Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=[O:8])[CH3:7].CN([CH:22]=[O:23])C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[C:6]([O:9][CH2:10][CH2:11][CH2:12][S:13][C:14]1[S:15][C:16]([CH:22]=[O:23])=[CH:17][CH:18]=1)(=[O:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(=O)OCCCSc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCCCSc1ccc(C=O)s1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
POCl3 (3.4 mL, 0.036 mol) was added dropwise to a solution of 61 (4.9 g, 0.023 mol) and dry DMF (3.5 mL, 0.045 mol) in 1,2-dichloroethane (100 mL) at 0° C. The resultant mixture was refluxed for 2 hours, poured into ice water and neutralized by addition of 6 M sodium carbonate. The reaction mixture was extracted with methylene chloride (3×100 mL). The combined extracts were washed with saturated brine, dried (MgSO4). After filtration, methylene chloride was removed using a rotary evaporator. The residue was purified by column chromatography over silica gel, eluting with 10% ethyl acetate in methylene chloride. The product was obtained as orange liquid (4.5 g, 82%). 1H NMR δ: 2 (m, 2 H, CH2—CH2—OCOCH3), 2.03 (s, 3 H, CH3), 3.04 (t, 2 H, J=7.2 Hz, S—CH2), 4.15 (t, 2 H, J=6.2 Hz, CH2—OCOCH3), 7.04 (d, 1 H, J=3.9 Hz, aromatic H), 7.59 (d, 1 H, J=3.9 Hz, aromatic H), 9.75 (s, 1 H, CHO); λmax/nm (εmax/dm3 mol−1cm−1) 339 (14,200); HRMS (EI+) calc. for C10H12O3S2: 244.0231. found 244.0228. The product was used without further purification in preparation of 63.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24](=O)[CH2:25][O:26][CH3:27])=[CH:19][C:18]=1[CH3:29])/[C:5]([O:7][CH3:8])=[O:6].Cl.[CH3:31][O:32][NH2:33]>CO>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20](/[C:24](=[N:33]/[O:32][CH3:31])/[CH2:25][O:26][CH3:27])=[CH:19][C:18]=1[CH3:29])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)COC)cc1C
Reactant: CON
Agent: Cl
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(/C(COC)=N/OC)cc1C
Yield: 46.8 %

Procedure:
In 30 mL of methanol, 0.2 g (0.50 mmol) of (E)-methyl 3-methoxy-2-(2-((4-(2-methoxyacetyl)-2,5-dimethylphenoxy)methyl)phenyl)acrylate obtained in Step 2 was reacted with 0.21 g (5 eq) of methoxyamine hydrochloride at room temperature for 15 hours with stirring. After completion of the reaction, the solvent was removed in a vacuum, and the residue was stirred in water (30 mL) and extracted twice with 30 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. Purification by silica gel chromatography afforded 0.1 g of (E)-methyl 3-methoxy-2-(2-((4-((Z)-2-methoxy-1-(methoxyimino)ethyl)2,5-dimethylphenoxy)methyl)phenyl)acrylate as a white solid (yield: 50%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.O[CH2:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:33])[O:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH:17]=[CH:18][CH:19]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCN(CCCOC(=O)Nc2cccc(CO)c2)CC1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(NC(=O)OCCCN4CCN(C)CC4)c3)c2n1
Reaction time: 0.5 h

Procedure:
98 mg (0.65 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one, 200 mg (0.65 mmol) of 3-(4-methylpiperazin-1-yl)propyl (3-hydroxymethylphenyl)carbamate and 325 mg (0.98 mmol) of polymer-bound triphenylphosphine (3 mmol/g) are suspended in 5 ml of DMF, and the mixture is shaken for 30 min. 229 mg (0.98 mmol) of di-tert-butyl azodicarboxylate are subsequently added. The reaction mixture is shaken at room temperature. The reaction mixture is filtered and rinsed with THF, and the filtrate is evaporated. The residue is purified by column chromatography on silica gel.
Reaction SMILES: C(OC(N1CCC2(O[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:12]2)CC1)=O)(C)(C)C.[C:36]([O:40][C:41]([N:43]1C2[CH2:49][CH2:50][CH:44]1CNC2)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH:44]2[CH2:50][CH2:49][CH:15]1[CH2:14][N:13]([CH2:17][C:18]1[S:26][C:25]3[C:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[N:23][C:22]([Cl:33])=[N:21][C:20]=3[CH:19]=1)[CH2:12]2)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in place of 4-ethoxy-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester. The title compound was obtained as a cream solid (245 mg, 58%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH:15]=2)[C:10]([C:26]([C:29]#[N:30])(C)C)=[CH:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:19]([N:17]([CH3:18])[C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:26][C:29]#[N:30])=[CH:9][NH:8]2)=[CH:12][CH:13]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1ccccc1)c1ccc2c(C(C)(C)C#N)cn(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccccc1)c1ccc2c(CC#N)c[nH]c2c1
Yield: 88.2 %

Procedure:
A solution of 6-(benzyl-methyl-amino)-3-(cyano-dimethyl-methyl)-indole-1-carboxylic acid tert-butyl ester (26.4 g, 90%, 58.9 mmol) in DCM-TFA (2:1,180 mL) was stirred for 20 h at 20° C. Evaporation of solvent gave a crude, which was redissolved in DCM and the solution was washed with water, aqueous sodium bicarbonate and water and dried over MgSO4. Evaporation of solvent gave a solid, which was triturated with hexane to give [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile as a solid (14.3 g). MS (ES): 304 (MH+). [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile was then treated in a manner similar to that described in Step 34D-H, but using greater than three equivalents of iodomethane, to give 6-(benzyl(methyl)amino)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].C(N(CC)CC)C.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[O:23])=[CH:20][CH:19]=1
Reactant: CCOC(CN)OCC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(CNC(=O)c1ccc(Br)cc1)OCC
Reaction time: 6 h
Yield: 66.1 %

Procedure:
To a stirred solution of aminoacetaldehyde diethyl acetal (6.66 g, 50.0 mmol) in CH2Cl2 (100 ml) was added triethylamine (5.06 g, 50.0 mmol), 4-bromobenzoyl chloride (10.97 g, 50.0 mmol), and the mixture was stirred for 6 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate. The solution was washed with 0.5N HCl aqueous solution, water, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was recystallized with ethyl acetate-bexane to give title compound (10.45 g, 66% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[CH:17]1([C:2]2[CH:3]=[N:4][N:5]([CH3:16])[C:6]=2[C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)[CH2:19][CH2:18]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1cc(-c2c(Br)cnn2C)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2c(C3CC3)cnn2C)cs1
Temperature: 70 °C
Yield: 95.2 %

Procedure:
To a 20 mL sealed tube reactor was added methyl 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (505 mg, 1.68 mmol), cyclopropylboronic acid (447 mg, 5.20 mmol), Cesium Carbonate (1.90 g, 5.84 mmol) and PdCl2(dppf)-CH2Cl2Adduct (43.6 mg, 0.05 mmol) in Tetrahydrofuran (THF) (8.5 mL). The reaction was heated to 70° C. for 1.5 hours, cooled and partitioned between CHCl3 and H2O. The organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (20-40% EtOAc/Hexane) affording the title compound (0.42 g, 1.60 mmol, 95%): LC-MS (ES) m/z=251 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:23][C:24]([CH3:26])=O.[OH-].[K+].C(Br)C=C>O>[N+:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH2:26][CH:24]=[CH2:23])[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])cnc2n1-c1ccc2c(c1)OCO2
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C=CCBr
Product: C=CCn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncc([N+](=O)[O-])cc21
Reaction time: 1.5 h

Procedure:
To a mixture of 1.1 g. (0.0036 mole) of the nitro product of Step C in 175 ml. of refluxing acetone, was added 400 mg. (0.0068 mole) of powdered potassium hydroxide. The mixture was stirred and heated for 15 minutes, 1 ml. of allyl bromide was added and reflux was continued for 1.5 hours. About 50 ml. of water was then added and the resulting solution was concentrated to about 75 ml. The product, 1.2 g. crystallized and melted at 152°-153° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[S:13][C:14]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])=[CH:5][N:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN(C=O)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]([NH:11][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[N:4][CH:5]=2)=[O:10])[S:13][C:14]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CCl)nc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cn2ccnc2)nc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
Compound 36 (97.1 mg, 0.240 mmol) was dissolved in DMF (2.5 mL), imidazole (49.0 mg, 0.721 mmol) was added thereto, followed by stirring at 95° C. for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under the reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound 37 (58.0 mg, 55%).
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[N:21]=[CH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc2ccccc2cn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(CCCCCCN(c1ccccn1)c1cc2ccccc2cn1)NO
Reaction time: 72 h
Yield: 54 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to II (40 mg, 0.1 mmol) in DMF (0.5 mL) and MeOH (1 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:8) to furnish III as a colourless oil (19 mg, 54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=1)[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=2)[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH:7]=1
Reactant: Cc1cc(N)c2cnn(-c3cccc(C(=O)OCc4ccccc4)c3)c2c1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)OCc2ccccc2)c1)C(F)(F)F
Temperature: 85 °C
Yield: 65.3 %

Procedure:
A solution of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 350 mg, 1.2 mmol), in acetonitrile (2 mL) was added to a mixture of phenylmethyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (357 mg, 1.0 mmol) and ytterbium(III) triflate (124 mg, 0.2 mmol). The mixture was stirred and heated to 85° C. under nitrogen in a greenhouse apparatus for 18 hours when the temperature was raised to 100° C. and the mixture heated under vigorous reflux for a further ˜21 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (50 mL) and aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted again with dichloromethane (50 mL) and the combined organic extracts were dried over anhydrous sodium sulphate and evaporated. The residue was purified by silica gel chromatography using the Flashmaster II (50 g cartridge) eluting with a cyclohexane to 1:1 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound as a white solid (424 mg).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11](Cl)[C:12]2[C:21]([N:22]=1)=[CH:20][C:19]([O:23][CH3:24])=[C:18]1[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]1)=[O:8].O>CN(C)C=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([O:3][CH2:2][CH3:1])[C:12]2[C:21]([N:22]=1)=[CH:20][C:19]([O:23][CH3:24])=[C:18]1[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]1)=[O:8]
Reactant: CC[O-]
Reactant: COC(=O)c1cc(Cl)c2c(cc(OC)c3ncccc32)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)nc2cc(OC)c3ncccc3c12

Procedure:
2 g of sodium ethylate are added to a solution of 6.2 g of 1-chloro-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester in 100 ml of anhydrous N,N-dimethylformamide and the mixture is heated, whilst stirring and with the exclusion of water, for 10 hours at 100°. The solution is then evaporated to dryness in vacuo, the residue is divided between three times 200 ml of chloroform and 200 ml of water, the organic phases are dried over sodium sulphate and evaporated to dryness in vacuo. By fractionated crystallisation from ethanol, the 1-ethoxy-6-methoxy-4,7-phenanthroline-3-carboxylic acid methyl ester having a melting point of 188°-190° is obtained from the residue.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]1.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O.O>CN(C=O)C>[F:28][C:27]([F:30])([F:29])[CH2:26][N:1]1[C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[C:3]([C:14]([O:16][CH3:17])=[O:15])=[CH:2]1
Reactant: COC(=O)c1c[nH]c2c1CCc1cnccc1-2
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CC(F)(F)F)c2c1CCc1cnccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of methyl 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylate E1 (0.44 mmol) in dry DMF (5 mL) NaH (0.52 mmol) was added. The reaction mixture was stirred at rt for 2 h. After cooling to 0° C., trifluoroethyl triflate (0.52 mmol) in DMF (5 mL) was added dropwise. The mixture was maintained at rt overnight and then poured into icy water and extracted with DCM. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (eluant: DCM/acetone 9:1) afforded the title compound (65% yield). ESI (+) MS: m/z 311 (MH+). 1H NMR: 2.82 (t, J=7.70, 2H), 2.92 (t, J=7.70, 2H), 3.76 (s, 3H), 5.41 (q, J=8.90, 2H), 7.56 (d, J=5.24, 1H), 7.75 (s, 1H), 8.41 (d, J=5.24, 1H), 8.44 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.[N:11]1([S:16]([CH:19]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])[CH3:20])(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:1][C:25](=[O:26])[NH:24][S:21]([CH:19]([S:16]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:17])=[O:18])[CH3:20])(=[O:22])=[O:23])[N:7]=1
Reactant: COc1cc(Cl)nc(N)n1
Reactant: CC(S(=O)(=O)N=C=O)S(=O)(=O)N1CCCC1
Solvent: ClCCl
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)C(C)S(=O)(=O)N2CCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 701.1 %

Procedure:
1.6 g (0.01 mol) of 2-amino-4-chloro-6-methoxypyrimidine are dissolved in 30 ml of dichloromethane, and 2.7 g (0.01 mol) of 1-pyrrolidinosulfonylethylsulfonyl isocyanate (Example 3b) in 30 ml of dichloromethane are added dropwise at room temperature. After the mixture has been stirred for 3 hours at room temperature, the organic phase is washed with 2N HCl and water, dried and evaporated. Trituration of the crude product with diethyl ether gives 30 g (70% of theory) of 3-(4-chloro-6-methoxypyrimidin-2-yl)-1-(1-pyrrolidinosulfonylethylsulfonyl)urea of melting point 158°-160° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][C@@H:15]([CH3:17])[NH:14][CH2:13][C@@H:12]1C.F[C:20]1C=CC([N+]([O-])=O)=CC=1.C[C@H]1CNC[C@@H](C)N1>>[CH3:17][C@H:15]1[NH:14][C@@H:13]([CH3:20])[CH2:12][N:11]([C:3]2[CH:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][CH:4]=2)[CH2:16]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2F)[C@@H](C)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)N1
Yield: 95 %

Procedure:
Crude cis-3,5-Dimethyl-1-(4-nitrophenyl)piperazine (4.91 g, 95% recovery) is prepared according to the method described above for the synthesis of racemic-1-(2-fluoro-4-nitrophenyl)-trans-2,5-dimethylpiperazine by treatment of 1-fluoro-4-nitrobenzene (3.08 g, 21.8 mmol) with cis-2,6-dimethylpiperazine (2.50 g, 21.8 mmol). The crude product is used in the next step without chromatographic purification. LCMS-ESI (m/z): calcd for C12H17N3O2, 235; [M+H]+ found, 236.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:10][C:11]1[N:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:14][C:15]=1[CH2:16][CH2:17]O.[OH-].[Na+]>O>[CH3:10][C:11]1[N:12]=[C:13]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:14][C:15]=1[CH2:16][CH2:17][O:2][N+:1]([O-:4])=[O:3]
Reactant: Cc1nc(-c2cccnc2)sc1CCO
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2cccnc2)sc1CCO[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
3-[4-Methyl-5-(2-nitrooxy-ethyl)-thiazole-2-yl]-pyridine was prepared by drop-wise addition of 1.145 gr. of nitric acid (70%) to 1.78 grams of cooled sulfuric acid (95-98%) at 0-5° C., followed by addition of 4 grams (0.0181 moles) 2-(4-methyl-2-pyridin-3-yl-thiazole-5-yl)-ethanol over a time period of 30 minutes at 0-5° C. After the addition was completed the reaction mixture was stirred for 30 minutes at 0-5° C., and for one additional hour at room temperature. The reaction mixture was then added carefully to 25 ml of cold water. The water solution was turned basic with an aqueous 20% solution of sodium hydroxide and the aqueous phase was extracted with three portions of 75 grams of dichloromethane. The extracts were combined, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The nitration step was confirmed initially by thin-layer chromatography stained with diphenylamine as a marker for the nitrate ester moiety (FIG. 1). Chromatography of the crude product on silica gel (using ethyl acetate as eluent) gave 1.5 grams (41% yield) of Pet-12 as a pale yellow liquid having a purity of 99% as determined by HPLC.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:40])[C:8]1[N:12]([C:13]2[N:14]=[C:15]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:16]3[N:21]=[N:20][N:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:17]=3[N:18]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:40][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:14]=[C:15]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[C:16]3[N:21]=[N:20][N:19]([CH:22]4[CH2:23][CH2:24][N:25]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:26][CH2:27]4)[C:17]=3[N:18]=2)[C:11]2[CH:34]=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:10]=2[N:9]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCNCC3)c2n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCN(S(C)(=O)=O)CC3)c2n1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 87.1 %

Procedure:
Methanesulfonyl chloride (0.09 mL, 1.16 mmol) was added dropwise to a mixture of the above amine (107 mg, 0.220 mmol) and powdered K2CO3 (274 mg, 1.98 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred for 16.5 hrs. Water was added, the phases were separated, and the aqueous phase was extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent removed under vacuum. Recrystallization from CH2Cl2/MeOH gave 5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-3-[1-(methylsulfonyl)-4-piperidinyl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (108 mg, 87%): mp 258-259° C.; 1H NMR (CDCl3) δ 7.81 (dd, J=8.4, 0.5 Hz, 1H), 7.41 (t, JHF=53.5 Hz, 1H), 7.39 (t, J=8.2 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 4.93 (tt, J=10.5, 4.2 Hz, 1H), 4.79 (br s, 2H), 4.16 (br s, 2H), 4.07 (s, 3H), 4.01-3.90 (m, 6H), 3.14 (m, 2H), 2.89 (s, 3H), 2.60 (m, 2H), 2.35 (m, 2H); Anal. Calcd. for C23H27F2N9O4S: C, 49.0; H, 4.8; N, 22.4. Found: C, 48.9; H, 4.8; N, 22.2%.