Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7](=[O:12])[CH2:8][NH:9][C:10](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:26][C:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:23]=[CH:22][C:5]=2[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:7](=[O:12])[CH2:8][N:9]=1
Reactant: COc1ccc(CN2C(=O)CNC(=O)c3cc(Cl)ccc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CN2C(=O)CN=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 120 %

Procedure:
In a 1 L 3-neck RBF equipped with magnetic stir bar, condenser and N2 inlet, C2 (45 g, 0.136 mol) was suspended in 400 mL of toluene. To this was added N,N-dimethylanaline (33 g, 0.272 mol) followed by the addition of POCl3 (23 g) and the reaction stirred for 3 min (RT). Reaction flask was placed into a 90° C. oil bath and the reaction mixture was heated for 5 h and then cooled. The reaction was quenched by adding 450 mL of ice water and stirred for 15 min. Organic layer was separated and quickly washed with cold water (2×250 mL) and brine (300 mL). Organic layer was dried over MgSO4, filtered and concentrated on a rotary evaporator to give 57 g of black crude product. Crude product was used for next step with no further purification. Yield 87.5%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].[CH:11]([Sn](CCCC)(CCCC)CCCC)=[CH2:12].CCOCC.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:11]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9])=[CH2:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)c1ccncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: C=Cc1cnccc1N(C)C
Temperature: 100 °C
Yield: 117.2 %

Procedure:
A mixture of the 3-bromo-4-dimethylaminopyridine prepared in Example 214A (1.29 g, 6.39 mmol) vinyltributyltin (2.23 g, 7.02 mmol), bis(triphenylphosphine)palladium(II) chloride (224 mg, 0.32 mmol) in toluene (10 mL) was heated at 100° C. for 12 hours. To the stirring reaction mixture at room temperature was added ether (30 mL), water (0.2 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL). The resulting mixture was filtered through silica gel (15 g), rinsed with ethyl acetate, and concentrated in vacua. The residue was purified by column chromatography (50% ethyl acetate-hexanes, then ethyl acetate) to give 3-vinyl-4-dimethylaminopyridine (1.11 g, contaminated with about 10 mol % of tributyltin. derivatives). 1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 8.26 (d, 1H), 6.77 (dd, 1H), 6.70 (d, 1H), 5.65 (dd, 1H), 5.29 (dd, 1H), 2.87 (s, 6H).
Reaction SMILES: Cl.N[C@@H]1C[C@H](NC2C(C)=NC3C(N=2)=C([C:18]2[NH:26][C:25]4[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=4[CH:19]=2)C=CC=3)C1.ClC(Cl)(Cl)S(OCC(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[NH:26]1[C:25]2[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=2[CH:19]=[CH:18]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1C[C@@H](N)C1
Agent: Cl
Agent: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1NCCc2[nH]ccc21
Temperature: 110 °C
Yield: 39.1 %

Procedure:
A solution of 2-(3-((cis-3-aminocyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (Example 435; 27.4 mg, 0.069 mmol), 2,2,2-trifluoroethyl trichloromethanesulfonate (Oakwood Products, Inc., West Columbia, S.C.; 0.073 mL, 0.446 mmol), and DIPEA (0.120 mL, 0.686 mmol) in a mixture of THF (1.0 mL) and DMF (1.0 mL) was heated in a sealed flask at 110° C. for 30 min. The reaction mixture was then cooled to RT, concentrated onto silica gel, and chromatographically purified (silica gel, 10-100% (3:1 EtOAc-EtOH)/hexanes). The product-containing fractions were concentrated in vacuo, and the residue was taken up in 5% MeOH/DCM (40 mL), sequentially washed with half-saturated aqueous NaHCO3 (30 mL) and water (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 2-(2-methyl-3-(1s,3s)-3-((2,2,2-trifluoroethyl)amino)cyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (11.8 mg, 0.027 mmol, 39% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 12.57 (1H, br. s.), 7.94 (1H, dd, J=7.5, 1.1 Hz), 7.68 (1H, dd, J=8.1, 1.1 Hz), 7.41 (1H, t, J=7.8 Hz), 7.14 (1H, d, J=2.2 Hz), 5.31 (1H, br. s.), 5.16 (1H, d, J=4.7 Hz), 4.13-4.27 (1H, m), 3.68 (2H, td, J=6.9, 2.4 Hz), 3.32-3.43 (1H, m), 3.23 (2H, q, J=9.4 Hz), 3.01-3.08 (2H, m), 2.99 (2H, t, J=6.8 Hz), 2.59 (3H, s), 1.80-1.94 (2H, m). 19F NMR (376 MHz, CDCl3) δ ppm −71.65 (3F, br. s.). m/z (ESI, +ve) 445.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([I:7])[N:6]=1.S(=O)(=O)(O)O.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[NH:6][C:5]([I:7])=[C:4]([N+:13]([O-:15])=[O:14])[N:3]=1
Reactant: Clc1nc(I)c[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1nc(Cl)[nH]c1I
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
2-Chloro-4-iodoimidazole (431 mg) was suspensed in concentrated nitric acid (d. 1.38) (2.5 ml), under ice-cooling, concentrated sulfuric acid (2.5 ml) was added, and stirred at a room temperature for 6 hours. Then, the diposited matters were collected by filtration, and dried, there was obtained 2-chloro-5-iodo-4-nitroimidazole (348 mg, yield: 67.0%) as yellow solid product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=2)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:10]=[C:9]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH3:20])[CH:13]=2)[C:26]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:32])[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCOc1cccc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cccc(N(C(=O)CCC(=O)O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Temperature: 140 °C
Yield: 39.3 %

Procedure:
A mixture of 5 g (0.015 mole) of 2,6-di-tertiarybutyl-4-(3'-ethoxyanilino)phenol and 1.5 g (0.015 mole) of succinic anhydride was heated under a nitrogen atmosphere at 140° C. for two hours. The reaction was cooled to room temperature and the resulting glass was diluted with water. The addition of 100 ml of 10% sodium hydroxide failed to give a solution so the mixture was acidified with 10% hydrochloric acid. The resulting solid was collected and then recrystallized first from a mixture of ethanol and water and then from a mixture of diethyl ether and hexane to give 2.6 g of tan solid 3-[N-(3,5-di-tertiary-butyl-4-hydroxyphenyl)-N-(3-ethoxyphenyl)carbamoyl]propionic acid, m.p. 128°-130° C. Analysis: Calculated for C26H35NO5 : % C, 70.7; % H, 8.0; % N, 3.2; Found: % C, 70.5; % H, 7.8; % N, 3.4.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH2:31]O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2].CCN(S(F)(F)[F:39])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:30][CH2:31][F:39])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(CCO)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CCF)CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C

Procedure:
To 500 mg (10.5 mmol) trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide in 6 ml CH2Cl2 were added 0.2 ml (1.6 mmol) DAST at −78° C. After 3.5 h at that temperature additional 0.2 ml (1.6 mmol) DAST were added and the mixture was slowly warmed to RT over night. The solution was added to a cooled aqueous solution of Na2CO3 and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO4. Column chromatography CH2Cl2/MeOH 98:2 yielded 125.4 mg (25%) trans-N-(4-{5-[Ethyl-(2-fluoro-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as brown oil, MS: 481 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[Na+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[CH:9][N:8]([S:21]([C:18]3[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1c[nH]c2ncc(Br)cc12
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.1 %

Procedure:
To a solution of 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (B-6-1) (1.2 g, 5.68 mmol) in THF (30 mL) was added NaH (0.34 g, 8.5 mmol) under N2 at 0° C., 4-bromophenylsulfonyl chloride (1.2 g, 6.8 mmol) was added 30 minutes later. The mixture was stirred at room temperature for 1.5 h. TLC (Petroleum ether: EtOAc=5:1) showed that the reaction was complete. Saturated aqueous NaCl (10 mL) was added, and the mixture was filtered to give 5-bromo-3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-2) (0.8 g) as a white solid. The organic layer was separated from the filtrate, concentrated to 8 mL, then filtered to give 5-bromo-1-(4-bromophenylsulfonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine (0.5 g). Two batches were combined to give 5-bromo-3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (B-6-2) (1.3 g, 65.2%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3Nc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (500 mg, 1.9 mmol), aniline (350 mg, 3.8 mmol) and p-toluenesulfonic acid (catalytic) in toluene (15 mL) was heated at reflux for 16 h with a Dean-Stark trap in place. The reaction was cooled, concentrated, and the imine was purified by flash column chromatography on silica (gradient of 5% to 50% ethyl acetate/hexanes). The imine was dissolved in methanol (10 mL) and sodium borohydride (140 mg, 3.8 mmol) was added portionwise. The reaction was stirred for 30 min and quenched with water, concentrated, and diluted with ethyl actetate. The organic phase was separated, absorbed onto diatomaceous earth and purified by flash column chromatography on silica (gradient of 2% to 20% ethyl acetate/hexanes) to provide 6-bromo-N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine as a brown oil. 1H-NMR (DMSO-d6): δ 8.04 (s, 1H), 7.61 (s, 1H), 7.25-7.21 (m, 4H), 6.80-6.72 (m, 3H), 4.84-4.78 (m, 1H), 3.86-3.82 (m, 1H), 2.27-2.21 (m, 2H), 2.08-2.00 (m, 1H), 1.89-1.78 (m, 3H). The oil was dissolved in diethyl ether and HCl (1.0 M in diethyl ether) was added. The resulting precipitate was collected by filtration to provide 6-bromo-N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (352 mg, 51%) as a yellow solid. 1H-NMR (DMSO-d6): δ 11.12 (s, 1H), 7.58 (s, 1H), 7.26 (d, 1H), 7.15-7.13 (m, 3H), 6.88-6.78 (m, 2H), 6.72-6.64 (m, 1H), 4.82-4.79 (m, 1H), 2.69-2.45 (m, 2H), 1.96-1.90 (m, 2H), 1.83-1.73 (m, 2H); MS m/z (M−1) 339, 341.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([C:17]([O:19]C)=[O:18])[C:10](=[CH:15][CH:16]=1)[C:11]([O:13]C)=[O:12])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].Cl>CO>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10](=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(C(=O)OC)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCOc1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
Dimethyl 4-pentyloxyphthalate (3.0 g, 10.7 mmol) was dissolved in methanol (20 ml), and a 1N aqueous sodium hydroxide solution (25 ml) was added to this solution. The mixture was stirred at room temperature for 6.5 hours. A 3N aqueous hydrochloric acid solution (20 ml) was added to this reaction mixture. The mixture was extracted with ethyl acetate (40 ml×3), and washed with saturated brine (30 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 4-pentyloxyphthalic acid. This crude product was not further purified, but used in the next reaction.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].Cl[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12]>[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:12])[CH:15]=[CH2:16]
Reactant: CSCC[C@@H](N)C(=O)O
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N[C@H](CCSC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 15.00 g D-methionine in 25.2 ml 4N sodium hydroxide cooled to about 0° C. is added, with stirring, 15.60 ml allyl chloroformate and 41.49 ml 4N sodium hydroxide. After the addition is completed, the reaction is stirred for an additional ten minutes at 0° C. and then allowed to warm to room temperature for an additional 20 minutes. The reaction mixture is then washed twice with ethyl ether. The aqueous layers are separated, acidified to pH2 with concentrated hydrochloric acid and then refrigerated for one hour. The cooled solution is then extracted three times with 100 ml portions of ethyl ether. The ether extracts are combined, dried over anhydrous sodium sulfate and the solvents removed under vacuum to afford the title product having
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10](=S)[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].[N:31]([Si](C)(C)C)=[N+:32]=[N-:33].C(OCC)(=O)C>ClCCl.[Fe](Cl)(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:33]=[N:32][N:31]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=S)NCc3ccncc3)c(=O)c1Br)C2(C)C
Agent: Cl[Fe](Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(Cc3nnnn3Cc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 23.4 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)ethanethioamide (38 mg, 0.077 mmol) in dichloromethane (1 mL) was mixed with azidotrimethylsilane (41 μL, 0.308 mmol) and iron trichloride (30 mg, 0.185 mmol) at room temperature and stirred at room temperature for 17 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=50/1) to give the desired product (9 mg, 24% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[C:4]([F:15])[CH:3]=1.[F:16][C:17]([F:49])([F:48])[CH2:18][NH:19][C:20]([C:22]1[C:31](=[O:32])[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH:23]=1)=[O:21].CN(C)C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CC(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:15][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][CH:38]=[C:33]([N:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][N:26]=4)[C:31](=[O:32])[C:22]([C:20]([NH:19][CH2:18][C:17]([F:48])([F:49])[F:16])=[O:21])=[CH:23]3)[CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]1[CH2:10][CH:9]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CC1(C)OB(c2cccc(-n3cc(C(=O)NCC(F)(F)F)c(=O)c4cccnc43)c2)OC1(C)C
Reactant: COC(=O)C1CC1c1ccc(Br)cc1F
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COC(=O)C1CC1c1ccc(-c2cccc(-n3cc(C(=O)NCC(F)(F)F)c(=O)c4cccnc43)c2)cc1F

Procedure:
To a solution of (+)-methyl 2-(4-bromo-2-fluorophenyl)cyclopropanecarboxylate from step 8 (1.2 eq) and boronate ester from step 4 (1 eq) in DMF-iPrOH (1:1, 0.1M), was added tris(dibenzylideneacetone)dipalladium(0) (0.055 eq), 2-(dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (0.13 eq) and a sodium carbonate solution (2M, 4 eq) The reaction mixture was heated at 78° C. for 2 h. The reaction mixture was filtered on Celite and silica gel (1:1) and washed with EtOAc. The filtrate was concentrated in vacuo and remaining solvents were distilled in vacuo. The resulting yellow solid is stirred vigourously in ether. The residue then isolated by filtration and washed with ether. Mother liquors were further purified by flash chromatography (toluene/EtOAc, 100:0 to 70:30).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[N+:15]([C:18]1[N:19]=[CH:20][NH:21][CH:22]=1)([O-:17])=[O:16].O>C(#N)C>[N+:15]([C:18]1[N:19]=[CH:20][N:21]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2=[O:8])[CH:22]=1)([O-:17])=[O:16]
Reactant: O=C1CCCCC1Cl
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1CCCCC1n1cnc([N+](=O)[O-])c1
Yield: 56.2 %

Procedure:
84.0 ml (0.736 mol) of 2-chlorocyclohexanone and 92.54 g (0.670 mol) of potassium carbonate were added to a suspension of 75.16 g (0.885 mol) of 4-nitroimidazole in 1 l of acetonitrile. The obtained mixture was heated under reflux for 18 hours and cooled by allowing to stand, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The obtained organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was triturated with ethyl acetate to give 86.46 g of the title compound as a light-brown powder (yield: 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].[Cl:14][CH:15]([Cl:19])[C:16](Cl)=[O:17]>C(OCC)(=O)C>[Cl:14][CH:15]([Cl:19])[C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:17]
Reactant: Nc1ccc(F)cn1
Reactant: O=C(Cl)C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)cn1)C(Cl)Cl
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
To 2-amino-5-fluoropyridine (250 mg) in ethyl acetate (10 mL), dichloroacetyl chloride (279 μL) was added at room temperature, followed by stirring at 60-70° C. for 2.5 hours. The reaction mixture was cooled, and saturated aqueous sodium hydrogencarbonate was added thereto for partitioning the mixture. The resultant organic layer was dried over magnesium sulfate anhydrate. The solvent was distilled away under reduced pressure, to thereby give the title compound (438 mg) as acrude product.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.[NH2:19][C:20]1[C:21]2[CH:34]=[C:33]([C:35]([NH:37][N:38]([CH3:45])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[S:32][C:22]=2[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[N:24]=1.CN1CCN(CC2C=CC(C(Cl)=O)=CC=2)CC1.O>N1C=CC=CC=1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[NH:37][C:35]([C:33]1[S:32][C:22]2[N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[N:24]=[C:20]([NH:19][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][C:10]([CH2:9][N:6]4[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)=[CH:11][CH:12]=3)[C:21]=2[CH:34]=1)=[O:36]
Reactant: CN1CCN(Cc2ccc(C(=O)Cl)cc2)CC1
Reactant: CN(NC(=O)c1cc2c(N)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN1CCN(Cc2ccc(C(=O)Nc3nn(C(=O)OC(C)(C)C)c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
391 mg (1.55 mmol) of 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride hydrochloride are added to a solution of 0.30 g (0.77 mmol) of tert-butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 16 mL of pyridine under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, a further 294 mg (1.16 mmol) of 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride are then added and stirring is continued for 5 hours. The reaction mixture is then cooled to a temperature in the region of 10° C. and then treated with 50 mL of water. The mixture is extracted twice with 100 mL of ethyl acetate. The organic phases are combined, washed with water to neutral pH, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum (3 kPa) at a temperature in the region of 30° C. The residue is purified by chromatography on a cartridge of 25 g of silica gel (0.015-0.040 mm), eluting successively with dichloromethane/methanol mixtures (98/2 by volume, and then 97/3, then 96/4 and finally 95/5) at a flow rate of 15 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (3 kPa) at a temperature in the region of 30° C. 0.14 g of tert-butyl 5-(N′-methyl-N′-phenylhydrazinocarbonyl)-3-[4-(4-methylpiperazin-1-ylmethyl)benzoylamino]thieno[2,3-c]pyrazole-1-carboxylate is thus obtained in the form of an off-white solid melting at 218° C. tert-Butyl 3-amino-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate is described in example 8. 4-(4-Methylpiperazin-1-ylmethyl)benzoyl chloride may be prepared according to patent WO 03/066 613 A1.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13]Cl)[N:8]=[C:7](C(Cl)(Cl)Cl)[N:6]=1>CO>[CH:11]1([C:9]2[N:10]=[C:5]([NH2:4])[N:6]=[C:7]([O:2][CH3:1])[N:8]=2)[CH2:13][CH2:12]1
Reactant: Nc1nc(CCCCl)nc(C(Cl)(Cl)Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(C2CC2)n1
Temperature: 60 °C
Reaction time: 1.33 h
Yield: 12.7 %

Procedure:
To a solution of 10.8 g of sodium methylate in 50 ml of methanol are added 28.9 g of 2-amino-4-(3-chloropropyl)-6-trichloromethyl-1,3,5-triazine, and the mixture is stirred at 60° C. for 80 minutes. The formed suspension is filtered under suction, diluted with 250 ml of water, and extracted 3 times with 200 ml of ethylene chloride each time. The organic phases are dried, filtered, and concentrated by evaporation. The oil which remains in purified through a silica gel column, the eluant is evaporated off to leave 2.1 g of the title product, which is recrystallised from ether/chloroform, m.p. 158°-159° C.