Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[OH:3][C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH3:17])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCCOc1ccc(O)c(C(=O)OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A 4 mol/L aqueous solution of sodium hydroxide (0.67 mL) was added to a dioxane (3.0 mL) solution of methyl 2-hydroxy-5-propoxybenzoate (0.19 g), followed by stirring at room temperature for 1 hour and 30 minutes and then at 55 to 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid (15 mL) was added thereto. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.13 g of 2-hydroxy-5-propoxybenzoic acid as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>O=P(Cl)(Cl)Cl>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[NH:9][C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc3ccc(F)cc3[nH]2)cc1

Procedure:
2-(4-Nitrophenyl)-5-fluoro benzimidazole was synthesized as follows: 1,2-diamino-4-fluorobenzene (1.26 g, 10.0 mmole was mixed with 4-nitrobenzoic acid (1.67 g, 9.8 mmole) and dissolved in POCl3 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHCO3 and used without further purification.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[C:7]([F:23])[C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19])=[O:4].[OH-].[Na+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:48][O:49][CH2:50][C@@H:51]([OH:53])[CH3:52].CCN(C(C)C)C(C)C>>[OH:53][C@@H:51]([CH3:52])[CH2:50][O:49][NH:48][C:3]([C:5]1[CH:6]=[C:7]([F:23])[C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19])=[O:4]
Reactant: COC(=O)c1cc(F)c2cncn2c1Nc1ccc(Br)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1cc(F)c2cncn2c1Nc1ccc(Br)cc1F
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 30.5 %

Procedure:
To a solution of 5-(4-bromo-2-fluoro-phenylamino)-8-fluoro-imidazo[1,5-a]pyridine-6-carboxylic acid methyl ester (351 mg, 0.92 mmol) in IMS (10 mL) was added sodium hydroxide (1.0 mL, 1M aqueous solution, 1.0 mmol). The reaction mixture was heated at 65° C. for 1 hour, and then concentrated in vacuo. The resultant residue was azeotroped with toluene and then suspended in dioxane. EDCI (353 mg, 1.84 mmol) and HOBt (248 mg, 1.84 mmol) were added and the mixture was stirred at room temperature for 20 minutes. (S)-1-Aminooxy-propan-2-ol hydrochloride (235 mg, 1.84 mmol) and DIPEA (0.63 mL, 3.68 mmol) were added and the resultant mixture was stirred for 18 hours, before being concentrated under reduced pressure. The resultant residue was taken up in ethyl acetate then washed with a saturated aqueous solution of sodium bicarbonate followed by water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 10%, methanol in dichloromethane) to give a pale yellow solid (124 mg), which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 85%, ramp time 15 minutes) to afford the title compound as an off-white solid (70 mg, 17%). LCMS (method A): RT=7.83 min, [M+H]+=441/443. 1H NMR (CDCl3): 9.45 (1 H, s), 8.99 (1 H, s), 7.76 (1 H, d, J=2.95 Hz), 7.59 (1 H, s), 7.29 (1 H, dd, J=10.10, 2.16 Hz), 7.12 (1 H, d, J=8.52 Hz), 6.50 (1 H, d, J=10.18 Hz), 6.41 (1 H, t, J=8.54 Hz), 4.03 (1 H, t, J=7.52 Hz), 3.94 (1 H, d, J=11.57 Hz), 3.70 (1 H, t, J=10.24 Hz), 1.14 (3 H, d, J=6.46 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([C:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:28]([C:25]2([CH2:22][CH:23]=[CH2:24])[CH2:27][CH2:26]2)(=[O:30])=[O:29])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2OCC3)CC1
Yield: 34.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.46 g, 0.001 mol) in dry pyridine (3 mL) was reacted with 1-allyl-cyclopropane sulfonyl chloride (0.25 g, 0.0014 mol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 0.19 g of the product (30% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]([N:23]1[C:27]([NH2:28])=[C:26]([CH3:29])[CH:25]=[N:24]1)[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:28][C:27]2[N:23]([CH2:21][CH3:22])[N:24]=[CH:25][C:26]=2[CH3:29])=[N:3][CH:4]=1
Reactant: CCn1ncc(C)c1N
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCn1ncc(C)c1Nc1cc(Nc2ccccc2C(=O)NOC)c(Cl)cn1
Temperature: 90 °C
Reaction time: 0.83 h

Procedure:
A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (300 mg, 0.96 mmol), 1-ethyl-4-methyl-1H-pyrazol-5-amine (253 mg, 2.01 mmol), cesium carbonate (939 mg, 2.88 mmol) and DMF (7 ml). The reaction mixture was degassed under nitrogen for 10 min and palladium (II) acetate (10.8 mg, 0.05 mmol) and BINAP (59.8 mg, 0.096 mmol) were added. The reaction mixture was heated in an oil bath at 90° C. for 5 hrs and then in a microwave at 150° C. for 50 min. It was evaporated and the residue was dissolved in MeOH, filtered thru celite and thru an Acrodisc and purified further on preparative Agilent HPLC (5 to 95% water:acetonitrile with 0.1% formic acid). Fractions were combined and evaporated. The brown oil residue was diluted in DMF and water was added. A precipitate crashed out. It was filtered off and dried under vacuum at 40° C. for 5 hrs. LC-MS [M+H]+=401.1. 1H NMR (400 MHz, DMSO-d6) ppm 11.92 (s, 1 H) 9.48 (br. s., 1 H) 8.27 (s, 1 H) 7.94 (s, 1 H) 7.59 (d, J=7.58 Hz, 1 H) 7.51 (d, J=3.54 Hz, 2 H) 7.22 (s, 1 H) 7.09-7.16 (m, 1 H) 6.40 (s, 1 H) 3.85 (q, J=7.33 Hz, 2 H) 3.71 (s, 3 H) 1.79 (s, 3 H) 1.21 (t, J=7.20 Hz, 3 H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@@H:7]([N:20]2[CH:28]=[N:27][C:26]3[C:25](=[O:29])[NH:24][C:23]([NH:30]C(=O)C)=[N:22][C:21]2=3)[C@@H:6]1[NH:34]C(=O)C(F)(F)F)(=O)C.CCN(CC)CC.CO>O>[NH2:34][C@@H:6]1[C@@H:5]([OH:4])[C@H:10]([OH:11])[C@@H:9]([CH2:15][OH:16])[O:8][C@H:7]1[N:20]1[CH:28]=[N:27][C:26]2[C:25](=[O:29])[NH:24][C:23]([NH2:30])=[N:22][C:21]1=2
Reactant: CC(=O)Nc1nc2c(ncn2[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2NC(=O)C(F)(F)F)c(=O)[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 14.56 g (25.35 mmol) of N-[9-[3,4,6-tris-O-acetyl-2-deoxy-2-[(trifluoroacetyl)amino]-β-D-glucopyranosyl]-6,9-dihydro-6-oxo 1H-purin-2-yl]-acetamide was added a solution composed of 45 mL of Et3N, 225 mL of CH3OH, and 180 mL of H2O. This solution was stirred at room temperature for 12 hours. At this time, the solution was concentrated to dryness in vacuo. The residue was recrystallized from H2O yielding a white powder (7.2 g, 69%). To 7.08 g of this white powder was added 140 mL of 30% (wt/vol) NH4OH, and the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was then concentrated to dryness in vacuo. To the residue was added H2O and the mixture was frozen and lyophilized to a white powder yielding 9-(2-amino-2-deoxy-β-D-glucopyranosyl)guanine quantitatively. FAB-MS: m/z 313 for (M+1)+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[Cl:37])[C:17]([CH:19]1[C:24](=O)[C@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[Cl:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:16]1[C:17](=[O:18])[C:19]2[C@H:20]3[C:26]([CH3:27])([CH3:28])[C@:23]([CH3:29])([CH2:22][CH2:21]3)[C:24]=2[NH:15]1
Reactant: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@@]2(C)CC[C@@H]1C2(C)C)c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trifluoroacetic acid (15 mL) was added in two portions to a cooled (0° C.) solution of N′-(2-chloro-4-fluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜7.2 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at 0° C. for 5 min and then at room temperature for 2 h. The reaction mixture was evaporated (using high vacuum in the end). Dichloromethane (100 mL) was added to the residue and the solution was washed with water (4×50 mL), and brine (50 mL), dried (magnesium sulfate), filtered, and evaporated to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (2.6 g, 113% of the expected amount) as a tan solid. This was used directly in subsequent steps without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.[OH-].[Na+].[H][H]>[Ni].O>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 90.2 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 150 ml of water, 8 g (0.2 mol) of caustic soda and 5 g of Raney nickel were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature of the resultant mixture was increased under agitation to 90° C. at which the mixture was then subjected to reaction for 8 hours until the absorption of hydrogen was stopped. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. The filtrate was then allowed to stand to separate an upper toluene layer. Most part of toluene layer was distilled off, and the resultant residual solid was crystallized from IPA and then dried to obtain 31.7 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 90.3%; melting point, 78° to 80° C.).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: [Pb+4]
Reactant: Cc1ccc(Br)cc1B(O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Br)cc1[Pb+3]
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a mixture of lead tetraacetate (11.25 g, 25.40 mmol) and mercuric diacetate (0.40 g, 1.27 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (35 ml). This mixture is warmed to 40° C., and 5-bromo-2-methylphenylboronic acid (4.96 g, 23.10 mmol) is added in one portion and the suspension is heated at this temperature for 5 hours. The mixture is then allowed to cool to room temperature, followed by further cooling to 0° C. then powdered anhydrous potassium carbonate (1.61 g) is added with rapid stirring for 5 minutes. The mixture is filtered, the filtrate is concentrated to half its volume, and hexanes added to induce precipitation. This mixture is further concentrated, the solvent decanted, and the solid washed with hexanes to afford 5-bromo-2-methylphenyllead triacetate (10.10 g) as a sandy coloured solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH2:37]>>[CH3:36][NH:37][C:25]([C:22]1[N:23]=[N:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)=[CH:20][CH:21]=1)=[O:26]
Reactant: CN
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from 6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazine-3-carboxylic acid and methylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 203. Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: [NH:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH2:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH:28]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH:28]=[N:2][NH:1][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C=O)c2)c1=O
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 2 h

Procedure:
1.0 g of ethyl hydrazinecarboxylate was added to a solution of 3.3 g of 3-[4-chloro-3-formylphenyl]-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine and 0.1 g of p-toluenesulfonic acid in 150 ml of toluene. After 2 hours, the solution was washed once with water, the organic phase was dried over sodium sulfate and evaporated down and the residue was stirred with petroleum ether. The precipitate was isolated, washed with petroleum ether and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[N+:33]([O-:35])=[O:34])[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1OCCCCl
Reactant: Cc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Product: Cc1ccc(C(OC2CCN(CCCOc3ccccc3[N+](=O)[O-])CC2)c2ccccc2)cc1

Procedure:
The procedure of Example 24 (a) was repeated except for using 4-[(4-methylphenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane instead of 4-[(2-chlorophenyl)-phenylmethoxy]piperidine and 1-chloro-3-(2-nitrophenoxy)propane to give oily 4-[(4-methylphenyl)-phenylmethoxy]-1-[3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:23][N:18]1[C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[N:15]=[C:14]1[S:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(OCCCCCSc2nc3ccccc3[nH]2)nc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(SCCCCCOc2ccccn2)nc2ccccc21
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
0.2 g of (Compound 1) was dissolved in 1.2 ml of DMF, added with 0.27 g of potassium carbonate and 0.12 g of methyl iodide and the mixture was stirred at 50° C. for 1.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methylene chloride=1:6) to obtain 0.15 g of the title compound (yield: 72%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][N:24]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:25][CH2:26]1
Reactant: Fc1ccc(CCN2CCNCC2)c(F)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)N1CCN(CCc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
Benzene sulphonyl chloride (0.15 g), the foregoing amine (0.193 g) and potassium carbonate (0.118 g) were heated together in MeCN (10 ml). Reaction was monitored by mass spectroscopy, and was completed after 2 h. The reaction mixture was cooled to room temperature, quenched with water and extracted into ethyl acetate. The organic extracts were combined, washed with water, dried (MgSO4) and concentrated to give a dark orange solid. This solid was purified by dry flash chromatography using SiO2, CH2Cl2 to 5% MeOH:CH2Cl2, followed by recrystallisation using pet. ether and CH2Cl2 to give the title product as a pale yellow solid (23%). MS: (M+H)+=367. δH (360 MHz, CDCl3): 2.50-2.60 (6H, m), 2.66-2.74 (2H, m), 3.02-3.10 (4H, m), 6.70-6.80 (2H, m), 7.05-7.14 (1H, m), 7.50-7.56 (2H, m), 7.56-7.62 (1H, m), 7.74-7.80 (2H, m). CHN C18H20 F2N2O2S: calc. C=59.00, H=5.50, N=7.65%; found C=59.12, H=5.43, N=7.56%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([NH:21][C:22](=[O:40])[CH2:23][NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]3[NH:35][CH2:36][CH2:37][CH2:38][N:39]=3)[CH:28]=2)=[O:26])[CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:53]([OH:65])[CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63]O>CC(N(C)C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]([NH:21][C:22](=[O:40])[CH2:23][NH:24][C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]3[NH:39][CH2:38][CH2:37][CH2:36][N:35]=3)[CH:28]=2)=[O:26])[CH2:17][C:18]([O:20][CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][OH:65])=[O:19])[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCCN2)c1)c1cc(Cl)cc(Cl)c1
Reactant: OCCOCCOCCOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: O=C(CNC(=O)c1cccc(NC2=NCCCN2)c1)NC(CC(=O)OCCOCCOCCOCCO)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To the product of Example 200 (200 mg, 0.00033 mole) in DMA (1.5 mL) was added carbonyldiimidazole (67 mg, 0.00041 mole). The reaction was stirred at room temperature for 1 hour. Tetraethyleneglycol (214 mg, 0.0011 mole) was then added and the reaction mixture was stirred overnight at 60° C. The reaction was cooled to room temperature and the product was isolated by RPHPLC to yield the title compound (120 mg after lyophilization) as a hygroscopic white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:16][CH:17]([CH2:38][CH2:39][C:40]([CH3:42])=[CH2:41])[CH:18]([CH3:37])[CH2:19][CH2:20][CH2:21][C:22]1([CH3:36])[CH:28]2[O:29][C:25]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:26][CH2:27]2)[CH2:24][O:23]1)(=[O:15])[CH3:14].C([O-])(O)=O.[Na+].O>C1C=CC=CC=1.CCOCC>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:25]12[O:29][CH:28]([CH2:27][CH2:26]1)[C:22]([CH2:21][CH2:20][CH2:19][CH:18]([CH3:37])[CH:17]([O:16][C:13](=[O:15])[CH3:14])[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41])([CH3:36])[O:23][CH2:24]2)[CH3:35]
Reactant: C=C(C)CCC(OC(C)=O)C(C)CCCC1(C)OCC2(CC(=O)OCC)CCC1O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC12CCC(O1)C(C)(CCCC(C)C(CC=C(C)C)OC(C)=O)OC2
Temperature: 130 °C
Yield: 94.6 %

Procedure:
p-Toluenesulfonic acid monohydrate (8.2 mg) is added to benzene (12 ml). The mixture is stirred and refluxed in a Dean-Stark apparatus and some of the benzene (4 ml) is drained from the side-arm. The bicyclic acetoxy ester, ethyl(1RS,4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-8-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetate (85 mg, 0.2 mM), dissolved in benzene (6 ml), is added at room temperature to the above mixture and the resultant mixture is stirred and refluxed (bath at 130° C.) for two hours. The temperature of the heating bath is then lowered to 90° C. and the stirring is continued at 90° C. for sixteen hours and then at room temperature for seventy-two hours. The reaction mixture is added to saturated NaHCO3 --H2O (10 ml) and ether (20 ml). The organic layer is separated, washed with saturated NaCl--H2O, dried with Na2SO4, filtered, and evaporated in vacuo to give ethyl(1RS, 4SR,5RS)-4-(5-acetoxy-4,8-dimethyl-7-nonenyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-acetate (80.4 mg, 95%).