Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15].C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)C(Br)C(N)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)C(NCc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of 41.60 g of p-nitrobenzylamine in 660 ml of dry ethanol was added 49.34 g of α-bromomalonamide and 38.2 ml of triethylamine. After being stirred for two hours under refluxing, the reaction mixture was cooled to room temperature. And then separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 53.36 g of α-(4-nitrobenzyl)aminomalonamide. And a mixture of 50.45 g of α-(4-nitrobenzyl)aminomalonamide, 177.8 g of triethyl orthoformate and 0.76 g of p-toluenesulfonic acid monohydrate in 1.3 liters of dry ethanol was stirred for three hours under refluxing in an argon atmosphere. The reaction mixture was cooled on an ice-bath and separated crystals were filtered off, washed with ethanol and isopropyl ether, and dried to give 50.78 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([CH2:12][C@@H:13]([OH:15])[CH3:14])[N:11]=2)[N:5]=[CH:6][C:7]=1[F:8].[Cl:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]2[CH:24]=[N:25][N:26]([CH2:27][C@@H:28]([OH:30])[CH3:29])[C:18]=12.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[Cl:16][C:17]1[C:22]([F:23])=[CH:21][N:20]=[C:19]2[CH:24]=[N:25][N:26]([CH2:27][C@@H:28]([O:30][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[CH3:29])[C:18]=12.[Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([CH2:12][C@@H:13]([O:15][CH:19]3[CH2:18][CH2:17][CH2:22][CH2:21][O:31]3)[CH3:14])[N:11]=2)[N:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](O)Cn1ncc2ncc(F)c(Cl)c21
Reactant: C[C@H](O)Cn1cc2ncc(F)c(Cl)c2n1
Reactant: C1=COCCC1
Solvent: C1CCOC1
Product: C[C@@H](Cn1cc2ncc(F)c(Cl)c2n1)OC1CCCCO1
Product: C[C@@H](Cn1ncc2ncc(F)c(Cl)c21)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-1-(7-chloro-6-fluoro-2H-pyrazolo[4,3-b]pyridin-2-yl)propan-2-ol and (S)-1-(7-chloro-6-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-ol in THF (10 mL) was added 3,4-dihydro-2H-pyran (0.332 mL, 3.66 mmol) and p-TSA monohydrate (580 mg, 3.05 mmol) and the mixture was stirred at room temperature for 3 hours and then concentrated to give a residue which was purified on silica gel column chromatography eluted with dichloromethane/Methanol (0-10%) to give 7-chloro-6-fluoro-1-((2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-pyrazolo[4,3-b]pyridine and 7-chloro-6-fluoro-2-((2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-2H-pyrazolo[4,3-b]pyridine which were used in next step. MS [M+H] found 314.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].CN1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=O)[C:26]3=[O:33])[CH:23]=2)CC1.CN(C(ON1N=NC2C=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:30]([CH:27]1[CH2:28][CH2:29][N:25]([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[N:48]([CH3:43])[CH:47]=[CH:46]3)[C:26]1=[O:33])=[O:32]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CN1CCc2ccc(N3CCC(C(=O)O)C3=O)cc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2cc(N3CCC(C(=O)NCCc4c[nH]c5ccc(Cl)cc45)C3=O)ccc21
Yield: 20.7 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.055 g; 0.233 mmol), 1-(1-methylindolin-6-yl)-2-oxopyrrolidine-3-carboxylic acid (0.064 g; 0.245 mmol), HATU (0.091 g; 0.240 mmol) and N,N-diisopropylethylamine (0.101 mL; 0.583 mmol) in DMF (3 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.021 g (21%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(1-methyl-1H-indol-5-yl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[N:6]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS(N1C2C(=CC=CC=2)C=N1)(=O)=O>>[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[N:6]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: Fc1cc(Cl)cc2nc(CCl)n(CCC(F)(F)F)c12
Agent: CS(=O)(=O)n1ncc2ccccc21
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)cc(F)c3n2CCC(F)(F)F)c2cnccc12

Procedure:
Example 5-1 was prepared in analogy to Example 4-1 by using 5-chloro-2-(chloromethyl)-7-fluoro-1-(3,3,3-trifluoropropyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and methanesulfonyl-1H-indazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([F:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([F:11])=[CH:9][N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1c[nH]c2nc(Cl)nc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(F)c2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
2,4-Dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (see Seela, et al., Helvetica Chimica Acta, 91(6):1083-1105 (2008)) (654 mg, 3.2 mmol) was dissolved in DMF (6.5 mL). After cooling to 0° C., NaH (254 mg, 6.35 mmol, 60% in mineral oil) was added. After complete addition, the mixture was warmed to rt and allowed to stir for 30 min. A solution of (2-(chloromethoxy)ethyl)trimethylsilane (529 mg, 3.2 mmol) in DMF (2 mL) was added dropwise to the mixture and stirring was continued for 3 hrs. The reaction was quenched by pouring the mixture over ice water (75 mL). The resulting aqueous layer was then extracted with Et2O (three×50 mL). The combined organics were washed with water (two times), brine (two times) and dried over MgSO4. After concentrating, the brown solid was purified via flash chromatography eluting with a gradient of 1%-10% EtOAc in heptanes to afford the title compound (0.45 g, 42% yield) as a white, low melting solid. 1H NMR (400 MHz, chloroform-d) δ ppm-0.03 (s, 9H), 0.87-0.97 (m, 2H), 3.48-3.58 (m, 2H), 5.57 (s, 2H), 7.14 (d, J=2.78 Hz, 1H). APCI (MH+). m/z (APCI+) for C12H16Cl2FN3OSi 336.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P(Cl)(Cl)(Cl)=O.Cl>O.C1(C)C=CC=CC=1>[C:14]1([O:5][C:4](=[O:6])[C:3]2[C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:2]=2[OH:1])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(C)c(C(=O)O)c(O)c1C
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=O)Oc2ccccc2)c(O)c1C
Temperature: 100 °C
Yield: 49.4 %

Procedure:
In a 500 ml three-necked flask fitted with a mechanical stirrer, a reflux condenser connected to a water pump to absorb the gaseous hydrochloric acid formed during the reaction, and a dropping funnel, were placed 200 ml of dry toluene and 54 g (0.3 mole) of 2-hydroxy-3,4,6-trimethylbenzoic acid prepared in step (1), and 56.4 g (0.6 mole) of phenol were added. The mixture was heated at 100° C. until the reagents were completely dissolved. 27 ml of phosphorus oxychloride were then added dropwise over 30 minutes, and the mixture was refluxed (110° C.) for 8 hours. A substantial evolution of gaseous hydrochloric acid took place. The mixture was cooled to 80° C. and 150 ml of water were added. The aqueous layer was decanted, and the organic layer was washed a second time with an aqueous solution of sodium bicarbonate. The aqueous layer was decanted and the toluene solution was dried with anhydrous magnesium sulfate. The solution was filtered, and the toluene solvent was distilled off. The residue was dissolved in 90 ml of boiling isopropanol and the desired product crystallized upon cooling. 38 g of a white product were obtained (M.P.=74° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11]C)[CH:3]=1>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1cc(I)cc([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(O)cc(I)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 1-iodo-3-methoxy-5-nitro-benzene (8.2 g, 29.39 mmol) in methylene chloride (600 mL) was added 1.0 M solution of borontribromide (58.78 mL, 58.78 mmol) in methylene chloride at −78° C. The resulting solution was stirred for 30 minutes and then the cooling bath was removed to warm to room temperature. After stirring for 15 h at this temperature, the reaction mixture was heated to reflux for 4 h in order to complete the reaction. Then, it was cooled to room temperature and diluted with water (100 mL) and the methylene chloride was removed under vacuum. Then, the organic compound was extracted into diethyl ether (2×100 mL) and the combined ether extracts were washed with brine solution (200 mL). Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 120 g column, eluting with 0-15% ethyl acetate in hexanes to obtain 3-iodo-5-nitro-phenol (4.8 g, 62%) as a light yellow solid: ES(+)-HRMS m/e calculated for C6H4INO3 (M−H)+ 263.9163, found 263.9162.
Reaction SMILES: [CH3:1][C:2]([N+:5]([O-:7])=O)([CH3:4])[CH3:3].C(O)(=O)C.[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>C(O)C.[Zn]>[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[N+:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[O-:7])=[CH:19][CH:18]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1ccc(-n2ccnc2)cc1
Temperature: 5 °C

Procedure:
To a suspension of 1,1-dimethylnitroethane (261.2 mg, 2.53 mmol) and zinc (247.0 mg, 3.78 mmol) in ethanol (3.0 ml) was added acetic acid (451.8 mg, 7.52 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 30 minutes. After cooling the mixture to 5° C. again, 4-(1-imidazolyl)benzaldehyde (216.5 mg, 1.26 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (chloroform/methanol=10/1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[CH2:11]1[C:16](=O)[CH2:15][C:13](=[O:14])[CH2:12]1.[NH2:18][C:19]1[NH:23][N:22]([CH3:24])[C:21](=[O:25])[CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:20]3[C:21](=[O:25])[N:22]([CH3:24])[NH:23][C:19]=3[NH:18][C:16]3[CH2:11][CH2:12][C:13](=[O:14])[C:15]2=3)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Cn1[nH]c(N)cc1=O
Reactant: O=C1CCC(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: Cn1[nH]c2c(c1=O)C(c1ccc(F)c(Br)c1)C1=C(CCC1=O)N2
Yield: 56.4 %

Procedure:
3-Bromo-4-fluorobenzaldehyde (0.3 g, 1.5 mmol), 1,3cyclopentadione (0.15 g, 1.5 mmol), and 5-amino-2-methyl-1,2-dihydropyrazol-3-one (0.17 g, 1.5 mmol), prepared by the method of (C. Taylor and J. Barton, J.Am.ChemSoc., (1959) 81, 2448) were processed as described in Example 1 to provide 0.32 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.21 (t, 2H), 2.59 (m, 2H), 3.38 (s, 3H), 4.75 (s, 1H), 7.13 (m, 1H), 7.2 (t, 1H), 7.42 (dd, 1H), 10.16 (s, 1H), 10.51 (bs, 1H); MS (ESI−) m/z 378 (M−H−) Anal. Calcd for C16H13N3BrFO2: C, 50.21;H, 3.56; N, 10.98. Found: C, 50.76;H, 4.09; N, 10.52.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[C:5]([O:7][CH3:8])=[O:6].[C:26](N1C=CN=C1)(N1C=CN=C1)=[S:27]>O1CCCC1.ClCCl.O>[CH3:25][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:15][CH2:14][CH2:13][N:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][C:26]1=[S:27]
Reactant: COC(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c(=S)n2CCCN(C)CCc1ccccn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
A mixture of methyl 3-amino-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)benzoate (4.09 g, 1 eq) and thiocarbonyldiimidazole (2.77 g, 1.3 eq) in tetrahydrofuran (100 ml) is stirred at approximately 20° C. for 15 hours. After concentration under reduced pressure at 40° C., the residue obtained is taken up in dichloromethane (150 ml) and water (50 ml). After decanting and extracting, the combined organic phases are washed with salt water, dried over Na2SO4 then evaporated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a foam (3.94 g; 85% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=O)C(F)(F)F)[CH2:14][C@H:13]2[O:24][CH2:25][CH:26]([F:28])[F:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.BrC1[S:43][C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][N:46]=1>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:43][C:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][N:46]=3)[CH2:14][C@H:13]2[O:24][CH2:25][CH:26]([F:28])[F:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)C(F)(F)F)C[C@H]2OCC(F)F)nc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC(F)F)C2)s1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
cis(±)-4-Chloro-N-{3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-yl}-5-ethyl-1H-imidazole-2-carboxamide obtained in Example (121f) (144 mg, 0.33 mmol) was dissolved in methanol (4 mL). A 2 N aqueous lithium hydroxide solution (0.4 mL) was added, and the mixture was stirred at 40° C. for 40 minutes. The pH was adjusted to 4 by adding a 1 N aqueous hydrochloric acid solution, and the solvent was evaporated under reduced pressure. The residue was dissolved in DMA (5 mL). Diisopropylethylamine (130 mg, 1 mmol) and ethyl 2-bromo-1,3-thiazole-5-carboxylate (155 mg, 0.66 mmol) were added, and the mixture was stirred at 75° C. for one hour. Dilution with ethyl acetate, washing with water and brine, drying over anhydrous magnesium sulfate, and concentration under reduced pressure gave a residue, which was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.12 g of the title compound as a colorless amorphous solid (74%).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>CN(C=O)C>[N:49]1([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(N2CCOCC2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 43 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-morpholin-4-ylaniline (0.026 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 43% yield: LCMS (ESI) m/z 367 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.8 %

Procedure:
A solution of 3.6 g (0.016 mole) of 3-cyclopentylamino-2,2-difluoro-propanoic acid ethyl ester in 3 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 3.2 g (0.016 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.47 g (0.064 mole) of sodium bicarbonate and 36 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 6.29 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-difluoro-propanoic acid ethyl ester (IV-20) as a yellow thick oil, which contained a small portion of a regioisomer. This material was used directly in the next step without further purification.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][CH:24]([N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[S:37][C:36]([C:38](OCC)=[O:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)[CH3:25].CO>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:36]3[S:37][C:33]([N:29]4[CH2:30][CH2:31][CH2:32][N:26]([CH:24]([CH3:25])[CH3:23])[CH2:27][CH2:28]4)=[CH:34][CH:35]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCCN(C(C)C)CC2)s1
Agent: C[Al](C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
Trimethylaluminium (0.751 ml, 1.50 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (148 mg, 0.60 mmol) and ethyl 5-(4-propan-2-yl-1,4-diazepan-1-yl)thiophene-2-carboxylate (178 mg, 0.60 mmol) in toluene (3.002 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The cooled reaction mixture was added to methanol (50 mL) and treated with HCL (2M aqueous solution, to pH7 or below) and purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure material. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (123 mg, 41%) as a yellow solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.O=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)C>C(O)(=O)C>[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:4]=1[NH:10][C:13]1[CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:16][CH2:17][C:18]2=1
Reactant: NNc1ccc(F)cc1Br
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC1CCCc2c1[nH]c1c(Br)cc(F)cc21
Yield: 29.5 %

Procedure:
To a suspension of 7.24 g of (2-bromo-4-fluorophenyl)hydrazine hydrochloric acid salt in 100 mL of acetic acid, 5.5 g of ethyl 2-(2-oxocyclohexyl)-acetate was added. The resulting mixture was heated to reflux for 1 h. Then 10 mL of ethanol was added and the reaction mixture was heated at reflux overnight. The solvent was evaporated and the residue was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, water, and brine successively. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography over silica gel (5% EtOAc/hexane) to afford 3.12 g of desired compound.
Reaction SMILES: ClCC[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:7]=[CH:6][N:5]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[OH:28].[CH3:29]C(C)([O-])C.[K+]>C1COCC1>[CH2:17]([CH:14]([NH:13][C:8]1[CH:7]=[C:6]([CH3:29])[N:5]=[C:4]([O:28][C:21]2[C:22]([CH3:27])=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=2[CH3:19])[C:9]=1[N+:10]([O-:12])=[O:11])[CH2:15][CH3:16])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: CCC(CC)Nc1ccnc(CCCl)c1[N+](=O)[O-]
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a mixture of (2-chloroethyl-3-nitro-pyridin-4-yl)-(1-ethyl-propyl)amine (80 mg, 0.31 mmol) and 2,4,6-trimethylphenol (43 mg, 0.31 mmol) in 2 ml of dry THF was added potassium tert-butoxide (35 mg, 0.31 mmol) and the resulting mixture was stirred at rt overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using 6:4 ratio of chloroform:hexane as eluent to give 91 mg (83%) of the title compound as yellow solid, mp 160-162° C. 1H NMR (CDCl3) δ 7.62 (d, 1H), 6.87 (s, 2H), 6.18 (s, 1H), 3.40 (m, 1H), 2.30 (s, 3H), 2.15 (s, 3H), 2.10 (s, 6H), 1.5-1.8 (m, 4H), 0.99 (t, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:19][CH2:18]2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:32][CH:33]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)cc1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2)cc1
Yield: 56.2 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(phenyl)benzamide (503.8 mg, 1.13 mmol) and acetic anhydride (0.128 ml, 1.36 mmol), the procedure of Inventive Example 94 was repeated to obtain 309.9 mg (71.0%) of the title compound in a light brown amorphous form.