Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na].[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O)([O-:31])=[O:30]>C(O)C>[N+:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:31])=[O:30]
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Na]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1C=Cc1ccccc1
Reaction time: 8 h

Procedure:
The triphenylphosphonium salt of benzyl chloride (38.9 g., 0.10 mole) is added to a solution of sodium (3.0 g.) in ethanol (200 ml.). The resulting solution is treated with 2-nitrobenzaldehyde (16 g., 0.10 mole) and stirred overnight. The mixture is filtered, washed with water and extracted with dichloromethane. The extracts are evaporated to a dark residue which is extracted with carbon tetrachloride, then these extracts are concentrated and passed through a column of alumina, eluting with hexane and carbon tetrachloride to give a yellow oil, 2-nitrostilbene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:25](O)=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[O:26])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cc(Cl)cc(C(=O)O)c1O

Procedure:
A solution of 5-chloro-2-hydroxybenzoic acid (102 g) and hexamethylenetetramine (166 g) in trifluoroacetic acid is heated overnight. Dilute hydrochloric acid is added to the mixture and the mixture is heated. After cooling, the precipitates are collected by filtration, whereby 5-chloro-3-formyl-2-hydroxybenzoic acid (96.9 g) is obtained. m.p. 218° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.CN.[CH2:12]([N:14](CC)CC)C>>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:14][CH3:12])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CCN(CC)CC
Agent: CN
Product: CNc1ncnc(Cl)c1N

Procedure:
5-Amino-4,6-dichloropyrimidine (15.0 g, 91.4 mmol) and methylamine (2M solution in THF, 5 eq) were initially charged, and triethylamine (27.76 g, 274 mmol) was added. The mixture was stirred under reflux until the conversion was complete (about 3 hours). The reaction mixture was then concentrated, and water was added to the residue. The pH was adjusted to 7-8 using saturated Na—HCO3 solution. The mixture was extracted 3× with methylene chloride, the combined organic phases were dried over sodium sulphate and filtered and the solvent was removed under reduced pressure.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:23])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:23])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)CCc1ccc(OC)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(CCc2ccc(OC)cc2)[nH]n1

Procedure:
Hydrazine hydrate (0.513 mL, 10.6 mmol) was added to a stirring room temperature solution of 22 (2.9241 g, 10.5 mmol) in EtOH (10.6 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (45 min): The reaction was concentrated and crystallized from EtOH to obtain 23. 1H (CDCl3, 400 MHz): δ 11.67 (1H, broad s), 7.06 (2H, d, J=8.3 Hz), 6.78 (2H, d, J=8.3 Hz), 6.57 (1H, s), 4.30 (2H, q, J=7.0 Hz), 3.76 (3H, s), 2.98 (2H, t, J=7.7 Hz), 2.88 (2H, t, J=7.7 Hz), 1.30 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 162.20, 158.13, 147.05, 141.79, 132.94, 129.42, 113.98, 106.61, 61.02, 55.36, 34.65, 28.23, 14.37 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 55.36, 14.37; CH2 carbons: 61.02, 34.65, 28.23; CH carbons: 129.42, 113.98, 106.61 ppm. HPLC: 9.200 min.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C)(C)[O:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:27]([CH2:37][O:38][CH3:39])[CH2:26]1)(C)(C)C>C1COCC1>[OH:24][C@H:25]1[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C@@H:27]([CH2:37][O:38][CH3:39])[CH2:26]1
Reactant: COC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
Tetrabutyl ammonium fluoride (21.3 ml) was added to a stirred solution of tert-butyl (2R,4R) 4-(tert-butyl-dimethyl-silyl)oxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (6.68 g) in THF (150 ml). The resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was evaporated to dryness and the residue was purified by flash chromatography on silica eluting with increasingly polar mixtures of methanol/dichloromethane (0/100-5/95). Fractions containing the desired product were combined and evaporated to give tert-butyl (2R,4R) 4-hydroxy-2-(methoxymethyl)pyrrolidine-1-carboxylate (3.32 g) as a solid. NMR Spectrum: (DMSOd6) 1.44 (9H, s); 1.81-1.86 (1H, m); 2.05 (1H, d); 3.09 (1H, d); 3.43-3.49 (3H, s); 3.52 (3H, m); 3.83 (1H, d); 4.20-4.25 (1H, m); 4.94 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1)([O-:18])=[O:17].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:14][C:13](=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:9]([CH3:11])[CH3:10])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: CC(C)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)N(CC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Subsequently, to a solution of (N-t-butoxycarbonyl-N-isopropyl-amino)-acetic acid (2.05 g, 9.44 mmol) and p-nitrobenzyl alcohol (2.89 g, 18.9 mmol) in methylene chloride (100 ml) were added WSC (3.62 g, 18.9 mmol) and 4-dimethylaminopyridine (120 mg, 0.98 mmol) in an ice bath under an atmosphere of nitrogen, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (5:2) as the eluant to afford (N-t-butoxycarbonyl-N-isopropyl-amino)acetic acid p-nitrobenzyl ester (1.93 g, yield 58%) as a pale yellow transparent syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:22]=[CH:23][CH:24]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:5][CH:4]=1.CO.[OH-].[Na+:39]>C1COCC1>[Na+:39].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21](/[CH:25]=[CH:26]/[C:27]([O-:29])=[O:28])[CH:22]=[CH:23][CH:24]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(/C=C/C(=O)O)c4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(/C=C/C(=O)[O-])c4)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Initially charge 76 mg (0.164 mmol) of (2E)-3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidin-4-yl]amino}phenyl)acrylic acid in 1.5 ml of a 1:1 mixture of methanol and THF and add 0.164 ml of 1N sodium hydroxide solution at RT. Stir the mixture at RT for 2 h, then concentrate under reduced pressure and dry the residue under high vacuum overnight. 79.6 mg (99.9% of theory) of the target compound are obtained as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.N1C=CC=CC=1.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][C:7]1[CH:6]=[C:5]([O:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Cl)cc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.7 %

Procedure:
To a 0° C. solution of 3-chloro-5-methoxy-phenol (Scheme #4, K) (16.62 g, 104.80 mmol) and pyridine (12.8 mL, 157.20 mmol) in dichloromethane (150 mL) was added methanesulfonyl chloride (8.9 mL, 115.28 mmol). The reaction was warmed to room temperature and stirred 24 hours. The dichloromethane was removed under reduced pressure and the crude material partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed 1N hydrochloric acid (4×), aqueous saturated sodium chloride (1×), saturated potassium carbonate (3×), aqueous saturated sodium chloride (1×), dried over magnesium sulfate, and solvent removed under reduced pressure. The crude solid was crystallized overnight from dichloromethane (50 mL) and crystals filtered off, washed with dichloromethane, and placed under high vacuum to give the title compound (9.35 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ 7.09 (t, J=2.0 Hz, 1 H), 7.05 (t, J=1.9 Hz, 1 H), 6.93 (t, J=2.1 Hz, 1 H), 3.82 (s, 3 H), 3.42 (s, 3 H); MS (APCI+) m/z 237 [M+1]+; tR=2.28 min.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl.[CH2:42](O)C>>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH:20]=3)[CH3:42])[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(F)c(-c2ccc(N(C)Cc3cccc(C(CC(=O)O)C4CC4)c3)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (148 mg) in ethanol (2.8 mL) was added 2N aqueous sodium hydroxide solution (695 μL) at room temperature, and the mixture was stirred for 5 hr. The mixture was further stirred at 50° C. for 2 hr, and the reaction mixture was cooled to 0° C. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (128 mg) as a colorless gummy substance.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[H-].[Na+].[C:27](OC)(=O)[C@H:28]([CH3:30])[OH:29].[Cl-].[NH4+]>O1CCCC1>[OH:29][C@H:28]([C:30]1[O:24][N:23]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:16])[CH2:11][CH2:10]3)[CH:4]=2)[N:1]=1)[CH3:27]
Reactant: COC(=O)[C@H](C)O
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](O)c1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
2,2-Dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}-1-piperazinecarboxylate (657 mg) was dissolved in tetrahydrofuran (10 mL), oily sodium hydride (82.6 mg) was added thereto and stirred at 60° C. for 15 minutes, then methyl (S)-lactate (0.333 mL) was added thereto and heated under reflux for 1 hour. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain 402 mg of the entitled compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][C:19]([CH3:38])(C2CCCCC2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:38][CH:4]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:5]2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(C)(c2ccccc2N2CCCCC2)C2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(CC(=O)NC(CC2CCCCC2)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
Ethyl 2-ethoxy-4-[N-(α-cyclohexyl-methyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (1.15 g, 2.21 mmol) in ethanol (12 ml) are stirred together with 1N sodium hydroxide solution (3.3 ml) for 2 hours at 50° C. Then 1N hydrochloric acid (3.3 ml) is added and the mixture is cooled in ice. The precipitate formed is filtered off, washed with a little ice cold ethanol and dried in vacuo at 100° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33]([NH2:37])(=[O:36])[CH2:34][CH3:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:33](=[O:36])[CH2:34][CH3:35])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)CC1
Reactant: CCC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.43 mmol) (as prepared in Example 1), propionamide (95 mg, 1.30 mmol), xantphos (25 mg, 0.043 mmol), and cesium carbonate (280 mg, 0.86 mmol) were dissolved in dry dioxane (3 mL) and argon was bubbled through the mixture for 10 minutes. Pd2(dba)3 (20 mg, 0.022 mmol) was then added, and the solution was degassed for an additional 10 minutes. The flask was fitted with a balloon of N2 and slowly heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature and diluted with a 4:1 mixture of ethyl acetate and THF (60 mL) and water (40 mL). The organic layer was separated and washed with brine and the aqueous layer was back extracted with the ethyl acetate/THF solution, which was then extracted with brine. The combined organic layers were dried over sodium sulfate and evaporated and the residue was purified by silica gel chromatography to give N-(2,5-difluoro-4-(2-propionamidopyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (130 mg, 60.7% yield). 1H-NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 10.52 (s, 1H), 9.79 (s, 1H), 8.19 (d, 5.6 Hz, 1H), 8.10-8.05 (m, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.59-7.53 (m, 3H), 7.16 (t, J=8.8 Hz, 2H), 6.74-6.72 (m, 1H), 2.33 (q, 0.7=7.2 Hz, 2H), 1.64-1.55 (m, 4H), 0.99 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[C:11]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:12][C:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(=O)c1ccc(C#N)cc1
Product: N#Cc1ccc(C(=O)C=Cc2cccc(C#N)c2)cc1

Procedure:
Part A. Employing methods similar to Example 1 Part A but using m-cyano benzaldehyde (0.91 gm, 6.89 mmol) and 4-acetyl benzonitrile (1.0 gm, 6.89 mmol), 4-[3-(3-cyanophenyl)-1-oxo-2-propenyl]benzonitrile was isolated as a pale yellow powder, 1.4 gm (79%), 1H NMR (CDCl3) 8.53(s,1H), 8.35(d,2H), 8.15-8.20(m,3H), 7.92(d, 1H), 7.82(d, 1H), 7.67(t, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50].C(O)(C(F)(F)F)=O>CN(C=O)C.CCCCCC.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
DIPEA (0.096 mL, 0.56 mmol) was added drop wise to 4-phenylamino-benzoic acid (47 mg, 0.22 mmol) in DMF (4 mL). EDCI (53 mg, 0.28 mmol) and HOBT (30 mg, 0.22 mmol) were added consecutively and, after 10 mins, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its TFA salt form (80 mg, 0.19 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added the resulting solid filtered to afford 68 mg of crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 80/20 EtOAc:Hexane as the eluent) afforded 45 mg (47% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-phenylamino-benzamide. LC-MS purity: 96.8%. 1H-NMR (DMSO-D6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (m, 5H), 7.6 (d, 1H), 7.3 (t, 2H), 7.2 (d, 2H), 7.1 (d, 2H), 6.9 (t, 1H), 4.1 (d, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.1 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Reactant: CS(=O)(=O)Cl
Product: Cc1ccc(Sc2ccc(OS(C)(=O)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 5 (80 mg, 0.195 mmol) was reacted with the methanesulfonyl chloride (22.3 mg, 0.195 mmol) for 18 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (36 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.88 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 7.76 (d, J=8.46 Hz, 1H) 7.45-7.51 (m, 1H) 7.35-7.42 (m, 2H) 7.26 (d, 2H) 7.19 (d, 2H) 6.33 (d, J=6.99 Hz, 1H) 3.34 (s, 3H) 2.75 (s, 3H) 2.40 (s, 3H); MS (DCI NH3+) m/z 452 (M+H)+.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH3:21])[CH2:17][CH:16]([C:18](Cl)=[O:19])[CH2:15]1>O1CCCC1.Cl>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([C:18]([CH:16]2[CH2:17][C:14]([CH3:21])([CH3:13])[CH2:15]2)=[O:19])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC1(C)CC(C(=O)Cl)C1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 104.1 %

Procedure:
Ethyl 4-iodobenzoate (600 mg, 2.17 mmol) was dissolved in tetrahydrofuran (6.0 mL) and brought to −40° C. Isopropylmagnesium chloride lithium chloride complex solution (1.0 M in tetrahydrofuran, 0.365 mL, 2.17 mmol) was added dropwise and the yellow-red solution was stirred at −40° C. for 40 min. Cul (124 mg, 0.65 mmol) was added in one portion and the mixture was then stirred at −15° C. for 20 min to dissolve all the solids. The yellow solution was then brought back to −40° C. and 3,3-dimethylcyclobutanecarbonyl chloride (Intermediate 22) (450 mg, 3.07 mmol) was added dropwise. The color changed from slightly green to yellow, then red, then yellow. The mixture was warmed to 0° C. over 2 h in the same bath. The mixture was diluted with 1 N HCl and extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was partially purified by silica gel flash chromatography (ethyl acetate/heptane) to give impure 4-(3,3-dimethyl-cyclobutanecarbonyl)-benzoic acid ethyl ester (588 mg). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 2H) 7.94 (d, J=8.4 Hz, 2H) 4.38-4.48 (m, 2H) 3.90 (quin, J=8.8 Hz, 1H) 2.16-2.29 (m, 2H) 2.04-2.13 (m, 2H) 1.42 (t, J=7.2 Hz, 3H) 1.28 (s, 3H) 1.09 (s, 3H); MS (M+1): 261.4.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>ClCCl.CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:19])[C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH+:9]([O-:25])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)[NH+]([O-])c2ccc(F)cc2)cn1
Yield: 13.2 %

Procedure:
To a solution of 6-dimethylamino-N-(4-fluoro-phenyl)-nicotinamide (0.027 g, 0.11 mmol, prepared as in Example 1) in 2 mL of dry dichloromethane/methanol (4:1) was added 3-chloroperoxybenzoic acid (0.020 g, 0.12 mmol) at 0° C. The reaction mixture was then heated to reflux and additional 3-chloroperoxybenzoic acid (0.040 g, 0.24 mmol) was added. After heating for a total of 7 h the reaction mixture was cooled, diluted with chloroform and washed with aqueous sodium carbonate (1M), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography, using 10% methanol/dichloromethane saturated with ammonia, yielded 4 mg (13%) of the desired product as a white solid. MS (EI) m/z 274.18 (M−H)−.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:11].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:11][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[N:15]1[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cncc(Cl)c1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-3-chloro-5-nitro-pyridine (700 mg, 2.948 mmol), tert-butyl piperazine-1-carboxylate (823.6 mg, 4.422 mmol) and DIPEA (762.0 mg, 1.027 mL, 5.896 mmol) in NMP (2.5 mL) was stirred overnight at RT. The reaction mixture was partitioned between EtOAc and water. Combined organic extract was washed with brine, dried over MgSO4, concentrated under reduced pressure to yield tert-butyl 4-(3-chloro-5-nitropyridin-4-yl)piperazine-1-carboxylate which was used in next step without further purification (1 g, 99%). MS (ES+) 343.1.