13][CH:14]=[CH:15][CH:16]=1)=O>C1COCC1.Cl>[CH:22]1([C:19]2[C:18]([OH:23])=[N:17][C:12]3[C:11]([CH:21]=2)=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:3][CH2:2]1
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1nc2ncccc2cc1C1CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (−78° C.) of LDA (2.0 M, 251 mmol) in 600 mL THF was added ester 4-3 (prepared from cyclopropylacetic acid and methanolic HCl solution, 15 g, 131 mmol) gradually over 30 min. The reaction mixture was stirred for 30 min at −78° C. Aldehyde 4-2 (22.5 g, 109 mmol) in 40 mL THF was added. The reaction mixture was stirred at −78° C. for 1 hr, then was warmed up to room temperature over 1 hr and quenched with 200 mL NH4Cl (sat.). The mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water, brine and dried over MgSO4 and concentrated to give a viscous residue which was subsequently dissolved in 200 mL 3N HCl. The mixture was refluxed at 105° C. for 24 hr. After concentration, the residue was poured into 500 mL ice-water and quenched with K2CO3 gradually (pH=9) to yield a solid as the desired product 4-4, which was filtered and dried in vacuum.
Reaction SMILES: [CH3:1][Mg]Cl.[Cl:4][C:5]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8]>C1COCC1>[Cl:4][C:5]1[C:6]([C:7](=[O:8])[CH3:1])=[CH:13][CH:14]=[C:15]([CH3:17])[N:16]=1
Reactant: CON(C)C(=O)c1ccc(C)nc1Cl
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C)nc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl magnesium chloride (3 M in THF, 10 mL) was slowly added at 0° C. to a solution of 2-chloro-N-methoxy-6,N-dimethyl-nicotinamide (2.4 g) in THF (100 mL). The reaction mixture was stirred at 0° C. for 1 h, then quenched with water. The resulting mixture was extracted with EtOAc, the combined organics dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, gradient from 0 to 25% in 25 minutes) to give 1-(2-chloro-6-methylpyridin-3-yl)-ethanone (0.85 g) as a brown oil.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:45])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:44])[C:27]2[CH:32]=[C:31]([CH2:33][N:34]([CH:36]=[O:37])[CH3:35])[CH:30]=[CH:29][C:28]=2[NH:38][C:39]([O:41]CC)=O)=[CH:21][CH:20]=1)[NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])([CH3:3])[CH3:2].[CH3:46]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>C(O)(=O)C.CC(O)C>[CH:1]([O:4][C:5](=[O:45])[C@H:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:26](=[O:44])[C:27]3[C:28](=[CH:29][CH:30]=[C:31]([CH2:33][N:34]([CH:36]=[O:37])[CH3:35])[CH:32]=3)[N:38]([CH3:46])[C:39]2=[O:41])=[CH:21][CH:20]=1)[NH:7][C:8](=[O:17])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Nc1ccc(CN(C)C=O)cc1C(=O)Nc1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)OC(C)C)cc1
Reactant: CN(C)C=O
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)c3cc(CN(C)C=O)ccc3n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 17.1 g of Nα-(2,6-dichlorobenzoyl)-4-{2-ethoxycarbonylamino-5-(N-formyl-N-methyl-aminomethyl)-benzoylamino}-L-phenylalanine isopropyl ester prepared in the foregoing step 1, there were added 68 mL of N,N-dimethylformamide, 6.8 mL of 2-propanol and 7.55 g of potassium carbonate, and then 5.89 mL of methyl p-toluene-sulfonate was added to the resulting mixture, followed by the stirring of the mixture at room temperature overnight. After confirming the completion of the reaction by HPLC, 6.25 mL of acetic acid was added to quench the mixture and then 84 mL of water was dropwise added thereto to separate out a solid material. The separated solid was isolated through filtration under reduced pressure, washed with 82 mL of water and then dried under reduced pressure to thus give 15.80 g of the intended compound as a white crystalline solid. The physical properties of the 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine methyl ester and 12 mL of N,N-dimethylformamide, and the resulting mixture was stirred overnight. Subsequently, 48 mL of methanol was dropwise added, the resulting mixture was stirred at 10° C. overnight and then the solid separated from the mixture was isolated through filtration under reduced pressure. The solid was then washed with 8 mL of methanol and dried at 70° C. for 5 hours under reduced pressure to thus give 5.50 g of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[N+:21]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:13]([OH:15])=[O:14])[CH2:9][CH:8]2[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:23])=[O:22]
Reactant: O=C(O)C1CC1(C(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)C1CC1(C(=O)O)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred slurry of 20.6 g. of 1-phenylcyclopropane-1,2-dicarboxylic acid (J. Med. Chem. 24:481) in 25 ml. of concentrated sulfuric acid at 0° C. is added 15 ml. of concentrated nitric acid over 30 minutes. The resultant solution is stirred at ambient temperature for 30 minutes and then poured onto ice. The crystalline product is recrystallized from hexane-ethyl acetate to give 1-(p-nitrophenyl)-cyclopropane-1,2-dicarboxylic acid as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[NH:11][C:4]=2[CH:3]=1.[Cl:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]([C:21](=[O:22])[CH2:20][CH2:19][Cl:18])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1OCO2
Reactant: O=C(Cl)CCCl
Solvent: Cc1ccccc1
Product: O=C(CCCl)N1c2ccccc2OCOc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A suspension of 2-chloro-12H-dibenzo[d,g][1,3,6]dioxazocine (10.65 g, 43 mmol, described in J. Mol. Struct., 131, 1985, 131-140) and 3-chloropropionyl chloride (6.55 g, 51.6 mmol) in dry toluene (100 ml) was heated at reflux temperature for 5 h. After cooling to room temperature, the reaction mixture was washed with a saturated solution of sodium bicarbonate (50 ml). The organic layer was dried (MgSO4), and evaporated in vacuo, affording 2-chloro-12-(3-chloropropionyl) -12H-dibenzo[d,g][1,3,6]dioxazocine (12.85 g , 88%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C1COCC1.ClCCl>[CH2:27]([O:14][CH:13]1[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1OCc1ccccc1
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a solution of benzyl rac-(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (600 mg, 1.8 mmol; prepared according to WO2004/050024A2) in THF (8 mL) cooled to 0° C. was added NaH (216 mg, 5.4 mmol [60%]) and the reaction mixture stirred for 1 hour. Benzyl bromide (430 μL, 3.57 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an additional portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography to afford benzyl rac-(3R,4R)-3-(benzyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate (200 mg, 26%). To the product was added 4N HCl (in dioxane, 5 mL) and the mixture was stirred 2 hours. All volatiles were removed, and the salt was dissolved in DMF (5 mL), to which was added {[3-(trifluoromethyl)benzoyl]amino}acetic acid (174 mg, 0.705 mmol), HATU (268 mg, 0.705 mmol), diisopropylethylamine (246 μL, 1.41 mmol) and HOBt (95 mg, 0.705 mmol) and the mixture was allowed to stir overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography to afford benzyl rac-(3R,4R)-3-(benzyloxy)-4-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1.[CH:14]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>C(OCC)C>[Cl:13][C:9]1[CH:8]=[C:7]([C:25]2([OH:27])[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:26]2=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Clc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2cccc(Cl)c2)c2ccccc2-c2ccccc21
Temperature: -40 °C

Procedure:
A 2.5M solution of butyllithium in hexanes (1.8 eq), (Aldrich) was added dropwise to a solution of 1-bromo-3-chlorobenzene (1.5 eq) in anhydrous diethyl ether with stirring under argon at -40° C. After stirring at room temperature for 0.5 h, a solution of 9-fluorenone (1 eq), (Aldrich) in anhydrous diethyl ether was added dropwise to the mixture with stirring and cooling at 0° C. The reaction mixture was stirred at room temperature for 1 h, poured into a saturated solution of ammonium chloride and extracted with dichloromethane. The combined dichloromethane extracts were washed with brine, dried (MgSO4), the solvent evaporated and the residue chromatographed on silica gel column with 10% ethyl acetate in hexanes to give the title compound as an oil.
Reaction SMILES: [C:1]([N:20]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=O)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32]>C(O)C.N1C=CC=CC=1.O>[C:1]([N:20]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][CH2:25][C:26]2=[N:31][OH:32])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCCc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: O
Product: ON=C1CCCc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 2-trityl-2,5,6,7-tetrahydro-indazol-4-one (1.32 mmol) in ethanol (5 mL) and pyridine (0.16 mL), hydroxylamine hydrochloride (1.2 eq) was added and the mixture was stirred at 55° C. for 1.5 h. After cooling to rt, the mixture was diluted with water and filtered. The solid was washed with water and dried. Obtained the title compound in 90% yield. ESI (+) MS: m/z 394 (MH+). 1H NMR: 1.69-1.88 (m, 2H), 2.07-2.25 (m, 2H), 2.59-2.67 (m, 1H), 2.77-2.86 (m, 1H), 6.99 (s, 1H), 7.19-7.31 (m, 15H), 9.94 (s, 1H).