Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:12][C:13]1[N:14]=[CH:15][S:16][C:17]=1[CH2:18][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Cc1ncsc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ncsc1CCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A mixture of 4-amino-3-nitrophenol (386 mg, 2.5 mmol), 2-(4-methyl-1,3-thiazol-5-yl)ethanol (0.299 mL, 2.5 mmol), polymer supported triphenylphosphine (1.25 g, 3 mmol/g, 3.75 mmol), and di-tert-butyl azodicarboxylate (864 mg, 3.75 mmol) in THF (10 mL) was stirred at room temperature for 16 hours. Filtered through Celite and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide 602 mg (86%) of the desired product. MS (DCI) m/e 279 (M+H)+, 1H NMR (300 MHz, DMSO-d6): □ 8.83 (s, 1H), 7.37 (d, J=3.05 Hz, 1H), 7.25 (s, 2H), 7.16 (dd, J=8.99, 2.88 Hz, 1H), 7.01 (s, 1H), 4.10 (t, J=6.27 Hz, 2H), 3.19 (t, J=6.27 Hz, 2H), 2.35 (s, 3H).
Reaction SMILES: CN(C)C=O.[C:6]([NH2:12])([NH2:11])=[N:7][C:8](N)=[NH:9].[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>O>[NH2:12][C:6]1[N:7]=[C:8]([NH2:9])[N:15]([CH2:13][CH3:14])[C:16](=[S:17])[N:11]=1
Reactant: CCN=C=S
Reactant: N=C(N)N=C(N)N
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(N)nc(N)nc1=S
Temperature: 100 °C
Yield: 104.9 %

Procedure:
To 15 ml of dry dimethylformamide were dissolved 1.52 g of diguanide and 1.31 g of ethylisothiocyanate, and the solution was heated at 100° C. for 4 hours. After cooling, the solution was added to 60 ml of water to produce white precipitates, which subsequently was dried to obtain 2.7 g of the title compound having the characteristics of:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)(C)C.O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18]([NH:17][C:15]1[CH:16]=[C:11]([C:9]2[N:8]=[C:5]3[N:4]([CH:10]=2)[N:3]=[C:2]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[C:26]([F:37])([F:36])[F:25])[CH:7]=[CH:6]3)[CH:12]=[CH:13][C:14]=1[CH3:24])=[O:23]
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: OB(O)c1cnccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2cn3nc(-c4cnccc4C(F)(F)F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 24.3 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.034 g, 0.1 mmol), [4-(trifluoromethyl)-3-pyridyl]boronic acid (0.038 g), bis(triphenylphosphine)palladium(II) dichloride (7 mg), Na2CO3 (0.032 g), and isopropanol-water (1 mL, 3:1). The mixture is heated at 80° C. for 16 hr, cooled, concentrated, taken up in 1:1 EtOAc and CH2Cl2, filtered, concentrated onto celite and purified by silica gel chromatography (10-100% EtOAc in Hexanes) to give the title compound (0.011 g, 25% yield). LCMS m/z=454.5 [M+H]+, tR=2.47 min. (compound same as Example 364)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[S:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.O>[N+](C1C=CC=CC=1)([O-])=O>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccs1
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A solution of 74.1 g (0.5 mole) of phthalic anhydride in 300 mL of nitrobenzene was treated with 147 g (1.1 mole) of aluminum chloride. The solution was stirred for two hours and 42.1 g (0.5 mole) of thiophene was added dropwise over 80 minutes at 40°-45°. The reaction was stirred at 50°-55° for two hours and then let sit at room temperature overnight. The reaction was poured into 2.8 L of cold water, stirred, separated, and the nitrobenzene was removed from the nitrobenzene layer by steam distillation. The residue was recrystallized from toluene to provide 31.1 g (27%) of 2-thienoylbenzoic acid, mp 141-143. The thienoylbenzoic acid was treated with methylhydrazine as described in Example 185 to provide 24.4 g (75%) of the phthalazinone product, mp 143-144, after recrystallization from ethyl acetate.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:12]([CH3:31])=[N:13][C:14]2[C:19]([N:20]=1)=[C:18]([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)[CH:17]=[CH:16][CH:15]=2.[NH2:32][CH:33]1[CH2:36][CH:35]([OH:37])[CH2:34]1>CS(C)=O>[OH:37][CH:35]1[CH2:36][CH:33]([NH:32][C:11]2[C:12]([CH3:31])=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]([C:21]2[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=2)[CH:17]=[CH:16][CH:15]=3)[CH2:34]1
Reactant: NC1CC(O)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CC(O)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4 (5H)-one (Example 126; 40 mg, 0.135 mmol), 3-aminocyclobutanol (35.3 mg, 0.405 mmol, Sigma Aldrich; mixture of cis- and trans-isomers), and DMSO (1.4 mL) stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-((3-hydroxycyclobutyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (mixture of cis- and trans-isomers): 1H NMR (DMSO-d6) δ: 12.31-12.44 (m, 1H), 7.86-7.95 (m, 1H), 7.51-7.61 (m, 1H), 7.26-7.40 (m, 2H), 7.04-7.11 (m, 1H), 6.91-7.02 (m, 1H), 5.12-5.26 (m, 1H), 4.37-4.53 (m, 1H), 3.86-4.07 (m, 1H), 3.41-3.48 (m, 1H), 2.88-3.01 (m, 2H), 2.75-2.85 (m, 1H), 2.55-2.59 (m, 4H), 2.26-2.48 (m, 2H), 1.94-2.09 (m, 1H). m/z (ESI, +ve) 364.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].COCCOC.[H-].[Na+].[CH3:21][S:22][CH2:23]Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:21][S:22][CH3:23])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CSCCl
Reactant: CNC(=O)Nc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)N(CSC)c1ccccc1F
Reaction time: 0.25 h

Procedure:
A solution of 16.8 g. (0.1 mol) of N-(2-fluorophenyl)-N'-methyl urea in 250 ml. of 1,2-dimethoxyethane was cooled to 0°C. Then 4.8 g. (0.1 mol) of a 50% dispersion of sodium hydride in mineral oil was added slowly. After addition was complete, the solution was stirred for 15 minutes. This solution was added slowly to a stirred solution of 9.7 g. (0.1 mol) of chloromethyl methyl sulfide in 100 ml. of 1,2-dimethoxyethane. The resulting mixture was stirred at room temperature for 65 hours. At the end of this time, the precipitate was removed by filtration and the resulting filtrate was evaporated to give an oil which solidified upon adding water. The solid was isolated by filtration, washed with hexane and dried. Recrystallization from a hexene-benzene mixture gave 12 g. crystalline solid, melting point 102.5°-103°C. An infrared spectrum showed sharp, strong adsorptions at 3.0, 6.1, 13.05 and 13.2μ .
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][N:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[S:19]([CH3:22])(=[O:21])=[O:20].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:27]3[CH:28]=[CH:29][C:24]([CH2:23][N:18]([CH3:17])[S:19]([CH3:22])(=[O:20])=[O:21])=[CH:25][CH:26]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: CN(Cc1ccc(B(O)O)cc1)S(C)(=O)=O
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1)S(C)(=O)=O
Reaction time: 8 h

Procedure:
A suspension composed of 5.74 mg (3.37 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4 ]benzothiadiazin-7-ol 5,5-dioxide, 926 mg (4.04 mmol) of (4-{[methyl(methylsulphonyl)amino ]methyl}phenyl)boronic acid, 920 mg (5.06 mmol), of copper(II) acetate, 817 μl (10.10 mmol) of pyridine and about 4 g of 4 Å molecular sieve in 50 ml of CH2Cl2 is stirred overnight. The reaction mixture is filtered, rinsing with CH2Cl2/MeOH (1/1). The filtrate is concentrated and then directly placed on a silica column which is eluted with a CH2Cl2/MeOH 95/5 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in ethyl ether. After filtering off the solid, the title product is recovered in the form of white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]#[N:21])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].OO.[OH-].[Na+].C(O)(=[O:41])C>CS(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH3:34])[CH:9]([CH3:22])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20]([NH2:21])=[O:41])[CH:19]=1)[NH:16][CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc(C#N)c2c(c1)CCN2
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)C(C)Cc1cc2c(c(C(N)=O)c1)NCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carbonitrile (120 mg) in dimethyl sulfoxide (2.5 ml) was added 30% hydrogen peroxide (0.26 ml), and the mixture was stirred at room temperature for 15 minutes. Then, to the reaction mixture was added a 5N sodium hydroxide solution (0.26 ml), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added acetic acid. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 127 mg of 5-[2-[N-tert-butoxycarbonyl-2-(2-ethoxyphenoxy)ethylamino]propyl]indoline-7-carboxamide as an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]1[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: O=c1[nH]nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(-c3ccc(Cl)cc3)ccn12
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a stirred mixture of 8-bromo-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (3.24 g, 10.0 mmol) in DMF (15 mL) at room temperature under argon was added K2CO3 (2.76 g, 20.0 mmol) and 3-(chloromethyl)-6-(trifluoromethyl)pyridine (2.34 g, 12.0 mmol). After stirring at room temperature for 3 d, HPLC indicated approximately 70% complete reaction. The mixture was then heated to 60° C. for 5 h, after which HPLC indicated complete reaction. The mixture was cooled to room temperature, diluted with water (100 mL), and stirred for 1 h. Solid was collected by filtration and washed with water (10 mL×5), then methanol (5 mL×2), and finally dried under vacuum. The title compound (4.4 g) was obtained as a yellow solid. HPLC/MS: retention time=3.8 min, [M+H]+=485.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([OH:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.C(N1C=CN=C1)(N1[CH:18]=[CH:17]N=C1)=O.C(O)C>CN(C)C=O>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)[CH3:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1nccnc1Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nccnc1Cl
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of (3-chloro-pyrazin-2-yl)-acetic acid (2.00 g) in N,N-dimethylformamide (“DMF”) (20 ml) was added 1,1′-carbonyldiimidazole (1.88 g) and the mixture stirred for 1 hour. To the reaction mixture was added ethanol (20 ml) and the mixture stirred for 1 hour at ambient temperature. The reaction mixture was concentrated and then purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give (3-chloro-pyrazin-2-yl)-acetic acid ethyl ester (1.93 g). 1H-NMR (400 MHz, CDCl3): 8.50 (s, 1H), 8.30 (s, 1H), 4.20 (q, 2H), 4.00 (s, 2H), 1.30 (t, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/B(O)O)=[CH:5][CH:4]=1.[CH3:16][C:17]([CH3:38])([CH3:37])[CH2:18][C:19]([NH:21][C:22]1[C:30](C2C=NC=CC=2)=[C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1)=[O:20]>>[CH3:16][C:17]([CH3:38])([CH3:37])[CH2:18][C:19]([NH:21][C:22]1[C:30](/[CH:10]=[CH:9]/[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=2)=[C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1)=[O:20]
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Reactant: OB(O)/C=C/c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1/C=C/c1ccc(C(F)(F)F)cc1

Procedure:
Trans-2-[4-(trifluoromethyl)phenyl]vinylboronic acid and the product from Example 110B were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.27-10.28 (bs, 1H), 9.11 (dd, J=6.9, 1.7 Hz, 1H), 8.69 (dd, J=4.1, 1.7 Hz, 1H), 7.63-7.73 (m, 5H), 7.34 (d, J=16.5 Hz, 1H), 7.15 (dd, J=6.9, 4.1 Hz, 1H), 2.35 (s, 2H), 1.09 (s, 9H); MS (ESI) m/z 403 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.[CH3:23][N:24]1[CH2:30][C:29]2[CH:31]=[C:32](/[CH:35]=[CH:36]/[C:37](O)=O)C=N[C:28]=2[NH:27][C:26](=O)[CH2:25]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:27]([CH3:28])[CH2:26][C:25]2[N:24]([CH3:23])[C:30]3[C:36]([CH:37]=2)=[CH:35][CH:32]=[CH:31][CH:29]=3)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN1CCN(Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2N)CC1
Yield: 14 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (136 mg, 14%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.7 (br s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.07 (br s, 2H), 7.55-7.01 (m, 6H), 6.41-6.17 (m, 1H), 5.07-4.85 (m, 2H), 3.73-3.62 (m, 7H), 3.11-2.98 (m, 8H), 2.73 (s, 3H); MS (ESI) m/e 433 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]1([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH3:6][N:4]([CH:3]=[C:19]1[C:18](=[O:21])[CH:17]=[CH:16][C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:20]1)[CH3:5]
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=C1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Temperature: 20 °C
Yield: 56.1 %

Procedure:
4.77 g of N,N-dimethylformamide dimethyl acetal are added to a solution of 2.48 g of 4,4-diphenylcyclohex-2-enone in 20 Cm3 of N,N-dimethylformamide. The mixture is refluxed for about 4 hours. After cooling to a temperature in the region of 20° C., the solution is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 50 cm3 of diisopropyl ether and allowed to precipitate for about 20 hours at a temperature in the region of 20° C. The solid is drained by suction, washed with three times 10 cm3 of diisopropyl ether and then dried under reduced pressure (13 kPa) over potassium hydroxide at a temperature in the region of 20° C. 1.7 g of 6-dimethylaminomethylene-4,4-diphenylcyclohex-2-enone are thus obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25]>O1CCCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)Nc1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CCC(=O)Nc1ccc(C#C[Si](C)(C)C)cn1
Temperature: 65 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a solution of methyl 4-[(5-bromo-2-pyridyl)amino]-4-oxo-butanoate (commercially available: 0.25 g, 0.871 mmol) in tetrahydrofuran was added bis(triphenylphosphine) palladium(II) dichloride (61.7536 mg, 0.087 mmol), copper(I) iodide (16.6 mg, 0.087 mmol), triethylamine (889 mg, 1.23 mL, 8.70 mmol) and ethynyltrimethylsilane (130 mg, 0.19 mL, 1.30 mmol). The reaction mixture was stirred at 65° C. overnight. The reaction was stopped and the solution was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layer was dried on magnesium sulfate and concentrated under vacuum. The residue was purified by flash chromatography eluting with cyclohexane-ethyl acetate (3/1) to give methyl 4-oxo-4-[[5-(2-trimethylsilylethynyl)-2-pyridyl]amino]butanoate (26 mg, 10% yield). 1H NMR (400 MHz, CDCl3) 8.39 (s, 1H), 8.14 (m, 2H), 7.74 (d, 1H), 3.72 (s, 3H), 2.74 (m, 4H), 0.24 (s, 9H) ppm.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[B-](F)(F)(F)F.CN(C(O[N:31]1[C:36](=[O:37])[CH2:35][CH2:34][C:32]1=[O:33])=[N+](C)C)C>CN(C=O)C>[CH2:35]1[C:36](=[O:37])[N:31]([O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:8])[C:32](=[O:33])[CH2:34]1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(ON1C(=O)CCC1=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To the solution of 4-iodobenzoic acid (1)(1.24 g, 5.0 mmol) and triethylamine (0.71 mL, 5.0 mmol) in DMF (30 mL) was added TSTU (1.51 g, 5.0 mmol). The solution was stirred at room temperature for 2 hours. The reaction was quenched by addition of 10% HCl (50 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to yield the title compound (2) as a white powder (1.42 g, 82%); m.p. 130-132° C.; vmax/cm−1(neat) 1769 (C═O, ester), 1719 (C═O, amide); (Found C, 38.40; H, 2.41; N, 4.15. C11H8INO4 requires C, 38.28; H, 2.34; N, 4.06%.); δH (300 MHz, CDCl3) 7.92 (2H, d, J 12.0 Hz, H2/6), 7.85 (2H, d, J 12.0 Hz, H3/5), 2.92 (4H, s, CH2); δc (75 MHz, CDCl3) 169.0 (OCO), 162.0 (NCO), 138.7 (C2/6), 132.0(C3/5), 125.3 (C1), 103.3(C4), 26.0 (CH2); m/z (E.I.), 345 (M+, 5%), 231 (100%), 202 (20%), and 76 (48%); HRMS for C11H8INO4 requires 344.9493 found 344.9493.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[N+](=[CH2:30])=[N-]>CO.CCOCC>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:30])=[O:20])=[CH:15][N:14]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)O)cn2)ccc(C(C)=O)c1O
Solvent: CO
Solvent: CCOCC
Product: CCCc1c(OCCCSc2ccc(C(=O)OC)cn2)ccc(C(C)=O)c1O
Temperature: 0 °C

Procedure:
The compound of Example 1 (500 mg, 1.284 mmoles) was dissolved in mixture of CH3OH (10 ml) and ether (10 ml) cooled to 0° C. Diazomethane was added until a slight yellow color persisted. The reaction mixture was concentrated to afford the title compound, m.p. 66°-68°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])=[O:6].Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[NH2:12][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[NH:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][CH:27]([C:25](=[O:26])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=2)[CH2:28][CH2:29]1)=[O:11]
Reactant: NC(=O)c1ccccc1NC(=O)CCCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)c1ccccc1NC(=O)CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 81 %

Procedure:
A mixture of 7.2 parts of 2-[(4-chloro-1-oxobutyl)amino]benzamide, 7.3 parts of (4-fluorophenyl) (4-piperidinyl)methanone hydrochloride, 10.1 parts of N,N-diethylethanamine and 120 parts of acetonitrile is stirred and refluxed for 24 hours. The reaction mixture is evaporated and water is added to the residue. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 10 parts (81%) of N-[2-(aminocarbonyl)phenyl]-4-(4-fluorobenzoyl)-1-piperidinebutanamide as a residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1ccc(F)cc1
Yield: 18.3 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.215 ml, 0.43 mmoles) was treated with 4-fluorophenylboronic acid (35 mg, 0.25 mmol) and Pd[PPh3]4 (14 mg, 0.012 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (9.5 mg, 20%). MS m/e 423.22 (M+H+)