Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:1]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:5][C:9]=2[CH:10]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)Cc1nc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Concentrated nitric acid (5 mL) was added to concentrated sulfonic acid (5 mL) at 0° C., and the solution was cooled thoroughly for an additional 10-15 minutes. Ethyl benzimidazole-2-acetate (Buchi, J.; Zwicky, H.; Aebi, A., Archiv. Der Pharmazie 1960, 293, 758; 1.09 g, 5.34 mmol, 1 equiv.) was added portionwise over several minutes The resulting yellow solution was stirred at 0° C. for 20 minutes then was poured carefully onto cracked ice (100 g). The pH was adjusted to 5 with cold 20% sodium carbonate (50-75 mL) and the mixture was extracted with ethyl acetate (3×50 mL). Drying (sodium sulfate), concentration, and silica gel chromatography (3:2 ethyl acetate/toluene) gave ethyl 5-nitrobenzimidazole-2-acetate (1.23 g, 92%) as a yellow solid. TLC (3:2 ethyl acetate/toluene) Rf 0.44; 1H NMR (400 MHz, CDCl3) δ 8.54 (br s, 1H), 8.21 (dd, J=8.9, 2.1 Hz, 1H), 7.58-7.70 (m, 1H), 4.31 (q, J=7.1 Hz, 2 H), 4.14 (s, 2 H), 1.35 (t, J=7.1 Hz, 3 H); IR (chloroform) 3390, 1727, 1523, 1345, 1309 cm-1 ; MS (ESMS) 250.0 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([C:25](=[O:27])[CH3:26])[CH:17]2[CH2:22][CH2:21][C:20]([CH3:23])([CH3:24])[CH2:19][CH2:18]2)[CH2:13][C@H:9]1[C:10]([N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1)=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCNCC1
Reactant: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccccc21)=[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: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)N2CCN(C)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
(4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]-L-proline (0.92 g, 2.41 mmol) obtained in Step C was dissolved in DMF (10 mL) and DIPEA (1.05 mL, 6.01 mmol) was added thereto. 1-methylpiperazine (0.32 mL, 2.89 mmol) and HBTU (0.91 g, 2.41 mmol) were also added thereto in order. After the reaction solution was stirred at room temperature for 2 hours, the solution was concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution. The extracted organic solution was dried over MgSO4, concentrated in vacuo and purified by column chromatography (eluent:MC/MeOH=10/1) to give the title compound (1.06 g, 95%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[C:23]([F:26])([F:25])[F:24])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccncc1Br
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cnccc1C(F)(F)F
Yield: 6.5 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-16c: 150 mg, 0.684 mmol) was reacted with 3-bromo-4-trifluoromethyl-pyridine (154.7 mg, 0.684 mmol), 1,4-dioxane (5 mL), copper iodide (12.96 mg, 0.0684 mmol), trans-1,2-diamino cyclohexane (23.39 mg, 0.2084 mmol) and potassium phosphate (434.6 mg, 2.05 mmol) to afford the crude product. Purification by preparative HPLC afforded 16 mg of the product (6.5% yield).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([O:38]CC)=[O:37])[CH2:31]2)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([OH:38])=[O:37])[CH2:31]2)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(C(F)(F)F)cn4)cc3C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2ncc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a reaction mixture of ethyl (3R)-1-(4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)butyl)amino)benzoyl)piperidine-3-carboxylate (4.96 g), ethanol (16 ml) and tetrahydrofuran (16 mL) was added 1M aqueous sodium hydroxide solution (15.9 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate/diisopropyl ether to give the title compound (4.37 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].OS(O)(=O)=O>>[N+:11]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:10])[C:5]=1[O:8][CH3:9])([O-:13])=[O:12]
Reactant: COc1ccc(Cl)cc1C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1c(C)cc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 41 %

Procedure:
4-Chloro-2-methylanisole (46.8 g) was added dropwise to a mixture of concentrated HNO3 (33 ml) and H2SO4 (99 ml) at 0° C. The reaction mixture was then poured into a ice water and extracted with dichloromethane. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 5% ethyl acetate in hexanes) to give 25 g (41%) of 2-nitro-4-chloro-6-methylanisole. 1H NMR (300 MHz, CDCl3) δ7.64 (d, J=2.5 Hz, 1 H), 7.40 (d, J=2.5 Hz, 1 H), 3.89 (s, 3 H), 2.36 (s, 3 H).
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS([Cl:24])(=O)=O>ClCCl>[Cl:24][CH2:11][CH:10]=[CH:9][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC/C=C/C#Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCC=CC#Cc1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (4.9 g, 31.0 mmol) and triethylamine (3.8 g, 38.0 mmol) in dry dichloromethane (200 mL) was added methanesulfonyl chloride (3.8 g, 33 mmol) dropwise. Stirring was continued at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue washed with heptane/dichloromethane (×2) to give 4.5 g (82%) crude (E)-(5-chloro-pent-3-en-1-ynyl-benzene.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a solution of (3R)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (9.0 g, 33.8 mmol) in methylene chloride (270 ml) were added methanesulfonyl chloride (2.88 ml, 37.2 mmol) and triethylamine (5.21 ml, 37.2 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford (3R)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (11.5 g, yield 99%) as a pale yellow solid.
Reaction SMILES: C1(NC(C)C)CCCCC1.C([Li])CCC.[C:16]([O:20][C:21]([CH:23]([CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:24](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].[N+:32]([C:35]1[CH:42]=[CH:41][C:38](CBr)=[CH:37][CH:36]=1)([O-:34])=[O:33]>C1COCC1.CCCCCC.CN1CCCN(C)C1=O>[CH2:30]([O:29][CH2:28][CH2:27][CH:23]([CH2:24][C:38]1[CH:41]=[CH:42][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=1)[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH3:31]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOCCC(C(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CCCCCC
Product: CCOCCC(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 67.5 %

Procedure:
To a solution of cyclohexylisopropylamine (1.42 ml) in dry THF (3 ml) at -76° C. under argon was added a 2.5M solution of n-butyllithium in hexane (3.5 ml). The resultant solution was stirred at -76° C. for 15 minutes before a solution of the product from step (b) (1 g) in dry THF (7 ml) was added dropwise. On completion of the addition, the reaction mixture was allowed to warm to 0° C. and stirred at that temperature for 15 minutes before a solution of 4-nitrobenzyl bromide (940 mg) in dry THF (3 ml) was added, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.5 ml). The resultant mixture was stirred at ambient temperature for 16 hours and then heated to reflux for 5 hours. The reaction mixture was evaporated to dryness and saturated ammonium chloride solution was added to the residue. The resultant mixture was extracted thoroughly with ethyl acetate and the combined extracts were washed with brine, dried (MgSO4) and evaporated to give a residue which was purified by flash chromatography on silica by elution with 20% ethyl acetate/hexane to give t-butyl 2-(2-ethoxyethyl)-3-(4-nitrophenyl)propionate (940 mg) as a pale yellow oil: NMR Spectrum (CDCl3) 1.19 (3H, t), 1.33 (9H, s), 1.76 (1H, m), 1.94 (1H, m), 2.78 (1H, m), 2.91 (2H, m), 3.44 (4H, m), 7.35 (2H, d), 8.13 (2H, d); Mass Spectrum m/Z 324 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:4]([F:14])[CH:3]=1.C([Li])CCC.CN(C)[CH:22]=[O:23].O>C1COCC1.C(=O)=O.CC(C)=O>[Cl:1][C:2]1[C:3]([CH:22]=[O:23])=[C:4]([F:14])[C:5]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Cl)ccc1OCC(F)(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: O
Product: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1F
Reaction time: 0.5 h

Procedure:
To 4-Chloro-2-fluoro-1-(2,2,2-trifluoro-ethoxy)-benzene (522, 0.80 g, 3.5 mmol) in THF (20 mL), cooled in dry ice/acetone bath and under an atmosphere of nitrogen, was slowly added n-butyllithium (1.60 M in Hexane, 2.30 mL). After an hour, N,N-dimethylformamide (0.298 mL, 3.85 mmol) was added to the reaction. After 30 minutes, the reaction was allowed to reach room temperature and was stirred for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound (523, 450 mg, 50%).
Reaction SMILES: B(F)(F)F.CCOCC.N[C:11]1[CH:12]=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[C:14]([CH3:17])=[N:15][CH:16]=1.COCCOC.N(OC(C)(C)C)=O.[C:47]([O:50]C(=O)C)(=[O:49])[CH3:48]>CCCCC>[C:47]([O:50][C:11]1[CH:16]=[N:15][C:14]([CH3:17])=[C:13]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[C:23]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[N:24]=[CH:25]3)=[CH:20][CH:19]=2)[CH:12]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCCCC
Solvent: CCOCC
Solvent: COCCOC
Product: CC(=O)Oc1cnc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a flask containing boron trifluoride etherate (0.100 mL, 0.789 mmol) at −15° C. (brine/ice bath) was added a solution of N-(7-(5-amino-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (119.1 mg, 0.3741 mmol) in 1,2-dimethoxyethane (1.0 mL, 9.6 mmol). tert-Butyl nitrite (67.0 uL, 0.563 mmol) was then added dropwise and the reaction mixture was stirred at −15° C. for one hour. 3 mL pentane was added and the mixture stirred for 5 minutes. The pentane layer was decanted, and the remaining oil was then dissolved in acetic anhydride (0.60 mL, 6.4 mmol) and stirred at 100° C. for 1.5 hours. The solvent was evaporated in vacuo, and the residue was suspended in 2M aqueous Na2CO3 and extracted twice with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 5-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-6-methylpyridin-3-yl acetate. This material was dissolved in tetrahydrofuran (3 mL, 40 mmol) and 1.0 M of lithium hydroxide in Water (1.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then neutralized with 10% aqueous citric acid and extracted 3× with dichloromethane. The combined organic extracts were dried over MgSO4, filtered, and evaporated in vacuo. The crude material was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 30-100% ethyl acetate in dichloromethane) followed by reverse phase HPLC to yield 3.3 mg (3%) of N-(7-(5-hydroxy-2-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=3.237, M+H=320.1, method=E; 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.17 (s, 1H), 8.49 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.6 Hz, 1H), 7.69 (d, J=9.7 Hz, 1H), 7.04 (s, 1H), 2.33 (s, 3H), 2.14-2.03 (m, 1H), 0.91-0.78 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17]N1C(=O)CCC1=O>CO>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[Cl:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 389 mg (1.79 mmol) tert-butylindole-5-carboxylate in 12 ml methanol is mixed with 335 mg (2.50 mmol) N-chlorosuccinimide and stirred at room temperature overnight. The methanol is removed by rotation and the resulting residue is taken up in 15 ml ethyl acetate. The organic phase is washed twice with 1M sodium hydrogen carbonate solution, dried on sodium sulfate and concentrated by rotation. Column chromatographic processing of the residue on silica gel (flow agent: hexane/ethyl acetate 9:1) yields a solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:17])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[F:18][CH:19]([F:36])[C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][C:23]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CCOC(C)=O.CCOCC.CN(C=O)C>[F:36][CH:19]([F:18])[C:20]1[C:25]([C:26]([NH:17][C:4]2[NH:5][C:6]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=3)=[C:2]([CH3:1])[N:3]=2)=[O:27])=[CH:24][C:23]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:22][N:21]=1
Reactant: Cc1nc(N)[nH]c1-c1ccc(C(F)(F)F)cc1
Reactant: CC(C)C(=O)NCc1cnc(C(F)F)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(=O)c2cc(CNC(=O)C(C)C)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1

Procedure:
In a thermally controlled reactor stir a mixture of 4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-amine (395 g, 1.63 mol, 1 equiv), 2-(difluoromethyl)-5-{[(2-methylpropanoyl)amino]methyl}pyridine-3-carboxylic acid (445.8 g, 1.63 mol, 1 equiv), DMF (3.16 L), DIPEA (856 ml, 4.91 mol, 3 equiv) and TBTU (630 g, 1.965 mol, 1.2 equiv) at an internal temperature of 75° C. for 18 hours. Cool the mixture; dilute with EtOAc (2.5 L); and wash with water (3×5 L) and brine (2×2.5 L). Extract the combined aqueous phases with EtOAc (2.5 L). Combine the organic extracts, and dry over MgSO4. Concentrate the to dryness to give a yellow semi-solid. Slurry this solid with Et2O (2.5 L) for 3 hours; collect the solids by filtration; and air dry for 16 hours then in vacuo at 50° C. for a further 48 hours to give the title product as a fine free flowing white solid (568 g, 66% yield). 1H NMR (MeOD-d4, 500 MHz): δ 8.63 (s, 1H), 8.13 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.67 (d, 2H, J=8.1 Hz), 7.36 (t, 1H, J=54.2 Hz), 4.47 (s, 2H), 2.52-2.45 (m, 4H), 1.13 (d, 6H, J=6.8 Hz); MS (m/z) 496 (M+1).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4].[F:15][C:16]([F:20])=[C:17]([F:19])[F:18].[OH-].[K+].O>CN(C)C=O>[CH3:1][N:2]([C:17]([F:19])([F:18])[CH:16]([F:20])[F:15])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(F)(F)C(F)F)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 80.8 %

Procedure:
A solution of 72 g of N-methyl-2-nitrobenzenesulfonamide, 35 g of tetrafluoroethylene and 4 g of powdered potassium hydroxide in 150 ml of dimethylformamide was heated at 85° for 3 hours in a pressure vessel. The reaction mixture was cooled to 25° and poured into 800 ml of water. A heavy oil was separated and the aqueous layer extracted with 150 ml of 1-chlorobutane. The heavy oil, the 1-chlorobutane extract and an additional 300 ml of 1-chlorobutane were combined and washed three times with water. The organic solution was dried over magnesium sulfate and concentrated in-vacuo to yield 85.1 g of N-methyl-N-(1,1,2,2-tetrafluoroethyl)-2-nitrobenzenesulfonamide as a viscous orange oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([CH3:9])([CH3:8])[CH2:6][SH:7].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([CH2:25]Cl)=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CO.O.C(OCC)(=O)C>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][C:22]([CH2:25][S:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH3:4])=[CH:23][CH:24]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CCl)nc1
Reactant: CC(C)(C)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)CSCc1ccc(CNC(=O)OC(C)(C)C)cn1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, add sodium methoxide (630 mg, 3.51 mmol, 30% w/w in methanol) to a stirring mixture of 2,2-dimethyl-propane-1-thiol (365 mg, 3.51 mmol) and methanol (10 mL) at room temperature and stir for 30 min. Add 3-(tert-butoxycarbonylamino-methyl)-6-chloromethyl-pyridine (450 mg, 1.76 mmol) in methanol (5 mL) and stir the mixture for 2 h. Dilute the mixture with water and ethyl acetate. Separate the layers and extract the aqueous layer with ethyl acetate. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo to obtain the desired intermediate suitable for use without additional purification. MS (APCI+) m/z: 325 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[O:25]([CH2:32][CH:33]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:33][CH2:32][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Reactant: O=CCOc1ccccc1
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CCOc3ccccc3)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with phenoxyacetaldehyde by the method of Example 1.
Reaction SMILES: Br[CH2:2][C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=3)[CH:11]=2)[C:6]2[N:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[CH3:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][C:32]1[N:33]([CH2:2][C:3]2[C:8](=[O:9])[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:26])[C:18]4[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=4)[CH:11]=3)[C:6]3[N:27]=[CH:28][CH:29]=[CH:30][C:5]=3[N:4]=2)[CH:34]=[CH:35][N:36]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(Nc1cccc(-n2c(=O)c(CBr)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1nc2cccnc2n(-c2cccc(NC(=O)c3cc(Cl)cc(Cl)c3)c2)c1=O
Yield: 47.5 %

Procedure:
The solution of 2-bromomethyl-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (105 mg) and 2-methylimidazole (171 mg) in N,N-dimethylformamide (10 ml) was stirred for 3 hours at 70° C. and 1 hour at 80° C. The mixture was poured into aqueous sodium hydrogencarbonate and extracted by ethyl acetate (100 ml). The organic layer was evaporated and chromatographed to obtain 2-[(2-methylimidazol-1-yl)-methyl]-4-[3-(3,5-dichlorobenzoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (50 mg) in brown powder form.