Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
1-Fluoro-4-nitrobenzene (10.6 g) and 2,2,2-trifluoroethanol (12.0 g) were dissolved in N,N-dimethylformamide (80 ml), and potassium carbonate (15.5 g) was added thereto. The mixture was stirred at 80° C. for 2 hr, and allowed to be cooled. To the reaction mixture was added ethyl acetate (100 ml), and the white precipitate was removed by filtration. The filtrate was concentrated under reduced pressure to give an orange residue. The obtained residue was again dissolved in ethyl acetate (400 ml), and the solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an orange crude solid. The obtained solid was washed with a mixed solvent of 10% diethyl ether/hexane to give the title compound (15.8 g) as yellow-white needle crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](Br)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(NC(C)C)(C)C>C(#N)C.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.[Cu]I>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2c(OCc3ccccc3)cccn12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine (10.0 g, 33.0 mmol), 9.39 mL (66.0 mmol) of ethynyltrimethylsilane, 0.580 g (0.825 mmol) of Pd(PPh3)2Cl2, 0.230 g (1.19 mmol) of CuI, and 5.09 mL (36.3 mmol) of diisopropylamine in 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20-50% EtOAc/hexanes) to provide 6.74 g of product: 321 m/z (M+H).
Reaction SMILES: Cl.[CH2:2](NC(N1CCN(C(C2CCCC2)=O)CC1)=O)C.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([NH2:32])[CH:23]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:31][O:30][C:29]1[CH:28]=[C:25]2[C:24](=[CH:23][C:22]=1[O:21][CH3:20])[N:32]=[CH:2][N:27]=[CH:26]2
Reactant: CCNC(=O)N1CCN(C(=O)C2CCCC2)CC1
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2cncnc2cc1OC
Reaction time: 0.5 h

Procedure:
Ethyl-4-(cyclopentylcarbonyl)piperazin-1-yl-for-mamidate hydrochloride (0.01 mole) is added to a solution of 4,5-dimethoxy-2-aminobenzonitrile (0.01 mole) in 30 ml. of N,N-dimethylformamide. Sodium hydride (0.02 mole of a 56% suspension in mineral oil) is added and the mixture stirred 0.5 hr. at room temperature and then at 100° C. for a period of 12 hr. When the reaction period is complete, water is added providing 4-amino-2-[4-cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]([CH3:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([CH3:21])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
Suspend lithium aluminum hydride (0.76 g, 20.0 mmol) in dry tetrahydrofuran (10 mL) and cool to 0° C. Add, dropwise with stirring, 1-benzyl-3-methyl-piperidin-4-one (4.06 g, 20.0 mmol) in tetrahydrofuran (20 mL). After 1 hr., quench with saturated potassium sodium tartrate solution. After 20 min., extract with ethyl acetate (2×100 mL), wash the combined organic layers with aqueous NaCl solution (100 mL), dry over sodium sulfate, filter, and concentrate to obtain the title compound (4.15 g, >100%). Mass spectrum (electrospray): m/z=206.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[OH-].[Na+:31]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O-:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Na+:31]
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Temperature: 60 °C

Procedure:
Ethyl 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (108 mg, 0.25 mmol) was dissolved in 3 ml of ethanol and 1 ml of water. Sodium hydroxide (4 equivalents) was added. The mixture was stirred at 60° C. until TLC showed no more SM (starting material) (˜2 hours). The reaction mixture was cooled down and extracted with ethyl acetate (3×). Dried over MgSO4. Sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}-phenyl)methyl]-2-pyridinecarboxylate was obtained as a white solid (94 mg).
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(=O)NCc1ccc(C(C)O)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)Cl)cc1

Procedure:
A solution of N-{[4-(1-hydroxyethyl)phenyl]methyl}acetamide (5.7 g) and thionyl chloride (2.6 ml) in chloroform (50 ml) was refluxed under heating for 1.5 hr. The solvent was evaporated to give a brown oil (6.7 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (5.5 g) as a pale-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:14])=O.CN(C)C=O>O>[Cl:14][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cnc1Cl
Temperature: 110 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
5-fluoro-2-hydroxy-3-nitropyridine (11.0 g, 69.4 mmol) prepared in Step 3 was added to a mixed solution of phosphorus oxychloride (38.8 ml, 416 mmol) and N,N-dimethylformamide (537 μl, 6.94 mmol). The reaction mixture was stirred for 5 hours at 110° C. Water (250 ml) was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer washed with a sodium chloride solution (250 ml) three times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate) to give 9.02 g of the titled compound as yellow solid. (Yield: 74%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([I:18])=[C:7]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[CH:11][C:10]=2[I:17])[CH:8]=1.B(Br)(Br)Br.C(Cl)Cl>C(=O)=O.CC(C)=O>[OH:15][C:13]1[CH:12]=[CH:11][C:10]([I:17])=[C:9]([C:7]2[CH:8]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=2[I:18])[CH:14]=1
Reactant: COc1ccc(I)c(-c2cc(OC)ccc2I)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Oc1ccc(I)c(-c2cc(O)ccc2I)c1
Reaction time: 18 h
Yield: 85 %

Procedure:
A flask containing 5,5'-dimethoxy-2,2'-diiodobiphenyl (10.0 g, 21 mmol) was cooled to -76° C. in dry ice/acetone. A 1.0M solution of boron tribromide in methylene chloride (64 ml, 64 mmol) was added via syringe to the cold substrate. The ice bath was removed and the reaction allowed to reach room temperature. After 18 hours, the solution was added slowly to 1 L of water. The aqueous mixture was stirred for 2 hours, and the white solid which formed was filtered, washed with water, and dried to give I, which melted at 181°-182° C., in 85% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][CH:10]([C:14](OC)=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
First, N-benzyl-pyrrolidine-3-methanol was prepared as follows. Methyl N-benzyl-5-oxo-pyrrolidine-3-carboxylate (11.66 g, 50 mmol) was dissolved in diethyl ether and cooled to 0° C. This solution was added to a 0° C. suspension of lithium aluminum hydride in diethyl ether under nitrogen atmosphere. After addition, the mixture was refluxed for 1 hr. and then cooled with an ice bath. To quench the reaction, sodium sulfate decahydrate was added and the mixture was stirred for 1 hr. After filtration, the filtrate was collected, and concentrated to dryness to give N-Benzyl-pyrrolidine-3-methanol. ESMS (C12H17NO): calcd. 191.13; obsd. 192–2 [M+H]+. Retention time (anal. HPLC: 10–70% MeCN/H2O over 5 min)=0.95 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18](=O)[CH2:17][CH:16]([C:20](OC)=[O:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:20][OH:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
To a suspension of 0.50 g of lithium aluminum hydride in 35 mL of THF at 0° C. was added (dropwise via cannula) a solution of 2.00 g of methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate in 10 mL of THF. The cooling bath was removed and the mixture was stirred for 2.5 h at room temperature. The mixture was recooled to 0° C. and quenched by careful, sequential addition of 0.5 mL of water, 0.5 mL of 15% aqueous NaOH, and 1.5 mL of water. The mixture was stirred at room temperature for 1 h, at which point all solids were white, then filtered. The solids were washed thoroughly with Et2O, and the filtrate was dried over MgSO4 and concentrated to give 1.61 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=O.C[Si]([C:26]#[N:27])(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:26]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:27]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2C#N
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a suspension of 10 g (35 mmol) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, the product of Example 1, was added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture was heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture was reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct was dehydrated by treatment with 15 mL of trifluoroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture was cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a colorless oil. The oil was purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexane to give 8.5 g (83% yield) of the title compound, m.p. 109°-110° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][CH:48]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:53][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][NH:39][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:52][CH:51]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1

Procedure:
Prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R )-yl]butanamide (Example 1, Step C) and 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 8, Step F) by the procedure described in Example 1, Step D. 1H NMR (200 MHz, CDCl3): δ1.14 (s, 3H), 1.19 (s, 3H), 1.23 (d, 6 Hz, 3H), 1.39 (s, 9H), 1.86 (m, 1H), 2.20-2.75 (m, 7H), 3.88 (m, 1H), 4.18 (d, 6 Hz, 2H), 4.48-4.66 (m, 3H), 4.92 (d, 15 Hz, 1H), 5.13 (d, 15 Hz, 1H), 7.10-7.43 (m, 20 H). CI-MS: calculated for C44H54N4O5 718; found 719 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c[n+]1[O-]
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Temperature: 90 °C
Reaction time: 20 h

Procedure:
5-Bromo-2-methylpyridine 1-oxide (5.36 g) was added to a mixture of conc. nitric acid (10.1 mL) and conc. sulfuric acid (8.94 mL), and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was poured into ice water, and the resulting pale-yellow precipitate was collected by filtration. The crude crystals were washed with water to give the title compound (3.83 g) as a pale-yellow solid. The filtrate was neutralized with 8N aqueous sodium hydroxide solution at room temperature, and extracted with a mixed solvent of ethyl acetate and THF. 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 purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (360 mg) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1.[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[N+:6]([O-:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(Br)c[n+]1[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 81 %

Procedure:
To a solution of 5-bromo-2-methylpyridine N-oxide (660 mg, 3.51 mmol) in sulfuric acid (1.6 mL) at 0° C. was added a premixed solution of nitric acid (1.5 mL) in sulfuric acid (2.5 mL). The resulting reaction was warmed to 25° C. then heated to 80° C. After 12 h, the solution was poured into ice then, neutralized with 6N NaOH and extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 1% MeOH in DCM) yielding the title compound (558 mg, 81%) as a yellow solid: LCMS (ES) m/z=235 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:15][CH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Yield: 82.4 %

Procedure:
A degassed solution of methyl 2-methyl-4-nitrobenzoate (3.5 g, 18.19 mmol), N-bromosuccinimide (3.9 g, 21.91 mmol, 1.2 eq) and benzoyl peroxide (3.63 mmol, 0.2 eq.) in 100 ml 0014 was heated at reflux for 4 hr. It was concentrated to dryness, dissolved in ether, washed 2× with water, aq. Na2S2O3, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 15% ethyl acetate in hexanes to provide 4.11 g of methyl 2-bromomethyl-4-nitrobenzoate.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[C:23](#[N:25])[CH3:24].C[O-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:24][C:23]#[N:25])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC#N
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Yield: 87.2 %

Procedure:
In a flask similar to that of Example 6 were placed under argon atmosphere 1.74 g (5.98 mmol) of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 0.80 mL (15.2 mmol) of acetonitrile, 8.0 mL of tetrahydrofuran (dielectric constant at 25° C.: 7.58), and 0.41 g (7.55 mmol) of sodium methoxide. The content was reacted at 52° C. for 4.5 hours. The resulting mixture was chilled in an ice bath. To the chilled mixture were slowly added under stirring 30 mL of toluene and 7.0 mL (7.00 mmol) of hydrochloric acid (1 mol/L), successively. The separated organic portion was taken out. After washing with two portions of saturated aqueous sodium chloride solution (10 mL), the organic portion was dried over anhydrous magnesium sulfate. The organic portion was then filtered and analyzed by high performance liquid chromatography (absolute quantitative analysis). It was confirmed that 1.64 g (yield: 88%) of 3-[2-cyclopropyl-4-(4-fluoro-phenyl)-3-quinolyl]prop-2-enenitrile was produced.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[N:8][C:7]=1[NH2:13])[CH2:4][CH3:5])[CH3:2].Cl[CH2:15][C:16](=O)[CH3:17].C(=O)(O)[O-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:17])[N:13]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nnc1N
Reactant: CC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2cc(C)nc12
Temperature: 100 °C

Procedure:
Heat 850 mg (4.74 mmol) of 4-(1-ethyl-propyl)-6-methyl-pyridazin-3-ylamine and 0.415 ml (5.22 ml) of chloroacetone in 20 ml of ethanol in microwave at 110° C. for 35 minutes. Add 1.2 g (14.2 mmol) of sodium bicarbonate and heat in oil bath with reflux condensor at 100° C. overnight. Evaporate solvents, take up in ethyl acetate and wash 3 X's with brine. Dry over sodium sulfate, filter, and evaporate to a brown oil. Chromatograph using hexanes to 6:1 hex:ethyl acetate to ethyl acetate gradient. Collect title compound as oil weighing 3.69 g (17.0 mmol, 84.4%). 1H-NMR (DMSO-d6): δ 7.34 (s, 1H); 6.84 (s, 1H); 2.85-3.10 (m, 1H); 2.43 (s, 3H); 2.32 (s, 3H); 1.70-1.80 (m, 4H); 0.712 (t, J=7.49 Hz, 6H) ppm. MS/ES+=219 (100%, M+2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][Br:20]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(Br)c(CBr)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 4-bromo-3-methylbenzoate (50 g; 218 mmol) in CHCl3 (1 L) were added NBS (46.6 g; 262 mmol) in one portion and α,α′-azoisobutyronitrile (0.72 g; 4.37 mmol). The reaction mixture was stirred at 70° C. for 2 days. It was cooled down to RT and water was added. The organic layer was washed with aq. NaHCO3, then brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with n-pentane to afford the title compound as a yellow solid. 1H NMR (DMSO-d6) δ 8.24 (d, J=1.9 Hz, 1H), 7.88-7.82 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H). HPLC (Method A): Rt 4.44 min (purity 97.9%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:18])=[CH:6][N:7]=1
Reactant: COC(=O)c1nccnc1N
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Commercially available methyl 3-amino-pyrazine-2-carboxylate (available from Aldrich Chemical Company) was brominated using a procedure similar to that of Russ, T., Ried, W., Ullrich, F., and Mutschler, E. Arch. Pharm. (Weinheim) 1992, 325, 761-767. To a solution of methyl 3-amino-2-pyrazine carboxylate (30.0 g, 200 mmol) in acetic acid (200 mL), bromine (11 mL) was added slowly via addition funnel. After complete addition of bromine, sodium carbonate powder was added slowly until precipitation occurred. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was reduced to half-volume in vacuo and then diluted with water (500 mL). The reaction mixture was shaken vigorously and the resulting solid was collected using vacuum filtration. The solid was washed with ether to afford a pure yellow solid (91% yield).
Reaction SMILES: [N:1]#[C:2]Cl.[Cl:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[Cl:12])[NH2:8].C(O)(=O)C.[OH-].[Na+]>C(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([NH:8][C:2]#[N:1])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: N#CCl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CNc1ccc(Cl)c(Cl)c1
Yield: 95.2 %

Procedure:
6.1 ml (0.12 mole) of cyanogen chloride were added, at a temperature below 10° C., to 16.3 g (0.1 mole) of 3,4-dichloroaniline in 150 ml of ethanol and 40 g of 50% strength acetic acid. 110 ml of 1N NaOH solution was then added dropwise. The mixture was stirred for a further hour and concentrated under a water pump vacuum until a bath temperature of 30° C. had been reached, and the residue was washed with water. 17.8 g (≅95% of theory) of 3,4-dichlorophenyl cyanamide were obtained. The substance was homogeneous according to examination by thin layer chromatography and gave a clear solution in 2N NaOH.