Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].C(Cl)Cl.[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18](Cl)(=[O:20])=[O:19])=[O:11])[CH2:6]1>O>[O:5]1[CH2:8][CH:7]([O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([NH2:1])(=[O:20])=[O:19])=[O:11])[CH2:6]1
Reactant: N
Reactant: O=C(OC1COC1)c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1ccccc1C(=O)OC1COC1

Procedure:
##STR18## 2.5 g of ammonia are passed into a methylene chloride solution of 2-(oxetan-3-oxycarbonyl)phenylsulfonyl chloride (Example H6) at a temperature of 0° to 5° C. in the course of 45 minutes. By adding water to the reaction mixture, washing the organic phase with water, drying and evaporating it and crystallising the residue from a methylene chloride/diethyl ether mixture, 6.7 g of 2-(oxetan-3-oxycarbonyl)phenylsulfonamide of melting point 169° to 170° C. are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1.[OH-].[K+].C(OCC)(=O)C>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH:14]1[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]1=[O:20]
Reactant: O=C1CCCC(=O)C1
Reactant: ClCCCc1ccccc1CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCCC(=O)C1Cc1ccccc1CCCCl

Procedure:
A solution of 155 g (0.75 mol) of 2-(3-chloropropyl)benzyl chloride 2 [Page, et al., J. Amer. Chem. Soc. 75:2053 (1953)], 91 g (0.81 mol) of 1,3-cyclohexanedione I [Aldrich Chem. Co. 10,160-5; Beilstein 7, 554], and 47 g of 85% KOH in 400 ml of methanol was refluxed 16 hours. After concentrating, the residue was partitioned between benzene and dilute aqueous NaOH solution. Acidification of the aqueous phase gave a solid that was recyrstallized from ethyl acetate to give 34 g of the dione 3, mp 143°-145° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23])([O-:19])=[O:18].O>O1CCOCC1>[N+:17]([C:20]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:21]=1[C:22]([NH:24][C:25]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:5]2[N:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[C:10]([Cl:16])[CH:11]=1)=[O:26])=[O:23])([O-:19])=[O:18]
Reactant: O=C=NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Nc1ccc(Oc2ccc(Br)nn2)c(Cl)c1
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])Nc1ccc(Oc2ccc(Br)nn2)c(Cl)c1
Yield: 40.7 %

Procedure:
1.10 g of 4-(6-bromo-3-pyridazinyloxy)-3-chloroaniline obtained in the same manner as in the above Synthetic Example 1 (1), was dissolved in 7 ml of dioxane. To this solution, 8 ml of a dioxane solution containing 0.87 g of 2,4-dinitrobenzoyl isocyanate was dropwise added, and the mixture was reacted at room temperature for 4 hours. After the completion of the reaction, the reaction product was poured into warm water, and the precipitates were separated by filtration. The precipitates were stirred in ethyl acetate, and again filtered to obtain 0.80 g of the desired product having a melting point of from 217° to 219° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[NH4+:18].[OH-]>>[F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH2:18])=[O:10])[CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: NC(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans-4-trifluoromethylcyclohexanecarboxylic acid (0.5 g, 2.55 mmol) in thionyl chloride (3.70 mL, 51.0 mmol) was heated to 60° C. for 1 h, cooled to RT and concentrated to dryness. The material was co-evaporated with toluene (2×), dissolved in EtOAc (5 mL), treated with satd. NaHCO3 (5 mL) followed by NH4OH (˜13M, 0.588 mL, ˜7.65 mmol) and stirred at RT for 0.5 h. The layers were separated, the aqueous layer extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford trans-4-(trifluoromethyl)cyclohexanecarboxamide (380 mg, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:4]([N+:17]([O-])=O)[C:3]=1[CH:20]=[O:21].C(O)(=O)C.Cl>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2=[CH:20][O:21][N:17]=[C:4]2[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: O=Cc1c(Cl)cc(CO)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: OCc1cc(Cl)c2conc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
To a mixture of 4-chloro-3′-fluoro-6-(hydroxymethyl)-2-nitrobiphenyl-3-carbaldehyde (0.50 g, 1.6 mmol), acetic acid (4 mL), and conc. HCl (4 mL) was added stannous chloride, dihydrate (1.4 g, 6.4 mmol). After stirring at room temperature for 2 hours, the resulting mixture was diluted with ethyl acetate, washed with water, brine, and then dried with sodium sulfate and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (0.104 g, 23%). LCMS calculated for C14H10ClFNO2 (M+H)+: m/z=278.0; Found: 278.0.
Reaction SMILES: [C:1]([C:4]1[C:16](=[O:17])[N:12]2[CH2:13][CH2:14][O:15][C:10]3[C:11]2=[C:6]([CH:7]=[C:8]([O:18][CH3:19])[CH:9]=3)[C:5]=1[OH:20])([OH:3])=O.[CH2:21]([O:23][C:24]([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1)=[O:25])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH2:21]([O:23][C:24]([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]1[C:1]([C:4]1[C:16](=[O:17])[N:12]2[CH2:13][CH2:14][O:15][C:10]3[C:11]2=[C:6]([CH:7]=[C:8]([O:18][CH3:19])[CH:9]=3)[C:5]=1[OH:20])=[O:3])=[O:25])[CH3:22]
Reactant: COc1cc2c3c(c1)c(O)c(C(=O)O)c(=O)n3CCO2
Reactant: CCOC(=O)C1Cc2ccccc2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)c1c(O)c2cc(OC)cc3c2n(c1=O)CCO3
Temperature: 90 °C
Reaction time: 3 h
Yield: 114.9 %

Procedure:
A mixture of 6-carboxy-2,3-dihydro-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.5 g), 2-ethoxycarbonylindoline (2.3 g) and 1,3-dicyclohexylcarbodiimide (3 g) in toluene (20 ml) was stirred at 90° C. for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (30:1) to give 2,3-dihydro-6-(2-ethoxycarbonyl-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.8 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:33]1[CH:34]=[CH:35][C:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:37])[NH:20][C:9]4[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)ccc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(OCC(F)(F)F)ccc2N1

Procedure:
The title compound was prepared from [2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-ethoxy)-phenyl]-carbamic acid tert-butyl ester (Example M54) (250 mg, 0.47 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (80 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:5]2.C1C(=O)N([Br:31])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:31][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:5]2
Reactant: Cc1ccc2nc(-c3ccccc3)c(-c3ccccc3)nc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: BrCc1ccc2nc(-c3ccccc3)c(-c3ccccc3)nc2c1

Procedure:
6-Methyl-2,3-diphenylquinoxaline (5.0 g, 16.9 mmol) was dissolved in dry, oxygen free benzene (50 ml). The solution was brought to reflux and a mixture of NBS (3.00 g, 16.9 mmol) and AIBN (0.1 g) added as a solid over a period of 30 minutes. The solution was then refluxed for 2 hrs, cooled, washed with water (3×100 ml), dried over MgSO4 and evaporated to leave a pale brown solid. This was recrystallised from hexane/toluene (1:1, 80 ml) to yield 6-bromomethyl-2,3-diphenylquinoxaline, 3.5 g, 56%. Traces of 6-methyl-2,3-diphenylquinoxaline were shown to be present by 1H NMR. A small sample was recrystallised from acetone for characterisation (m.pt. 146-148° C.). Found: C,; H,; N, %; C21H15N2Br requires C, 67.21; H, 4.03; N, 7.47%. 1H NMR (CDCl3 , 300 MHz) δ 8.16 (d, J 8.7 Hz, 1H, Hs of quinoxaline), 8.16 (d, J 2.2 Hz, 1H, Hs of quinoxaline), 7.78 (d of d, J 8.7 Hz, J 2.2 Hz, 1H, Hs of quinoxaline), 7.48-7.56 (m, 4H, phenyl ring), 7.30-7.40 (m, 6H, phenyl ring), 4.71 (s, 2H, CH2Br).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[CH:12]([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:11]([CH:12]([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)F)sc2c1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 84 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 84%). NMR(CDCl3) δ: 2.51 (3H, s), 3.10 (3H, s), 6.80 (1H, t, J=54.8 Hz), 7.19 (1H, s), 7.33 (1H, app d, J=8.3 Hz), 7.68 (1H, bs), 7.71-7.74 (2H, m), 7.81 (1H, d, J=8.6 Hz), 8.01-8.04 (2H, m); mp 183-184° C. (ethanol)
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:24][CH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[C:28](=[O:45])[N:29]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:30]([CH3:36])=[N:31]2>CN(C=O)C>[O:44]=[C:38]1[CH:37]([N:29]2[C:28](=[O:45])[C:27]3[C:32](=[CH:33][CH:34]=[CH:35][C:26]=3[CH2:25][NH:24][C:7](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)[N:31]=[C:30]2[CH3:36])[CH2:42][CH2:41][C:40](=[O:43])[NH:39]1
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)c1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a stirred solution of m-toluic acid (0.24 g, 1.8 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.31 g, 1.9 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.59 g, 1.8 mmol) was added, and the mixture was stirred for 45 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-methyl-benzamide as a light green solid (560 mg, 76% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.00 min (99.2%); mp, 263-265° C.; 1HNMR (DMSO-d6) 2.18-2.21 (m, 1H, CHH), 2.38 (s, 3H, CH3Ar), 2.59-2.88 (m, 6H, CHCH2, CH3), 4.95-5.12 (m, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.33-7.76 (m, 7H, Ar), 8.89 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.83, 20.92, 23.29, 30.60, 42.12, 56.52, 117.65, 123.98, 124.32, 125.40, 127.76, 128.26, 131.85, 133.93, 134.23, 137.65, 141.04, 148.50, 154.80, 161.11, 166.39, 169.53, 172.61. LCMS MH=419; Anal Calcd For C23H22N4O4+0.6H2O: C, 64.36; H, 5.45; N, 13.05. Found: C, 64.36; H, 5.24; N, 13.22.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([Cl:12])[C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:12][C:11]1[C:4]2[N:3]=[C:2]([O:27][C:20]3[C:21]([CH3:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=3[Cl:18])[N:6]([CH3:7])[C:5]=2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 100 °C
Yield: 63.7 %

Procedure:
A solution of 2,4-dichloro-7-(1-ethylpropyl)-1-methyl-1H-benzimidazole (5.5 g, 20.2 mmol), 2,4-dichloro-6-methylphenol (10 g, 56.5 mmol) and potassium carbonate (8.4 g, 60.8 mmol) in N,N-dimethylformamide (55 mL) was heated at 100° C. for 9 h. To the mixture was added 2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate (4.2 g, 30.4 mmol) and heated at 100° C. for 16 h. Additional 2,4-dichloro-6-methylphenol (5 g, 28.3 mmol) and potassium carbonate (4.2 g, 30.4 mmol) were added and heated at 100° C. for 9 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH silica gel eluting with a 12.5% ethyl acetate/n-hexane. The resulting solids were recrystallized from a 10% ethyl acetate/n-hexane to give 5.3 g (64%) of the title compound as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[CH3:38]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=2[CH3:38])[N:8]=1)=[O:5]
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Reactant: Cc1cc([N+](=O)[O-])ccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 0.5 h

Procedure:
To a solution of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (for a preparation see Intermediate 9)(1.5 g, 6.72 mmol) in THF (30 ml) at ambient temperature under nitrogen was added 1.0 M lithium bis(trimethylsilyl)amide in THF (6.5 ml, 6.50 mmol, Aldrich). The solution was stirred for 30 min. To the solution was added a solution of 1-(bromomethyl)-2-methyl-4-nitrobenzene (1.5 g, 6.52 mmol) in THF (20 ml). The resulting pale orange solution was stirred at ambient temperature under nitrogen over the weekend. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (150 ml) and saturated aqueous sodium hydrogen carbonate (50 ml). The phases were separated and the aqueous layer washed with ethyl acetate (25 ml). The combined organic phases were dried (MgSO4), filtered and the solvent removed in vacuo to leave a yellow oil (2.87 g). The sample was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.6 g); LCMS: (System 4) MH+=373, tRET=2.65 min.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)=[N:25]2)=[N:18][CH:19]=1.O>CC(C)=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][O:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)=[N:25]2)=[N:18][CH:19]=1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC(O)CO)cn4)c3)n2)cn1
Temperature: 80 °C
Reaction time: 120 h

Procedure:
75 mg (0.68 mmol) of 3-chloro-1,2-propanediol and 322 mg (0.99 mmol) of caesium carbonate are added to 150 mg (0.41 mmol) of 2-[3-(5-hydroxy-pyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one, and the mixture is suspended in acetone. The reaction mixture is stirred at 80° C. for 5 days. Water is added to the reaction mixture, which is then extracted a number of times with ethyl acetate, dried over sodium sulfate and evaporated. The crude product is purified by means of column chromatography on silica gel.
Reaction SMILES: [NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@:5]([Si](C(C)(C)C)(C)C)([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].C1COCC1>>[NH2:1][O:2][C@@H:3]1[C@@H:7]([CH2:8][OH:9])[O:6][C@@H:5]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:4]1
Reactant: Cc1cn([C@@]2([Si](C)(C)C(C)(C)C)C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 72 %

Procedure:
3'-O-Amino-(t-butyldimethylsilyl)thymidine was deblocked with (Bu)4NF/THF in standard way to furnish compound 4 (72%). Crystallized from ether/hexanes/ethanol as fine needles, mp 81° C. 1H NMR (Me2SO-d6) δ1.78 (s, 3, CH3), 2.17 and 2.45 (2 m, 2, 2'CH2), 3.70 (m, 2, 5'CH2), 3.88 (m, 1, 4'H), 4.16 (m, 1, 3'H), 4.8 (br s, 1, 5'OH), 6.05 (dd, 1, 1H), 6.2 (br s, 2 NH2), 7.48 (s, 1, C6H), and 11.24 (br s, 1, NH). Anal. Calcd. for C10H15N3O5 : C, 46.69; H, 5.87; N, 16.33; found: C, 46.55; H, 5.91; N, 16.21.
Reaction SMILES: C(OC([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=O)(C)(C)C.[CH2:14]([O:16][C:17](=[O:25])[CH2:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1)[CH3:15]>>[CH3:9][NH:8][CH2:10][C:11]([NH:24][C:21]1[S:22][CH:23]=[C:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:25])[N:20]=1)=[O:13]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1csc(NC(=O)CNC)n1

Procedure:
The subtitle compound was prepared from N-tert-butoxycarbonyl sarcosine (6.0 g) and 2-amino-4-thiazoleacetic acid ethyl ester (6.6 g) by the method of example 10 step (i). Yield 5.24 g
Reaction SMILES: [O:1]1[C:5]2[N:6]=[CH:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1>C(O)C.[Pd]>[O:1]1[C:5]2[NH:6][CH2:7][C:8]3[N:9]([CH:11]=[CH:12][CH:13]=3)[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: C1=Nc2occc2Cn2cccc21
Agent: [Pd]
Solvent: CCO
Product: c1cc2n(c1)Cc1ccoc1NC2

Procedure:
A solution of 1 mmol of 4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and 0.2 g of 10% Pd/C in 10 ml of 10 ml of ethanol is hydrogenated for 18 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated in vacuo to give the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=NN(C)C)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:20]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CN(C)N=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Product: O=C(C(=O)C(F)(F)F)c1ccc(Br)cc1
Temperature: 45 °C
Yield: 92 %

Procedure:
3-(4-bromophenyl)-3-(2,2-dimethylhydrazono)-1,1,1-trifluoropropan-2-one (2.0 g, 6.2 mmol) was suspended in 5N sulfuric acid (60 mL) and heated at 45° C. for 6 h. The temperature was raised to 85° C. for 2 h, and upon cooling a precipitate formed. This material which was isolated by filtration to give 1-(4-bromophenyl)-3,3,3-trifluoropropane-1,2-dione 1.6 g (92%) as a yellow solid. The dione (1.6 g, 5.7 mmol) was taken up in methanol (30 mL), N-(tert-butoxycarbonyl)-L-prolinal (1 g, 5.0 mmol) was added, followed by addition of 28% ammonium hydroxide solution (10 mL). The reaction was stirred at room temperature for 18 h, poured onto dichloromethane (200 mL), washed with water and dried with MgSO4. Filtration, concentration and application to a 40 M Biotage cartridge, gradient elution with 5%-30% ethyl acetate/Hexanes, gave J32.a 1.3 g (50%). 1H NMR (300 MHz, DMSO-d6) δ 12.88 (br.s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 4.84-4.70 (m, 1H), 3.57-3.49 (m, 1H), 3.39-3.29 (m, 1H), 2.31-2.20 (m, 1H), 1.98-1.78 (m, 3H), 1.39/1.13 (m, 9H). LRMS: Anal. Calcd. for C19H20BrF3N3O2 458.07; found: 458.06 and 460.06 (M−H)−. HRMS: Anal. Calcd. for C19H22BrF3N3O2 460.0847; found: 460.0866 and 462.0840 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:23](O)[CH3:24].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoic acid (9.98 g, 33.01 mmol) in dichloromethane were added ethanol (5.59 mL, 99.01 mmol), 4-dimethylaminopyridine (400 mg, 3.27 mmol), triethylamine (13.81 mL, 99.08 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.6 g, 39.65 mmol) under ice cooling, and the resulting solution was stirred for 20 minutes under ice cooling and then for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate, and the ethyl acetate layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 6.77 g of the title compound.