Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[N:7][C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[N:5]1.[C:21](OCC)(=[O:23])C>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH:8]([O:23][CH3:21])[NH:7][C:6]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)=[N:5]1
Reactant: O=c1cnc(-c2cc(Cl)cc(Cl)c2)nn1CC(F)(F)F
Reactant: CCOC(C)=O
Solvent: CO
Product: COC1NC(c2cc(Cl)cc(Cl)c2)=NN(CC(F)(F)F)C1=O
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-1,2,4-triazin-6-one (70 mg, 0.21 mmol) dissolved in 3 mL of a 1:1 mixture of ethyl acetate and methanol was added a small scoopula of neutral alumina. After stirring for 20 minutes, the mixture was filtered through a small plug of glass wool and concentrated. The product (80 mg) was afforded in 96% purity and 100% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.O>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)C(=O)c3cc(F)ccc32)cc1
Reaction time: 0.25 h
Yield: 80 %

Procedure:
5-Fluoro-1H-indole-2,3-dione (956 mg, 5.79 mmol, 1 eq) was added as a solution in dry DMF to a stirred slurry of sodium hydride (278 mg, 11.6 mmol, 2 eq) in dry DMF drop wise over 15 minutes under an inert atmosphere with adequate pressure release to accommodate H2 evolution. The resulting mixture was stirred for 1 hour and p-methoxybenzyl chloride was added via syringe to the reaction. The solution was then stirred ca 2 hours and worked up by addition of water followed by extraction into ethyl acetate. The organic layer was washed twice with water and then dried over MgSO4. Column chromatography with ethyl acetate/hexane afforded 5-Fluoro-1-(4-methoxy-benzyl)-1H-indole-2,3-dione as a red solid (1.3 g, 80% yield). 1H NMR (CDCl3) δ (ppm): 7.3-7.24 (m, 3H), 7.20 (td, J=8.7, 2.7 Hz, 1H), 6.9-6.86 (m, 2H), 6.76 (dd, J=8.6, 3.6 Hz, 1H), 3.81 (s, 2H), 3.78 (s, 3H). LC/MS=286.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:19]1[N:23]2[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[N:27][C:22]2=[N:21][CH:20]=1)CCC>>[F:13][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[N:23]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[N:27][C:22]3=[N:21][CH:20]=2)=[CH:7][C:6]=1[C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Fc1ccc(Br)cc1-c1nccs1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1nccs1

Procedure:
2-(5-Bromo-2-fluorophenyl)thiazole (50 mg, 0.2 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.3 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol gave 3-[4-fluoro-3-(thiazol-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 7.29 (1H, d, J 7), 7.44 (1H, dd, J 11 and 9), 7.56-7.62 (2H, m), 7.97 (1H, dd, J 3 and 2), 8.15 (1H, s), 8.57 (1H, dd, J 7 and 2), 8.86 (1H, d, J 7); m/z (ES+) 364 (M++H).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[CH:5]1([NH:11][C:12]2[CH:13]=[C:14]([C@@H:18]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH:5]1([NH:11][C:12]2[CH:13]=[C:14]([C@@H:18]([N:32]3[CH2:37][CH2:36][N:35]([CH2:1][CH2:2][CH3:3])[CH2:34][CH2:33]3)[C:19]3[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CCC=O
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(NC3CCCCC3)c2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCN1CCN([C@@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC3CCCCC3)c2)CC1
Reaction time: 8 h
Yield: 61498.2 %

Procedure:
To a room temperature solution of propionaldehyde (40.6 μL 0.56 mmol) and COMPOUND 27 (250 mg; 0.56 mmol) in 1,2-dichloroethane was added sodium triacetoxy borohydride (380 mg; 1.79 mmol) and acetic acid (31.9 μL; 0.56 mmol). The reaction mixture was stirred overnight then was washed with saturated sodium bicarbonate, followed by water. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 73 (169 g; 62% yield). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.99 (t, J=7.91 Hz, 2H), 1.10-1.16 (m, 3H), 1.28-1.33 (m, 4H), 1.61-1.65 (m, 4H), 1.75-1.79 (m, 4H), 1.83-1.90 (m, 4H), 2.97-3.01 (m, 2H), 3.13-3.15 (m, 2H), 3.17-3.28 (m, 8H), 3.42-3.46 (m, 2H), 3.52-3.54 (m, 1H), 5.08 (s, 1H) 7.24-7.29 (m, 3H), 7.48-7.51 (m, 3H), 7.55-7.57 (m, 1H), 7.62 (d, J=7.42 Hz, 1H). Found: C, 56.59; H, 7.89; N, 8.25. C31H46N4O×4.3HCl×0.6H2O has C, 56.56; H, 7.89; N, 8.51%. [α]D16=+14.5 deg [c 0.50, MeOH].
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:21][CH2:22][CH2:23]Br)(=[O:20])[CH3:19].[I-].[Na+]>CN(C)C=O.O>[C:18]([O:21][CH2:22][CH2:23][O:11][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]([F:10])=[CH:8][CH:7]=1)(=[O:20])[CH3:19]
Reactant: O=Cc1c(O)ccc(F)c1F
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc(F)c(F)c1C=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a suspension of 2,3-difluoro-6-hydroxybenzaldehyde (2.64 g) and potassium carbonate (3.47 g) in N,N-dimethylformamide (33 mL) were added 2-acetyloxyethyl bromide (2.03 mL) and sodium iodide (0.5 g), and the mixture was stirred at 60° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 6-(2-acetyloxyethoxy)-2,3-difluorobenzaldehyde (3.35 g). This material was dissolved in tetrahydrofuran (27 mL). To the solution were added water (2.7 mL) and sodium borohydride (0.52 g) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes, and then stirred at room temperature for 1 hour. The reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 6-(2-acetyloxyethoxy)-2,3-difluorobenzyl alcohol (3.2 g). To the solution of the obtained 6-(2-acetyloxyethoxy)-2,3-difluorobenzyl alcohol (1.81 g) and triethylamine (0.97 g) in ethyl acetate (25 mL) was added methanesulfonyl chloride (0.63 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The insoluble material was removed by filtration, and the insoluble material was washed with ethyl acetate (15 mL). The filtrate and washing were combined. To the solution was added lithium bromide (1.92 g), and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was poured into water, and the organic layer was separated. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.12 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][C:7]=2[CH:36]=1)#[N:2].[CH3:37]I.[H-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([CH3:37])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][C:7]=2[CH:36]=1)#[N:2]
Reactant: CI
Reactant: CCOC(=O)C(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (±)-tert-butyl 4-(1-(5-cyanobenzo[d]oxazol-2-yl)-2-ethoxy-2-oxoethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-B) (139.5 mg, 0.285 mmol) in DMF (2.850 mL) were added successively MeI (0.080 mL, 1.282 mmol) and NaH (34.2 mg, 0.855 mmol) at 0° C. After stirring for 2.5 hrs at this temperature another additional aliquot of MeI (0.045 mL, 0.57 mmol) were added to the mixture. The mixture was allowed to stir at room temperature overnight. The reaction mixture was quenched with a saturated aq. solution of ammonium chloride at 0° C. and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic layers were concentrated to give crude product that was purified via FCC: Heptane/AcOEt:100/0 to 50/50 to obtain the title compound. MS (ESI+) m/z 504.38 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]>>[CH3:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]3[NH:30][C:11]([C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=5)[NH:7][N:6]=4)=[N:31][C:26]=3[CH:25]=2)[CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(N)c2)ccn1
Product: CNC(=O)c1cc(Oc2ccc3[nH]c(-c4n[nH]c5ccc(F)cc45)nc3c2)ccn1

Procedure:
The title compound was synthesized from 5-fluoro-1H-indazole-3-carbaldehyde and 4-(3,4-diamino-phenoxy)-pyridine-2-carboxylic acid methylamide using the method described above in Example 4. LC/MS (m/z) 403.1 (MH+), Rt 2.26 minutes.
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:26]([O:25][C:23]([CH:22]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[N:8]1[C:4]2[CH:3]=[C:2]([I:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(I)ccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21
Reaction time: 2 h

Procedure:
3.00 g (8.33 mmol) of tert-butyl 5-iodo-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIb) were dissolved in dry DMF (50 ml) in a heat-dried flask under a nitrogen atmosphere. 364 mg (5.09 mmol) of sodium hydride (60% suspension in mineral oil) were added at 0° C. while stirring, and the reaction solution was then stirred at room temperature for 30 min. After renewed cooling in an ice bath, 2.37 g (8.75 mmol) of tert-butyl bromo-phenylacetate were added, and the mixture was stirred while cooling in ice for 1 h and then at room temperature for 2 h. The reaction solution was diluted with ethyl acetate, mixed with 10% aqueous ammonium chloride solution and then extracted with ethyl acetate (3×). The combined organic phases were washed with water and saturated NaCl solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 10-30% ethyl acetate in cyclohexane). Yield: 4.20 g (91%) of colorless solid
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][N:17]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20](=[O:27])OC2=O)[CH:13]=[CH:12][N:11]=1)=[O:8])[CH3:2].Cl.[C:31]([C:33]1[CH:41]=[CH:40][C:36]([CH2:37][O:38][NH2:39])=[CH:35][CH:34]=1)#[N:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][NH:17][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:20](=[O:27])[NH:39][O:38][CH2:37][C:36]2[CH:40]=[CH:41][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[CH:13]=[CH:12][N:11]=1)=[O:8])[CH3:2]
Reactant: N#Cc1ccc(CON)cc1
Reactant: CCOC(=O)CNC(=O)Nc1cc(Cn2c(=O)oc(=O)c3ccccc32)ccn1
Agent: Cl
Product: CCOC(=O)CNC(=O)Nc1cc(CNc2ccccc2C(=O)NOCc2ccc(C#N)cc2)ccn1

Procedure:
To a stirred solution of 1-(2-amino-pyridin-4-ylmethyl)-1H-benzo[d][1,3]oxazine-2,4-dione (600 mg, see preparation 7b) in pyridine (7 ml) was added isocyanato-acetic acid ethyl ester (0.4 ml). The reaction mixture was stirred at room temperature for 3 hours, and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting oil was treated with EtOAc (3 ml) and gave a precipitate that was isolated by filtration and dried in vacuo, affording {3-[4-(2,4-Dioxo-4H-benzo[d][1,3]oxazin-1-ylmethyl)-pyridin-2-yl]-ureido}-acetic acid ethyl ester (0.53 g). Step 2: This anhydride intermediate was converted into the title compound by reaction with O-(4-cyanobenzyl)hydroxylamine hydrochloride (see preparation 10), using general procedure 1A. 13C-NMR (DMSO-d6) δ 170.3, 167.4, 154.8, 153.5, 151.4, 148.5, 146.7, 141.8, 132.7, 132.2, 129.1, 128.0, 118.6, 115.4, 114.8, 112.9, 111.5, 110.7, 109.3, 76.0, 60.3, 45.2, 41.2, 14.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCCC1

Procedure:
Using analogous procedures to those described in Note [33] immediately above, 1-(tert-butoxycarbonyl)-L-proline was reacted with piperidine to give (2S)-1-(tert-butoxycarbonyl)-2-piperidinocarbonylpyrrolidine which was deprotected and reacted with 2-bromoethanol. There was thus obtained the required starting material; NMR Spectrum: (CDCl3) 1.5–1.9 (m, 10H), 1.9–2.0 (m, 1H), 2.1–2.2 (m, 1H), 2.4–2.5 (m, 1H), 2.55–2.65 (m, 1H), 2.8–2.9 (m, 1H), 3.3–3.7 (m, 6H), 4.3 (br s, 1H); Mass Spectrum: M+H+ 227.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:13][CH2:14][CH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(CCCO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
N-piperazine carboxylic acid ethyl ester (25.50 g, 161.39 mmol), 3-bromo-1-propanol (22.43 g, 161.39 mmol), potassium carbonate (55.68 g, 403.48) and anhydrous acetonitrile (200 mL) were placed in a 500 mL round bottom flask, heated for refluxing and stirred overnight. The reaction was cooled down to room temperature, filtered, concentrated and subjected to a column chromatography (eluting agent: dichloromethane/methanol/triethylamine system, v/v/v 100:1:0.5) to obtain a light yellow oily substance, 26.60 g, yield 76.3%, which was directly used in the next step of reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(C(F)(F)F)c2)cc1
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(C(F)(F)F)c2)cc1
Yield: 101.4 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-trifluoromethylphenyl)benzamide (256.0 mg, 0.474 mmol) and acetic anhydride (0.13 ml, 1.40 mmol), the procedure of Inventive Example 94 was repeated to obtain 267.0 mg (96.2%) of the title compound in a colorless amorphous form.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[N:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1)[CH2:29][CH2:30][CH3:31]
Reactant: Brc1cnc(N2CCOCC2)cn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N2CCOCC2)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To compound 4-(5-bromopyrazin-2-yl)morpholine (0.25 g) taken in dry THF (5 ml) and cooled to −78° C., n-butyl lithium (0.4 ml, 1M solution in Hexane) was added stirred for 2 hrs at −78° C. To the above reaction mixture tri-n-butyl tin chloride (1.1 mmol) was added drop wise at −78° C. Reaction mixture was stirred at −78° C. for one hour, quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×15 ml). The organic layer was washed with water (20 ml) followed by brine, dried over anhydrous sodiumsulphate and concentrated using rotary evaporator. The resulting crude was purified by column chromatography to afford 4-(5-(tributylstannyl)pyrazin-2-yl)morpholine as pale yellow color liquid.
Reaction SMILES: [OH:1][C:2]1[C:3](I)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36]>CN(C=O)C.O.[Pd](Cl)Cl>[OH:1][C:2]1[C:3]([C:35](=[CH2:36])[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1ccc(O)c(I)n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C(=O)OCC)c1nc(C)ccc1O
Temperature: 120 °C

Procedure:
To a solution of 3-hydroxy-2-iodo-6-methylpyridine (1.175 g, 5.0 mmol) in DMF (9.5 ml) and water (0.5 ml) were added potassium acetate (1.23 g, 12.5 mmol), triphenylphosphine (105 mg, 0.40 mmol), palladium chloride (36 mg, 0.20 mmol) and ethyl acrylate (1.63 ml, 1.50 g, 15.0 mmol). The mixture was placed under nitrogen and heated at 120° C. for 1.5 h. The mixture was cooled, filtered from deposited palladium black, and added to water (100 ml). The product was extracted into ethyl acetate (3×30 ml). The combined extracts were washed with water (2×25 ml) and with brine (25 ml), then dried over sodium sulphate and evaporated. This left a tan solid, the product (951 mg, 91%). mp 192°-195° C. (dec)
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[N+:20]([O-:22])=[O:21].C=O.C(O)C>Cl.O>[N+:20]([C:5]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:15]2)=[CH:9][C:4]=1[CH:3]=[O:2])([O-:22])=[O:21]
Reactant: COC(OC)c1cc(N2CCC(NC(C)=O)CC2)ccc1[N+](=O)[O-]
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])c(C=O)c2)CC1

Procedure:
0.3 Gram of 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde dimethylacetal, 5 ml of formalin, 1 ml of ethanol and 2 drops of concentrated hydrochloric acid were refluxed by heating. After the reaction was completed, the solvent was removed by evaporation to obtain the residue, then water was added to the residue. The crystals formed were collected by filtration to yield 0.22 g of 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:29])[C:18](=[CH:24][NH:25][CH:26]3[CH2:28][CH2:27]3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12](F)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]3[C:13]([C:17](=[O:29])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:25]3[CH:26]3[CH2:28][CH2:27]3)=[CH:14][C:15]=2[F:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCN(C(C)=O)CC2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2cc(C3CCN(C(C)=O)CC3)c(F)cc2c1=O
Reaction time: 1.5 h

Procedure:
A solution of 3.49 g (8.30 mmol) ethyl 4-(1-acetyl-4-piperidinyl)-α-[(cyclopropylamino)methylene]-2,5-difluoro-β-oxobenzenepropionate in 35 ml of t-butyl alcohol was treated with 0.93 g (8.30 mmol) potassium t-butoxide and stirred in an oil bath at 65° for 1.5 hours. The mixture was evaporated under vacuum and the residue extracted with 0.5 N hydrochloric acid. The organic layer was dried (MgSO4) and evaporated. The title compound was isolated by chromatography on silica gel and crystallization from toluene, mp 195°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13](O)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:9]1=[O:22].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[CH3:23])[CH2:32][CH2:33]2)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:20])[CH3:21])(=[O:17])=[O:18])[C:9]1=[O:22]
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccccc2Cl)C1=O
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccccc3Cl)CC2)c1

Procedure:
In analogy to example 1, (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 519.3 ([M+H]+)