Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([C:11]([N:9]3[CH2:10][CH:7]([O:6][C:5]4[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=4)[CH2:8]3)=[O:12])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CCN(c2ccccc2)CC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
A mixture of 2.8 g (0.01 mole) of 3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 25 ml of tetrahydrofuran was stirred for 10 min then 1.6 g (0.01 mole) of 1-phenylpiperazine was added. After stirring for 30 min, approximately 2 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml), dried and concentrated in vacuo to yield 5.1 g of crude dark yellow oil, which solidified when cooled to -78° C. Recrystallization from isopropyl ether yielded 2.2 g (54.3%) of pale yellow crystals, m.p. 93°-94° C.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH2:20][CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(C)C>CC(N(C)C)=O>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:22][CH2:21][CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: NCCc1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CC(C)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCc1ccccc1

Procedure:
A solution of 5.6 g of 2-fluoro-5-nitrobenzoic acid and 14.5 g of 2-phenylethylamine in 20 ml of dimethylacetamide is reacted and worked up in analogy to Example 1. Yellow crystals from isopropanol, melting point 116°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]3SC)[CH:5]=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].CO>[Ni].CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[CH:4][C:3]=1[C:21]([F:24])([F:22])[F:23]
Reactant: CSC1C(=O)Nc2ccc(Oc3ccc(C(F)(F)F)c(Cl)c3)cc21
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1Cc2cc(Oc3ccc(C(F)(F)F)c(Cl)c3)ccc2N1
Temperature: 50 °C

Procedure:
A stirred mixture of 5-[(2-chloro-α,α,α-tri- fluoro-p-tolyl)oxy]-3-(methylthio)-2-indolinone (25.0 g, 0.067 mol) in a 5:1 mixture of methanol and dimethylformamide is heated to 50° C., under a nitrogen atmosphere, treated portionwise with an aqueous slurry of Raney nickel W-2 catalyst until disulfurization is complete as determined by chromatography, cooled to room temperature and filtered through a bed of diatomaceous earth. The filtrate is concentrated in vacuo, diluted with a 1:1 mixture of ethyl acetate and ether, washed with water, dried over MgSO4 and reconcentrated in vacuo to afford the title product as a tan solid, 16.5 g (75%), identified by 1HNMR analysis.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:21](=[O:22])[C:17]2[N:18]=[CH:19][S:20][C:16]=2[C:15](=[O:23])[CH:14]=1>C(O)C>[CH3:10][N:5]([CH2:6][CH2:7][CH2:8][NH:9][C:13]1[C:21](=[O:22])[C:17]2[N:18]=[CH:19][S:20][C:16]=2[C:15](=[O:23])[CH:14]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:13]1[C:21](=[O:22])[C:17]2[N:18]=[CH:19][S:20][C:16]=2[C:15](=[O:23])[CH:14]=1
Reactant: COC1=CC(=O)c2scnc2C1=O
Reactant: CN(CCCN)CCCN
Solvent: CCO
Product: CN(CCCNC1=CC(=O)c2scnc2C1=O)CCCNC1=CC(=O)c2scnc2C1=O
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 54.4 %

Procedure:
57 μl (0.37 mmol; 0.48 equivalent) of N-(3-aminopropyl)-N-methylpropane-1,3-diamine is added to 150 mg (0.77 mmol) of 5-methoxy-1,3-benzothiazol-4,7-dione in solution in 6 ml of ethanol. The reaction mixture is maintained under stirring at 85° C. for 90 minutes, then the solvent is evaporated off under reduced pressure and the expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol mixture 94/6) and 95 mg (yield=26%) of 5.5′-[(methylimino)bis(propane-3,1-diylimino)]bis(1,3-benzothiazole-4,7-dione) is obtained in the form of a red powder. Melting point: 223-224° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:39][CH:40]([F:42])[F:41])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:31])[CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cn[nH]c2cc1C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 70.9 %

Procedure:
Using the compound (1.92 g, 4.37 mmol) of Example 244, step B and 2,2-difluoroethyl trifluoromethanesulfonate (1.49 g, 6.96 mmol), and according to the method of Example 241, step C, the title compound (1.56 g, yield 71%) was obtained as a colorless amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:19]2[CH:20]=[C:15]([Cl:14])[N:16]=[C:17]([NH2:22])[N:18]=2)[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1nc(Cl)cc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidin-2-amine (120 mg g, 0.71 mmol) and Cs2CO3 (290 mg, 0.88 mmol), and the reaction mixture was heated to 80° C. for 30 h. Then the reaction was cooled to RT. EtOAc was added and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a colorless oil.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:13]1([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cccn2)cc1
Temperature: 130 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of ethyl 4-fluorobenzoate (105 g) in DMSO (250 mL) were added pyrazole (34.0 g) and potassium carbonate (138 g), and the mixture was heated with stirring at 130° C. for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (73.7 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:32])[N:16]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[C:17](=[O:24])[C:18]3[C:23]=2[C:22]=1[CH:21]=[CH:20][CH:19]=3>CN(C)C=O>[Cl:1][C:12]1[C:11]([NH:10][CH3:9])=[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]2=[C:14]([CH:13]=1)[C:15](=[O:32])[N:16]([CH:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)[C:17]3=[O:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1ccc2c3c(cccc13)C(=O)N(C1CCN(C)CC1)C2=O
Solvent: CN(C)C=O
Product: CNc1c(Cl)cc2c3c(cccc13)C(=O)N(C1CCN(C)CC1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A slurry of N-chlorosuccinimide (0.255 g; 1.90 mmol) and 2,3-dihydro-6-methylamino-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.65 g; 1.80 mmol), prepared as in Example 5, in N,N-dimethylformamide (12 mL) was stirred approximately 72 hours. The solvent was removed and acetone (approximately 25 mL) was added to the residue. The acetone mixture was heated to boiling and then stirred for 1 hour at room temperature. The solid was collected from the mixture, stirred again in acetone, and recollected. Drying under vacuum gave 5-chloro-2,3-dihydro-6-methylamino-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.65 g; 1.65 mmol), m.p. 298°-302° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([N:30]3[CH2:29][CH2:28][N:27]([C:24]4[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=4)[CH2:32][CH2:31]3)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)N3CCN(c4ccc(F)cc4)CC3)s2)c(C)[nH]c1=O
Yield: 99 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-(4-fluorophenyl)piperazine as described in Step 5, Example 24 to give the title compound as a solid (99% yield). LC/MS: RT 3.92 min; m/e 462 (M+H); 1H NMR (δ, ppm): 11.84 (1H, s), 7.65 (1H, d); 7.38 (1H, s); 7.30 (1H, d), 6.94 (4H, m), 3.12 (8H, m), 2.39 (2H, q), 2.33 (3H, s), 1.07 (3H, t); 19F NMR −123.8.
Reaction SMILES: [C:1]([C:9]1[C:17]2[O:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=2[CH:12]=[C:11]([Br:20])[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH2:1]([C:9]1[C:17]2[O:16][CH2:15][C:14]([CH3:18])([CH3:19])[C:13]=2[CH:12]=[C:11]([Br:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)COc2c(C(=O)c3ccccc3)cc(Br)cc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)COc2c(Cc3ccccc3)cc(Br)cc21

Procedure:
Following General Procedure J and using 7-benzoyl-5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran (Intermediate 38, 2.15 g, 6.53 mmol), anhydrous dichloromethane (10 mL), trifluoroacetic acid (4.12 mL, 53.5 mmol) and triethyl silane (8.4 mL, 52 mmol) followed by flash column chromatography, the title compound was obtained (1.57 g, 76%). 1H NMR (300 MHz, CDCl3): δ 7.23-7.14 (m, 5H), 7.02 (d, 1H, J=1.9 Hz), 6.97 (d, 1H, J=1.9 Hz), 4.17 (s, 2H), 3.85 (s, 2H), 1.36 (s, 6H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][CH2:13][C@@H:14](OS(C)(=O)=O)[C@@H:15]1[CH2:19][C@@H:18]([CH3:20])[C:17](=[O:21])[O:16]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN1C(=O)N(C)CCC1>[N:1]([C@H:14]([C@H:15]1[O:16][C:17](=[O:21])[C@H:18]([CH3:20])[CH2:19]1)[CH2:13][O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: C[C@@H]1C[C@@H]([C@@H](COCc2ccccc2)OS(C)(=O)=O)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: C[C@@H]1C[C@@H]([C@H](COCc2ccccc2)N=[N+]=[N-])OC1=O
Temperature: 60 °C
Reaction time: 72 h
Yield: 91.2 %

Procedure:
2.93 g of sodium azide (45.1 mmol) was added to a solution of 9.90 g of methanesulfonic acid (R)-2-benzyloxy-1-[(2S,4R)-4-methyl-5-oxotetrahydrofuran-2-yl]ethyl ester obtained in Example (76d) (30.1 mmol) in N,N′-dimethylpropyleneurea (100 ml) at room temperature, and the mixture was stirred at 60° C. for three days. The reaction mixture was cooled and then poured into ice water, followed by extraction with diethyl ether. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=5/1) to obtain 7.56 g of the title compound (yield: 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][NH2:13])=[N:7][N:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20](O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1=[N:12][N:13]=[CH:20][N:7]1[N:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1nnc(-c2ccccc2)c2cc(Cl)ccc12
Reactant: CCO
Product: Clc1ccc2c(c1)c(-c1ccccc1)nn1cnnc21

Procedure:
The compound of the title is prepared by following essentially the same procedure outlined in example 114 above but using 6-chloro-4-phenyl-1-hydrazinophthalazine instead of 4-phenyl-1-hydrazinophthalazine. M.p. 189°-90° C. (from ethanol).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:16][CH:15]=[CH:14]2)=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(F)c1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1ccnc(F)c1-n1cccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
2-Fluoro-4-methylpyridin-3-amine (1.0 g, 7.93 mmol) and 2,5-dimethoxytetrahydrofuran (1.08 mL, 1.05 equiv.) were suspended in 3 mL of acetic acid and refluxed for 2 hours. The reaction was cooled down to room temperature. The solvents were removed and the residue was purified by silica gel chromatography (EtOAc/hexanes=1:8, Rf=0.3) to afford 1.0 g (72%) oil. 1H NMR (400 MHz, CDCl3) δ 8.10 (dd, J=0.8, 5.1 Hz, 1H), 7.17 (d, J=5.1 Hz, 1H), 6.74 (td, J=2.1, 0.9 Hz, 2H), 6.40 (t, J=2.1 Hz, 2H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.2, 157.8, 149.6, 149.5, 145.5, 145.4, 123.80, 123.76, 122.1, 109.8, 17.29, 17.25. HRMS (m/z) calcd for C10H10FN2 (M+H) 177.0828. found 177.0827. Richards, et al. (2008) Bioorg. & Med. Chem. Lett. 18:4325-27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C=O)C.S(Cl)([Cl:29])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][CH2:18][C:19]([Cl:29])=[O:21])[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CCC1(c2ccc(Cl)c(Cl)c2)CCC(=O)NC1=O
Temperature: 60 °C

Procedure:
Under a nitrogen atmosphere, 20 g of 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, 200 ml of toluere and 0.5 ml of DMF are mixed. The medium is heated to 60° C and 14.9 g of thionyl chloride and 40 ml of toluene are introduced dropwise. The stirring is maintained for 5 hours at 60° C. The toluene and the excess thionyl chloride are evaporated off and then the reaction medium is dried in an oven (40° C.) overnight.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[N:26]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=2)[CH2:17][CH2:16]1.CN1CCCC1=O.N>CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:26]2[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[N:23]=[C:22]2[NH:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][NH:12][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=3)[CH2:16][CH2:17]2)=[CH:29][CH:30]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: N
Solvent: CO
Solvent: CN1CCCC1=O
Product: Nc1nc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)ccc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 3.4 parts of 6-chloro-3-nitro-2-pyridinamine, 7.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-amine and 10 parts of 1-methyl-2-pyrrolidinone was stirred and heated for 2 hours at 150° C. The reaction mixture was cooled and taken up in methanol saturated with ammonia. The whole was evaporated and water was added to the residue. The product was extracted three times with 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated in vacuo. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 5 parts (50%) of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinediamine; mp. 205.7° C. (compound 63).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:42][CH2:41][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:46]CO>>[C:1]([O:5][C@@H:6]([C:12]1[C:38]([CH3:39])=[N:37][C:36]2=[CH:40][C:33]3=[N:34][N:35]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:46][CH2:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][O:31][CH2:32]3)[CH2:41][CH2:42]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCO
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1ccccc1COC3
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCCCc1ccccc1COC3
Yield: 59.6 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (37 mg, 0.062 mmol) and NaOH (0.312 mL, 0.312 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then filtered and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-{4,26-dimethyl-11,25-dioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl}acetic acid (21 mg, 0.037 mmol, 59.6% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.29 (d, J=7.7 Hz, 1H), 7.26-7.19 (m, 2H), 7.17-7.11 (m, 1H), 6.53 (s, 1H), 5.71 (s, 1H), 4.74-4.58 (m, 4H), 4.50-4.42 (m, 1H), 3.68-3.20 (m, 4H), 2.82-2.75 (m, 1H), 2.66 (d, J=8.4 Hz, 2H), 2.51 (s, 3H), 1.90-1.81 (m, 2H), 1.71-1.51 (m, 8H), 1.19 (s, 3H), 1.15 (s, 9H). LCMS (M+1)=565.3.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].N1C=CC=CC=1>CCOC(C)=O>[F:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
EtSO2Cl (21.5 mL, 0.22 mol) was added drop wise to a mixture of 4-fluoro-3-nitroaniline (29.6 g, 0.19 mol) and pyridine (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (1 L). The resulting solution was washed with HCl 2N (4×200 mL), NaHCO3 saturated solution (4×200 mL) and water (4×200 mL). The organic phase was dried over anhydrous Na2SO4 and the solvent was removed to provide the title product as beige solid (46.3 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Cl)c1Nc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A solution of 1-chloro-2-fluoro-3-nitrobenzene (983 mg, 5.60 mmol) in DMSO (3 mL) was purged with a stream of nitrogen prior to addition of phenylamine (1.0 mL, 11.2 mmol) and then stirred in a sealed tube at 100° C. for 3 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The organic layer was then washed with a saturated solution of KHSO4 (×3), then with water, followed by brine, dried (Na2SO4) and concentrated in vacuo affording (2-Chloro-6-nitrophenyl)phenylamine as a dark orange oil (1.35 g, 97%). 1H NMR (CDCl3, 400 MHz): δ 8.15 (1H, s), 8.03 (1H, dd, J=8.40, 1.49 Hz), 7.63 (1H, d, J=7.90 Hz), 7.32-7.23 (2H, m), 7.08-6.99 (2H, m), 6.86 (2H, d, J=7.90 Hz).
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH2:9]([O:16][C:17]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Br)C=C>C1COCC1>[CH2:9]([O:16][C:17]([C:19]1([CH2:8][CH:6]=[CH2:7])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)C1CCCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1(C(=O)OCc2ccccc2)CCCC1
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Next, to a stirred solution of LDA (4 mmol, 2M in Hexane) in THF (8 mL) at −78° C. is added a solution of cyclopentanecarboxylic acid benzyl ester (817 mg, 4 mmol) in THF (3 mL) dropwise. After the addition, the mixture is stirred at −78° C. for 5 hours then allyl bromide (726 mg, 6 mmol) is added dropwise. The mixture is warmed to room temperature during 4 hours then the reaction mixture is quenched with saturated NaHCO3. Magnesium sulfate (2 g) is added and stirred until all the MgSO4 is dissolved. The mixture is extracted with ethyl acetate and the organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (hep:EtOAc, 10:1) to give 1-allyl-cyclopentanecarboxylic acid benzyl ester. Next, Ozone is bubbled through a solution of 1-allyl-cyclopentanecarboxylic acid benzyl ester in methylene chloride (15 mL) for 30 min then PS-triphenolphosphine (300 mg) is added and the mixture is stirred at room temperature for 5 hours. The resin is filtered and solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 10:1) to give 1-(2-oxo-ethyl)-cyclopentanecarboxylic acid benzyl ester MS 247.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>C(#N)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:26])[CH2:3][CH2:2]1
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: O
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of Step 3 intermediate (3.89 g, 10.72 mmol) was added N-iodosuccinimide (2.69 g, 11.79 mmol) in acetonitrile at room temperature. The reaction temperature was then raised to 60° C. and stirred for 4 h. The reaction mixture was then cooled to room temperature, diluted with water and stirred for 20 min. The filtered solid was washed with water and dried to afford 5.19 g of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.33 (m, 2H), 0.54-0.56 (d, J=7.2 Hz, 2H), 1.22 (br s, 1H), 3.77-3.81 (m, 5H), 7.06-7.14 (m, 2H), 7.27-7.29 (d, J=7.2 Hz, 1H), 7.49-7.52 (m, 1H), 7.57 (s, 1H), 7.96 (d, J=3.9 Hz, 1H), 8.18 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 481.45 (M+H)+.