Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([C:32]([C:34]([F:37])([F:36])[F:35])=[CH2:33])=[CH:27][C:26]=1[F:38].Cl>CN(C=O)C.O>[Cl:24][C:25]1[C:26]([F:38])=[CH:27][C:28]([C:32]2([C:34]([F:37])([F:35])[F:36])[O:13][N:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=4[CH:10]=3)[CH2:33]2)=[CH:29][C:30]=1[F:31]
Reactant: C=C(c1cc(F)c(Cl)c(F)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(F)c(Cl)c(F)c4)(C(F)(F)F)C3)cc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 34.4 %

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (200 mg, 0.98 mmol) in DMF (7 mL) at rt was added NCS (157 mg, 1.17 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. This mixture was added dropwise to a solution of 2-chloro-1,3-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (237 mg, 0.98 mmol) and TEA (218 mg, 2.16 mmol) in DMF (7 mL) at 0° C. The mixture was stirred at this temperature for 1 h, and then at rt overnight. The mixture was acidified with 3 N HCl to pH of 2, then poured into water and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=2:1) to give the final title compound (150 mg, yield 35%) as white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.24 (s, 1H), 7.82-7.73 (m, 3H), 7.71-7.60 (m, 2H), 4.50 (d, J=18.3 Hz, 1H), 4.44 (d, J=18.3 Hz, 1H), 1.51 (s, 3H), 1.50 (s, 3H) ppm; HPLC purity: 95.5% at 214 nm and 97.8% at 254 nm; MS: m/z=446 (M+1, ESI+).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccccc1I
Product: COc1ccccc1NC(=O)c1ccccc1
Yield: 20.7 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with 2-iodoanisole (135 μL, 1.04 mmol) at 40° C. for 18 h. The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 15 mL fractions). Fractions 8-12 provided 49 mg (21% yield) of the product as a colorless oil. The 1H NMR spectrum was in accord with that reported by Narasaka et al. Tsutsi, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 1869.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2[nH]ncc2c1
Yield: 103.6 %

Procedure:
To a stirred solution of methyl 1H-indazole-5-carboxylate (6.5 g, 1.0 eq) in 200 mL MeOH was added a solution of NaOH (4.4 g, 3.0 eq) in 150 mL H2O. The mixture was refluxed for 1 h. The organic solvent was removed in vacuo, the remaining aqueous solution was washed with EtOAc, acidified with 3 N HCl to pH=5-6, and the precipitate was collected by filtration, and washed with water, to give the desired product as a yellow solid (6.2 g, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[O:3]1.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:15](=[O:16])[CH:14]([Cl:18])[Cl:13])[CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[O:3]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)OCC1CNC(C)(C)O1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)OCC1CN(C(=O)C(Cl)Cl)C(C)(C)O1

Procedure:
In a similar manner as Example I, 27.7 milliliters of 25 percent w/v, 2,2-dimethyl-5-isopropoxymethyl oxazolidine solution in 50 milliliters of benzene and 4.9 grams of dichloroacetyl chloride was added 4.1 grams of triethylamine. After the appropriate work up procedure, there was obtained a yield of 8.9 grams, nD30 1.4564. Analytical data supports the structure.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29]6[N:30]=[CH:31][CH:32]=[CH:33][N:34]=6)[CH2:24][CH2:25]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(c2ncccn2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 2-(piperazin-1-yl)pyrimidine (1.2 equiv) to give 177 (8.7 mg, M+1 460.1)
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:33])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[C:4]2[N:10]=[C:9]([CH:11]3[CH2:13][CH:12]3[C:14]([O:16]CC)=O)[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:35]>>[Br:1][C:2]1[C:3]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][C:26](=[O:33])[NH:27][C:28]3[S:29][CH:30]=[CH:31][N:32]=3)[CH2:23][CH2:24]2)=[C:4]2[N:10]=[C:9]([CH:11]3[CH2:13][CH:12]3[C:14]([NH2:35])=[O:16])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C1CC1c1nc2c(N3CCN(CC(=O)Nc4nccs4)CC3)c(Br)cnc2[nH]1
Agent: [OH-]
Product: NC(=O)C1CC1c1nc2c(N3CCN(CC(=O)Nc4nccs4)CC3)c(Br)cnc2[nH]1

Procedure:
A solution of ethyl 2-(6-bromo-7-(4-(2-oxo-2-(thiazol-2-ylamino)ethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopropanecarboxylate (15 mg, 0.028 mmol) in ammonium hydroxide (2.5 mL) was heated in a sealed tube at 100° C. for 16 h. After this time, LC-MS analysis showed that only the desired product was present. Evaporation of the solvents in vacuo provided the product (9 mg, 64%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 1.40 (app. quintet, J=4.4 Hz, 1H, cyclopropane CHAHB), 1.46-1.51 (m, 1H, cyclopropane CHAHB), 2.20-2.24 (m, 1H, cyclopropane CH), 2.40 (br s, 1H, cyclopropane CH), 2.74 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.38 (s, 2H, NCH2CO), 3.54 (br s, 4H, piperazine N(CH2)2), 6.53 (d, J=3.7 Hz, 1H, thiazole H-4 or H-5), 6.83 (br s, 2H, NH2), 6.92 (d, J=3.7 Hz, 1H, thiazole H-4 or H-5), 7.02 (br s, 1H, CONH), 7.74 (br s, 1H, imidazo[4,5-b]pyridine H-5);
Reaction SMILES: [N:1]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].C(O)(=O)C.[C:18]([O:22][C:23](=[O:39])[N:24]([CH2:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH2:28][CH:29]=O)[CH3:25])([CH3:21])([CH3:20])[CH3:19].[Na]>CO.C(=O)(O)[O-].[Na+]>[C:18]([O:22][C:23](=[O:39])[N:24]([CH2:26][C@H:27]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[CH2:28][CH2:29][N:11]1[CH2:12][CH2:13][CH:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:7])[CH2:9][CH2:10]1)[CH3:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: O=C1CCCCN1C1CCNCC1
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of [1,4′]bipiperidinyl-2-one (4.5 g) in methanol (100 mL) was added acetic acid (1.49 mL). The solution was stirred for several minutes before (S)-[2-(3,4-dichloro-phenyl)-4-oxo-butyl]-methyl-carbamic acid tert-butyl ester (26 mmole) was added in methanol (25 mL). Stirring was continued for 20 minutes after which time, sodium cyanoborohyuride (1.64 g) was then added in methanol (5 mL). The mixture was stirred for two days and then diluted with aqueous sodium bicarbonate and concentrated. It was then partitioned between layers of water and dichloromethane. The aqueous layers were washed with dichloromethane and the organic phases were combined, dried and evacuated to viscous oil which was purified by flash chromatography eluting with methanol:dichloromethane (5:95). This material formed a white foam upon drying under vacuum (9.4 g). MS: m/z=512(M+1).
Reaction SMILES: [Li+].[OH-].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:35]=[CH:34][C:17]2[CH2:18][CH:19]([CH2:29][C:30]([O:32]C)=[O:31])[C:20](=[O:28])[N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:22][C:16]=2[CH:15]=1>C1COCC1.O>[O:28]=[C:20]1[CH:19]([CH2:29][C:30]([OH:32])=[O:31])[CH2:18][C:17]2[CH:34]=[CH:35][C:14]([O:13][CH2:12][CH2:11][CH2:10][NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=3)=[CH:15][C:16]=2[CH2:22][N:21]1[CH2:23][C:24]([F:27])([F:25])[F:26]
Reactant: COC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CN(CC(F)(F)F)C1=O
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
1.0 N LiOH (0.44 mL, 0.44 mmole) was added to a solution of methyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (159.5 mg, 0.34 mmole) in THF (1.7 mL) and H2O (1.3 mL) at RT. The yellow, cloudy reaction became homogeneous within 10 min. After 24 hr, the reaction was concentrated to dryness and the yellow residue was dissolved in H2O (4 mL). The solution was filtered, then was carefully neutralized (pH≈7) with 1.0 N HCl. The precipitate was collected, washed with plenty of H2O, and dried in high vacuum at 40-45° C. to afford the title compound (130.0 mg, 83%) as an off-white solid: HPLC (PRP-1®, 25% CH3CN/H2O containing 0.1% TFA) k′=3.1; 1H NMR (400 MHz, DMSO-d6) δ 7.91-8.00 (m, 1 H), 7.28-7.40 (m, 1 H), 7.02 (d, J=9.2 Hz, 1 H), 6.76-6.87 (m, 2 H), 6.51-6.02 (m, 1 H), 6.39-6.50 (m, 2 H), 5.30 (d, J=16.6 Hz, 1 H), 4.10-4.30 (m, 3 H), 4.02(t, J=6.3 Hz, 1 H), 3.70-3.82 (m, 1 H), 3.20-3.45 (m, 2 H, partially obscured by residual solvent signal), 2.99 (dd, 1 H), 2.59-2.74 (m, 2 H), 2.39 (dd, J=16.9, 4.8 Hz, 1 H), 1.90-2.03 (m, 2 H); MS (ES) m/e 452 (M+H)+. Anal. Calcd for C22H24F3N3O4.0.5 H2O: C, 57.39; H. 5.47; N, 9.13. Found: C, 57.39; H, 5.18; N, 9.00.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C.O.NN>CO>[N:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccncc2)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc(-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
4-(4-nitro-phenyl)-pyridine (250 mg, 1.25 mmol) is dissolved in MeOH (20 mL). To this solution is added FeCl3.6H2O (24 mg, 0.09 mmol) and active charcoal (12 mg, 1.0 mmol). The suspension is heated to reflux. Hydrazine hydrate (1.3 mL) is added, and reflux is continued for 3 h. After the mixture is cooled to room temperature, the active charcoal is filtered off through Celite, and the MeOH is removed under reduced pressure. The residue is purified with flash chromatography to provide the 4-pyridin-4-yl-phenylamine (200 mg, 94%). 1H NMR (400 MHz, CDCl3) ∂ 8.57 (2H, d, J=8.8 Hz), 7.44-7.52 (4H, m), 6.77 (2H, d, J=7.2 Hz), 3.87 (2H, br); MS (ESI) m/z 171 (M+H)+1.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:18]=[C:17]([CH2:19]O)[CH:16]=[CH:15][C:14]=3[CH3:21])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].P(Br)(Br)([Br:28])=O>C(Cl)Cl.CCOC(C)=O>[Br:28][CH2:19][C:17]1[CH:16]=[CH:15][C:14]([CH3:21])=[C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:22])[C:5](=[O:23])[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:12]3=[CH:11][CH:10]=2)[CH:18]=1
Reactant: Cc1ccc(CO)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: O=P(Br)(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(CBr)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of 51-1 (150 mg, 0.44 mmol) in DCM (2 mL) at 0° C. was added phosphorus oxybromide (126 mg, 0.46 mmol). After 4 hours, the reaction was diluted with EtOAc, and washed with water, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give product as a white foam. MS (M+H)+: observed=402.0/404.0, calculated=402.3/404.3.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:25][CH2:26][CH2:27][N:12]4[CH:11]=2)[CH:15]=[C:16]([C:21]#[C:22][CH2:23]O)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Pt].C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([O:25][CH2:26][CH2:27][N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][CH2:22][CH3:23])[CH:17]=3)=[O:9])=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(C#CCO)cc3c1=O)OCC2
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: CCCc1cc2c3c(c1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn3CCO2
Yield: 34 %

Procedure:
A mixture of 50 mg of N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide of Example 2 and 20 mg of 5% platinum on carbon in 2 mL of 1:1 THF-methanol is stirred vigorously under 1 atmosphere of hydrogen gas for 3 hours, then filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure, and the residue chromatographed on silica using 2-3% methanol in dichloromethane. Following concentration under reduced pressure, the upper eluting fractions provide 16.5 mg of N-(4-chlorobenzyl)-7-oxo-9-propyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide (3B); the lower eluting fractions similarly afford 27.5 mg of N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide (3A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:39])([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][Si](C)(C)C)[CH:22]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:39])([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C#C[Si](C)(C)C)c1)cc(=O)n2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc(-c2cc(=O)n(C)c3ccc(C(O)(c4ccc(Cl)cc4)c4cncn4C)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (3.88 g, 7.03 mMol) was dissolved in THF (10 mL) under an atmosphere of dry N2. To this solution was added a solution of 1.0 N tetrabutylammonium fluoride in THF (20 mL, 20 mMol). The reaction mixture was stirred overnight at ambient temperature and was then concentrated under vacuum. The residue was partitioned between 4-(dicyanomethylene)-2-methyl-6-(4-dimethylamino-styryl)-4H-pyran (DCM) and water. The DCM layer was saved and washed 3 more times with water and then with brine. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (4:96) to give 3.01 g of the titled compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)[CH2:27][CH2:26]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>ClCCl>[C:41]([O:40][C:38]([N:45]1[CH2:50][CH2:49][N:48]([C:35](=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][N:28]2[CH2:27][CH2:26][N:25]([CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:30][CH2:29]2)[CH2:47][CH2:46]1)=[O:39])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCCN1CCN(CCCCC(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCN1CCN(CCCCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Carbonyldiimidazole (129 mg, 0.796 mmol) was added to a solution of 5-[4-(4-tert-butoxycarbonylaminobutyl)piperazin-1-yl]pentanoic acid (111) (219 mg, 0.613 mmol) in anhydrous dichloromethane (8 mL) and the mixture was stirred at room temperature for 2 hours. N-Boc piperazine (148 mg, 0.796 mmol) was then added in one portion and the reaction mixture was stirred at room temperature for an additional 16 hours. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by Biotage silica gel column chromatography using methanol/dichloromethane (gradient 0% to 2%) to give 4-{5-[4-(4-tert-butoxycarbonylaminobutyl)piperazin-1-yl]pentanoyl}piperazine-1-carboxylic acid tert-butyl ester 112 as a viscous, yellow oil (309 mg, 96%): 1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.48 (s, 9H), 1.55 (m, 6H), 1.66 (m, 2H), 2.35 (m, 8H), 2.48 (m, 6H), 3.11 (m, 2H), 3.40 (m, 2H), 3.44 (m, 4H), 3.58 (m, 2H), 5.30 (br, 1H). m/z (ESI) 526 [C27H51N5O5+H]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH:23]=C(C)C)[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:30]=[O+][O-]>CO.ClCCl>[CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:27])[CH:21]([CH2:22][CH2:23][OH:30])[O:20]3)[CH:12]2[O:28][CH3:29])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[O+][O-]
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Solvent: ClCCl
Solvent: CO
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CCO
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-cyclohexylcarbamoyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (20 mg) in a mixture of methanol (0.1 ml) and dichloromethane (5 ml) was passed through ozone at -78° C. for 3 minutes. Nitrogen was bubbled into the solution at the same temperature to remove excess ozone. The solvents were evaporated and the residue was dissolved in methanol (2 ml). To the solution was added sodium borohydride (10 mg) in one portion at 5° C. The mixture was stirred at 5° C. for 10 minutes and then concentrated in vacuo. The residue was dissolved in dichloromethane (20 ml), washed with brine, dried, and evaporated. The crude oil was purified by column chromatography on silica gel eluted with diethyl ether to yield 6-cyclohexylcarbamoyloxy-4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (11.6 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:23])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoic acid (5.26 g, 23.4 mmol) in tetrahydrofuran (50 mL) were added N,N-dimethylformamide (40 μL) and oxalyl chloride (2.8 mL, 31.9 mmol), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give 2-chloro-3-(trifluoromethyl)benzoyl chloride. To a solution of 5-amino-2-methylphenol (2.62 g, 21.2 mmol) in tetrahydrofuran (20 mL) was added water (30 mL) in which sodium hydrogen carbonate (2.68 g, 31.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. To the mixture was added dropwise a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate, and filtered through a pad filled with silica gel. The solvent was concentrated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (6.37 g, 91%) as a pale-brown powder. The obtained compound was used for the next reaction without further purification operation.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>C1COCC1>[NH2:19][C:11]1[CH:12]=[CH:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:18])[C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: N
Reactant: O=c1c([N+](=O)[O-])c(Cl)ccn1Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccn(Cc2ccccc2)c(=O)c1[N+](=O)[O-]
Yield: 91.4 %

Procedure:
A solution of 1-benzyl-4-chloro-3-nitro-1H-pyridin-2-one (1.30 g, 4.91 mmol) and 28% aqueous ammonia (4.92 g, 39.3 mmol) in THF (30 mL) was stirred at room temp for 17 h. The solvent was evaporated under reduced pressure and water was added to the residue. The resulting precipitate was collected by filtration, and washed with water to give 4-amino-1-benzyl-3-nitro-1H-pyridin-2-one (1.10 g, 91% yield). 1H-NMR (DMSO): δ 8.13 (m, 2H), 7.69 (d, 1H, J=8.0 Hz), 7.31 (m, 5H), 5.94 (d, 1H, J=8.0 Hz), 4.96 (s, 2H). MS: calculated for C12H11N3O3+H 246.1; found: 246.2.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[C:6]([OH:11])(=[O:10])[C:7]([OH:9])=[O:8].[CH2:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28](O)=[C:27]([OH:32])[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OC(=O)C)(=O)C>[C:6]([OH:11])(=[O:10])[C:7]([OH:9])=[O:8].[CH2:12]([N:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([O:3][C:1](=[O:4])[CH3:2])=[C:27]([O:32][C:7](=[O:8])[CH3:6])[CH:26]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)[O-]
Reactant: Oc1ccc(C2CCCN(Cc3ccccc3)C2)cc1O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C2CCCN(Cc3ccccc3)C2)cc1OC(C)=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 224.9 %

Procedure:
9.8 g of anhydrous sodium acetate were added to a mixture of 9.8 g of the product of Step B and 120 ml of acetic acid anhydride and the mixture was stirred at 20° C. for 3 hours and was then filtered. The filter was washed with ethanol and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in water and ethyl acetate and the solution was made alkaline with an aqueous solution saturated with sodium bicarbonate. The ethyl acetate phase was recovered by decanting, was dried and evaporated to dryness. The residue was dissolved in 50 ml of isopropanol and a solution of 4 g of oxalic acid in 50 ml of isopropanol was added thereto. The mixture was refluxed until dissolution occurred and was cooled to 20° C. and vacuum filtered to obtain 13.5 g of N-benzyl-3-(3',4'-diacetoxyphenyl)-piperidine oxalate melting at 145° C.