Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[I:9].[Br:10]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1>[Br:10][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)c(I)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: Clc1ncc(CBr)cc1I
Yield: 64 %

Procedure:
4.60 g (18.15 mmol) of 6-chloro-5-iodo-3-methylpyridine (Setliff et al., J. Chem. Engineering Data (1976), 21(2), 246-7), 3.39 g (19.06 mmol) of N-bromosuccinimide and 0.30 g (1.82 mmol) of 2,2′-azobis(2-methylpropionitrile) in 500 ml of chlorobenzene are boiled under reflux for about 16 hours. The reaction mixture is washed with saturated aqueous sodium sulphite solution and sodium bicarbonate solution and then dried over sodium sulphate and concentrated under reduced pressure. Column cluomatography of the residue on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (1:10) gives 3.86 g (38% of theory) of 3-bromomethyl-6-chloro-5-iodopyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:3]=1.[CH:17]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].O>CC(C)=O>[Cl:8][C:6]1[N:7]=[C:2]([NH:24][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:5]=1
Reactant: NC1CCCCCC1
Reactant: Fc1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Fc1cccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)c1

Procedure:
To 159a (1.0016 g, 3.9 mmol) dissolved in acetone (20 mL) was added a solution of cycloheptylamine (0.5 mL, 3.9 mmol) in acetone (5 mL) followed by addition of 2.5 N NaOH (1.6 mL, 3.9 mmol) and water (4 mL). The reaction mixture was allowed to stir at reflux for 3 hours under nitrogen. The reaction mixture was extracted 3 times with dichloromethane; the combined organic layers were washed with brine and dried over potassium carbonate. The filtered sample was concentrated by rotary evaporation and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded an off-white solid (159b, 908 mg, 69%), mp 148° C.; HPLC: Inertsil ODS-3V C18, 30:70 [KH2PO4 (0.0M, pH 3.2): CH3CN], 264 nm, Rt 22.3 min, 79.2% purity; MS (TOF MS ES+): m/z 413 (60.4), 338 (44.0), 336 (M+H, 100).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]([CH3:34])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C(F)(F)F.[OH-].[OH-].[Pd+2]>[CH3:34][CH:11]1[CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:13][CH:9]([NH2:8])[CH2:10]1
Reactant: [H][H]
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC(F)(F)F
Product: CC1CC(N)CC1c1cnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Yield: 97.9 %

Procedure:
To a solution of N,N-dibenzyl-3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (3.0 g, 5.30 mmol) in trifluoroethanol (200 mL) was added 20% wet palladium hydroxide on carbon (0.6 g, 4.27 mmol). The mixture was stirred under 40 psi of hydrogen at about 50° C. for about 90 min. The catalyst was removed by filtration through a pad of Celite® and the filtrate was concd under reduced pressure to yield 3-methyl-4-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (2.0 g, 98% yield) as a brown amorphous solid. LC/MS (Table 1, Method a) Rt=1.86 min; MS m/z 386 (M+H)+.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCCCC.[N:15]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]1.CI>O1CCCC1>[CH3:1][C:18]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16][N:15]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
A 250-mL round bottom flask equipped with an overhead mechanical stirrer, addition funnel, N2-inlet and temperature probe was charged with diisopropylamine (7.31 g, 71.5 mmol) and tetrahydrofuran (22 g) then chilled to less than −15° C. (internal temperature). Hexyllithium (2.25 M in hexane: 21.8 g, 68.5 mmol) was carefully charged to the addition funnel. The hexyllithium solution was added through the addition funnel over 45 minutes with a maximum internal temperature of −17° C. The reaction was mixed for 1 hour at an internal temperature of approximately −15° C. to 0° C. The flask was equipped with another addition funnel and the toluene solution obtained from Example 7 (15.01 g, 58.33 mmol) was added through the addition funnel, followed by 4 g of tetrahydrofuran. The total addition time was 1 hour 45 minutes with a maximum internal temperature of −15° C. The solution was stirred at about −20° C. for 30 minutes. The flask was equipped with an addition funnel, which was charged with methyl iodide (9.3 g, 64-64 mmol) and tetrahydrofuran (3 g); this solution was added to the reaction mixture over 30 minutes, maintaining the internal temperature at no more than −15° C. After 30 minutes, the reaction was quenched into a chilled (˜5° C.) 2M HCl solution (prepared from 31 mL, water and 8 g of concentrated HCl) while maintaining the temperature below 10° C. The reaction flask was rinsed with toluene (10 mL), which was added to the quench flask. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was rinsed with 17% NaCl solution (prepared by dissolving 2.5 g of NaCl in 15 g water). The tetrahydrofuran/toluene solution was used directly in the next step.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O1[C:7]23[C@:23]([CH3:28])([CH2:24][CH2:25][C:26](=[O:27])[CH:6]12)[C@@H:22]1[C@H:10]([C@H:11]2[C@:19]([CH3:29])([CH2:20][CH2:21]1)[C@@H:14]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3.[N-:30]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:4])(=[O:3])[CH3:2].[NH2:30][C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH:8]=[CH:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=C(N)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a vigorously stirred solution of the (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one acetate (2.0 g, 5.15 mmole) obtained in Example 7, in dimethyl sulfoxide (70 mL) and heated to 60° C., there was added sodium azide (5.4 g) and then concentrated sulfuric acid (0.37 mL). The mixture was quickly brought to a temperature of 100° C. and held at that temperature for 1 hour. The cooled mixture was then poured into cold water (450 mL). The solids were collected by filtration, washed with water, and dried by suction to give a yellow solid which was purified by flash chromatography to give (20S)-4-amino-21-hydroxy-20-methylpregna-4,6-dien-3-one acetate (1.04 g, 52.5%). IR 3488, 3446, 3360, 1740, 1668, 1612 (m), 1592 (m), 1562 (m), 1252 cm-1 ; MS (CI) 386 (20%, M +1), 326 (100%, M+1 - AcOH); 1H NMR (CDCl3) δ 0.78 (3H, s, C18 -Me), 1.03 (d, C22 -Me), 1.06 (s, C19 -Me), 2.07 (s, Ac-Me), 3.69+3.78 (3H, v br+dd, NH2 1/2 C21 -CH2), 4.09 (1H, dd, 1/2 C21 -CH2), 5.97 (1H, dd), 6.30 (1H, dd). This compound has the following structure: ##STR5##
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:25])[CH2:11][CH2:12][CH2:13][C:14]([CH:17]1[O:21][C:20]([CH2:23][Br:24])([OH:22])[CH2:19][CH2:18]1)([OH:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]OC(OC)OC.S(=O)(=O)(O)O.CO.C(=O)(O)[O-].[Na+]>[Cl-].[Na+].O.CCOCC>[CH2:1]([O:8][CH2:9][CH:10]([CH3:25])[CH2:11][CH2:12][CH2:13][C:14]([CH:17]1[O:21][C:20]([CH2:23][Br:24])([O:22][CH3:26])[CH2:19][CH2:18]1)([OH:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: CC(CCCC(C)(O)C1CCC(O)(CBr)O1)COCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COC1(CBr)CCC(C(C)(O)CCCC(C)COCc2ccccc2)O1
Reaction time: 66 h

Procedure:
7-Benzyloxy-2-(2-bromomethyl-2-hydroxy-tetrahydrofuran-5-yl)-6-methyl-heptan-2-ol (16.9 g, 41 mM) is treated with distilled trimethylorthoformate (51 ml, 66 mM) and 0.1 N sulfuric acid/methanol (15.3 ml) at 0° C. for 0.5 hours and then at 5° C. for 66 hours. The solvent is removed in vacuo and the residue obtained is treated with ether, saturated sodium bicarbonate and brine. The layers are separated, the aqueous phase is extracted with ether and the combined ether extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give crude 7-benzyloxy-2-[2-bromomethyl-2-methoxy-tetrahydrofuran-5-yl]-6-methyl-heptan-2-ol.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH2:13]([CH2:15][CH2:16][CH2:17][C:18](CC([O-])=O)=[O:19])[CH3:14]>>[O:19]=[C:18]1[N:1]([C:3]2[CH:4]=[C:5]([S:9]([OH:12])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=2)[N:2]=[C:16]([CH2:15][CH2:13][CH3:14])[CH2:17]1
Reactant: NNc1cccc(S(=O)(=O)O)c1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2cccc(S(=O)(=O)O)c2)C(=O)C1

Procedure:
From the reaction of 3-hydrazinobenzenesulfonic acid and ethylbutyrylacetate, 3-(4,5-Dihydro-5-oxo-3-propyl-1H-pyrazol-1-yl)-benzenesulfonic acid is obtained. Subsequent reaction with 2-ethylaniline yields 3-(4-(2-ethylanilinomethylene)-4,5-dihydro-5-oxo-3-propyl-1H-pyrazol-1-y 1)-benzenesulfonic acid, Mp 258.6° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2cccc(C)c2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2cccc(C)c2C1=O

Procedure:
The mixture of 3.94 g of N-(4-nitro-o-tolyl)-3-methylphthalimide, 200 ml of ethyl acetate and 2.2 g of Raney nickel (pre-washed with water and ethyl acetate) is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated, the residue triturated with chloroform, filtered again, the filtrate evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-3-methylphthalimide of the formula ##SPC5##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:22])[CH:16]=[C:17]([N:19]([CH3:21])[CH3:20])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:16]([C:15]([O:14][CH2:12][CH3:13])=[O:22])[C:17]([N:19]([CH3:20])[CH3:21])=[N:18][C:17]=1[NH2:18])=[O:22])[CH3:13]
Reactant: CCOC(=O)C=C(N)N(C)C
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C1=C(N)N=C(N(C)C)C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1

Procedure:
After boiling a solution of 7.5 g of 3-nitrobenzaldehyde and 15.8 g of N,N-dimethyl-3,3-diaminoacrylic acid ethyl ester in 150 ml of ethanol for 4 hours, the solution was concentrated in vacuo. On triturating the resulting oil with ether, filtering off the crystals which separated out and crystallizing these from isopropanol, the yellow-orange colored crystals of 2-amino-6-dimethylamino-4-(3'-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester, of melting point 149° C, were obtained. Yield, 61% of theory.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:27][C:28]1[CH:29]=[C:30](F)[CH:31]=[CH:32][C:33]=1[Cl:34].C([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[CH2:21][CH2:22][CH:23]([O:26][C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[C:33]([Cl:34])[CH:32]=3)[CH2:24][CH2:25]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 8 h

Procedure:
To a solution of potassium tert-butoxide (139.0 g, 1.24 mol) in THF (500 ml) was added a solution of the product of Step 1 (176.2 g, 0.62 mol) in THF (1000 ml). The reaction mixture was stirred 10 minutes before the additon of 3,4 dichlorofluorobenzene (122.8 g, 0.74 mol), this caused a green colouration that subsequently faded. The reaction mixture was then heated at reflux for 90 minutes. The reaction mixture was then cooled to room temperature before the addition of saturated NaHCO3 (1600 ml). The layers were separated and the organic layer stripped to leave an orange semi-solid. The solid was dissolved in DCM (1500 ml) and dried (MgSO4), filtered and the solvent removed. To the resultant solid was added methyl tert-butyl ether (MTBE) (54 ml) and iso-hexane (1000 ml) to give a slurry which was stirred overnight. The slurry was then filtered and washed with isohexane (200 ml) and the solid dried in vacuo at 50° C. to give the sub-titled compound as a pale powder, (211.6 g, 80%; MS: (M+H) 429).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[NH:10][C:9]1=S.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>O=P(Cl)(Cl)Cl>[Cl:22][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=1
Reactant: O=c1c2cc(F)ccc2[nH]c(=S)n1-c1ccccc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc(F)ccc2nc(Cl)n1-c1ccccc1Cl

Procedure:
A suspension of 306 mg (1.0 mmol) of 3-(2-chloro-phenyl)-6-fluoro-2-thioxo-2,3-dihydro-1H-quinazolin-4-one in 2.0 mL of POCl3 was treated with 350 mg of PCl5 and the mixture was refluxed for 2.5 hours. The solvent was evaporated and the residues were taken up in ethyl acetate, washed with water and brine, and then the solvent was evaporated to give 2-chloro-3-(2-chloro-phenyl)-6-fluoro-3H-quinazolin-4-one as a solid. This material was dissolved in 15 mL of absolute ethanol and 238 mg (2.20 mmol) of 2-aminomethylpyridine and the mixture was refluxed overnight. The reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed twice with water. The organic layer was dried with brine and with MgSO4 and evaporated to give a gum which was crystallized from ether to give 190 mg (50%) of the desired product, m.p. 156-158 ° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21][NH:22][OH:23])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([N:28]=[C:29]=[O:30])(C)(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15](/[CH:19]=[CH:20]\[CH2:21][N:22]([OH:23])[C:29]([NH2:28])=[O:30])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: ONC/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)N(O)C/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of the product of Step 5, above (17, 0.66 g, 2.1 mmol), in THF (10 ml) was added TMSNCO (0.42 ml, 3.1 mmol) under a nitrogen atmosphere and the reaction mixture was stirred at room temperature for 1 hour. Methanol (5 ml) was then added and after stirring for 10 minutes, solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate/methanol to afford the title compound (18, 340 mg, 45% yield) as colorless solids.
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2].[S:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>C1(C)C=CC=CC=1>[P:1]([O-:38])([O:34][CH2:35][CH2:36][C:40]1[S:39][CH:43]=[CH:42][NH+:41]=1)([O:3][CH2:4][CH:5]([O:28][C:29]1[CH:33]=[CH:32][O:31][N:30]=1)[CH2:6][O:7][C:8](=[O:27])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:2]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCBr)Oc1ccon1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCNC(=O)OCC(COP(=O)([O-])OCCc1[nH+]ccs1)Oc1ccon1
Reaction time: 96 h

Procedure:
A solution of 0.940 g of (2RS)-3-(N-heptadecylcarbamoyloxy)-2-(3-isoxazolyloxy)propyl 2-bromoethyl phosphate [prepared as described in Example 11(a)] and 1.06 ml of thiazole in toluene was heated on an oil bath kept at 70° C. for 4 days, whilst stirring. The solvent was then distilled off, and the resulting residue was dissolved in 10 ml of a 95:5 by volume mixture of tetrahydrofuran and water. The solution thus obtained was passed over 11 ml of Amberlite (trade mark) MB 3 resin. The eluate was repeatedly passed six times through the same column, and the column was finally washed with a 95:5 by volume mixture of tetrahydrofuran and water. The eluates and the washings were combined and concentrated by evaporation under reduced pressure. The residue was purified by medium pressure liquid chromatography using a Lobar B column. 0.312 g of the title compound was obtained as a resinous material from the fractions eluted with a 60:35:5 by volume mixture of methylene chloride, methanol and water.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][N+:13]([O-:24])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc[n+]([O-])cc1

Procedure:
A solution of 40.6 g of 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine and 40 g of m-chloroperbenzoic acid in 500 ml methylene chloride is stirred 16 hours at room temperature. Solution is washed with 2N sodium hydroxide and water, dried sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyldimethylsilyloxymethyl)-pyridine-N-oxide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22](=[N:34][OH:35])[C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29]>>[F:33][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[N:21]=[C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:10]=3)[O:35][N:34]=2)=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cc(C(N)=NO)ccc1F
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Product: COC(=O)c1cc(-c2noc(-c3ccc(N4CCCCC4C)c(C(F)(F)F)c3)n2)ccc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 15 (106.09 mg; 0.50 mmol) and Intermediate 45 (106.09 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (dd, J=7.0, 2.3 Hz, 1H), 8.46 (dd, J=8.3, 2.1 Hz, 1H), 8.41-8.36 (m, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.62 (dd, 1H), 3.93 (s, 3H), 3.23-3.14 (m, 1H), 2.99-2.92 (m, 1H), 2.66-2.58 (m, 1H), 1.82-1.75 (m, 2H), 1.67-1.30 (m, 4H), 0.79 (d, J=6.1 Hz, 3H). LC/MS (Method B): 464.3 (M+H)+. HPLC (Method A) Rt 3.82 min (Purity: 99.9%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[CH2:15][C:16]#[N:17]>ClCCl.C(N(CC)CC)C>[C:16]([CH2:15][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-Boc piperazine (5 g) in dry dichloromethane (100 ml), triethyl amine (10 ml) followed by chloro acetonitrile (25.02 ml) were added dropwise. The reaction mixture was allowed to stir at room temperature for overnight. The solvent was removed under vacuum and residue was diluted with dichloromethane (200 ml). The organic layer was washed with water, brine and concentrated to dryness under reduced pressure to afford tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate, which was used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][C:18]=1[F:27]>CN(C=O)C>[F:27][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([F:24])([F:25])[F:26])[C:17]=1[CH2:16][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnn(Cc2c(F)cccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Nitropyrazole (Aldrich; 4.974 g, 44.0 mmol) was dissolved in DMF (100 ml) and potassium carbonate (9.12 g, 66.0 mmol) was added. The reaction mixture was allowed to stir at ambient temperature under nitrogen for approximately 5 minutes. 2-(Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (Aldrich; 11.31 g, 44.0 mmol) in DMF (25 ml) was then added over a period of approximately 5 minutes and the reaction was left to stir overnight.
Reaction SMILES: CC1C=CC(CN)=CC=1.[CH3:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][NH:16][C:17]2[C:18]([NH2:32])=[CH:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH:22]=2)=[CH:13][CH:12]=1.[C:35]1(=[O:45])[C@H:43]2[C@@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]2)[C:37](=O)[O:36]1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=[CH:19][C:18]=3[N:32]=[C:37]2[C@@H:38]2[CH2:39][CH2:40][CH2:41][CH2:42][C@H:43]2[C:35]([OH:45])=[O:36])=[CH:33][CH:34]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@@H]12
Reactant: Cc1ccc(CNc2cc(OCc3ccc(C)cn3)ccc2N)cc1
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2c([C@@H]3CCCC[C@H]3C(=O)O)nc3ccc(OCc4ccc(C)cn4)cc32)cc1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using p-tolylmethanamine in Step A then for Intermediate I using N1-(4-methylbenzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and racemic trans-hexahydroisobenzofuran-1,3-dione followed by the hydrolysis according to Example Example 111. MS (ESI): mass calcd. for C29H31N3O3, 469.24; m/z found, 470.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.33 (s, 1H), 7.65 (d, J=8.0, 1H), 7.47 (d, J=8.7, 1H), 7.44 (s, 1H), 7.11 (d, J=7.9, 2H), 7.03 (d, J=8.1, 2H), 6.98 (d, J=2.2, 1H), 6.95 (dd, J=8.7, 2.3, 1H), 5.44 (s, 2H), 5.12 (s, 2H), 3.15 (td, J=11.2, 4.9, 1H), 3.02-2.94 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 2.21 (d, J=12.2, 1H), 1.85 (d, J=11.5, 1H), 1.70 (d, J=13.3, 1H), 1.46 (dt, J=28.3, 14.0, 4H), 1.31-1.16 (m, 1H).