Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[C-:12]#[N:13].[K+]>CN(C=O)C.C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:12]#[N:13])[O:10][C:3]=12
Reactant: Clc1ccnc2cc(I)oc12
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc2nccc(Cl)c2o1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
In a sealed tube 7-chloro-2-iodofuro[3,2-b]pyridine (0.200 g, 0.72 mmol), KCN (0.093 g, 1.4 mmol), and copper (I) iodide (0.014 g, 0.072 mmol) were dissolved in 2 mL DMF. Pd(Ph3P)4(0.041 g, 0.036 mmol) was added, the tube was flushed with nitrogen, and the reaction in the tube was stirred overnight at 100° C. The reaction was cooled to RT, diluted with DCM, and washed with water. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chlorofuro[3,2-b]pyridine-2-carbonitrile as a white solid. MS: M+H+=179.4.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29](=O)[C:28]4[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=4[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[NH2:42][NH2:43]>CO>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29]4=[N:42][NH:43][C:31](=[O:33])[C:27]5[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=54)[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C(C)C)CC3)c1)C(c1ccncc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccncc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
A mixture of methyl 3-(3-(4-isobutyryl piperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg, 0.26 mmol) in 85% hydrazine monohydrate (10 mL) and methanol (3 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give compound 9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (11 mg, yield 8%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.1-1.13 (m, 6H), 2.95-2.98 (m, 1H), 3.26-3.68 (m, 8H), 4.40-4.42 (d, J=8.4 Hz, 1H), 4.82-4.84 (d, J=8.4 Hz, 1H), 7.19-7.32 (m, 4H), 7.36-7.39 (m, 3H), 7.59-7.68 (m, 2H), 8.41-8.42 (d, J=6.0 Hz, 2H); LC-MS (ESI) m/z: 523(M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:15]=[C:5]2[C:6]([N:10]3[CH2:13][CH:12]([OH:14])[CH2:11]3)=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.N1CC(O)C1.Cl[C:22]1[CH:30]=[C:29]2[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1>>[OH:14][CH:12]1[CH2:11][N:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:22]4[CH:30]=[C:29]5[C:25]([C:26]([CH3:33])([CH3:32])[C:27](=[O:31])[NH:28]5)=[CH:24][CH:23]=4)[N:15]=3)[CH:9]=[CH:8][N:7]=2)[CH2:13]1
Reactant: Nc1nc2c(N3CC(O)C3)nccn2n1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Agent: OC1CNC1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(N5CC(O)C5)nccn4n3)ccc21

Procedure:
1-(2-Amino-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-azetidin-3-ol, available by nucleophilic substitution of 8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine with azetidin-3-ol using general procedure 3, is reacted under amination conditions described in general procedure 2 with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one giving the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][Mg]Cl.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1.C[Si](Cl)(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH:14]1[CH2:15][CH2:16][CH2:17][C:12](=[O:18])[CH2:13]1
Reactant: O=C1C=CCCC1
Reactant: COc1cccc(C[Mg]Cl)c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CC2CCCC(=O)C2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 3-methoxybenzylmagnesium chloride (19.8 mole) in tetrahydrofuran (20 ml) was added a mixture of 2-cyclohexen-1-one (1.9 g) and trimethylsilyl chloride (5.8 ml) in tetrahydrofuran (30 ml) at -78° C. under N2. The mixture was stirred for 1 hour at 0° C. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid and the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give 3-(3-methoxybenzyl)cyclohexanone (2.12 g).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4].C1(=O)[NH:22]C(=O)C2=CC=CC=C12.[K]>CN(C)C=O.O>[NH2:22][CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(CBr)C1=CC2(CCCC2)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: NCC(O)C1=CC2(CCCC2)c2ccccc21

Procedure:
Crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (7.3 g; prepared as described in Example 3) in dimethylformamide (100 g) is stirred at 40° C. for 4 hours with potassium phthalimide (5.0 g), then diluted with water and extracted three times with chloroform. The combined extracts are dried and evaporated to dryness. The crude 2-phthalimido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is added to ethanol (100 ml) containing hydrazine hydrate (1.5 g). The reaction mixture is stirred under reflux for 4 hours, concentrated hydrochloric acid (2 ml) is added, and the mixture is heated for 15 minutes. The solution is cooled, filtered from the solid precipitate and concentrated to a small volume. The concentrate is made alkaline with 2 N sodium hydroxide solution and repeatedly extracted with diethyl ether. Evaporation of the ether and crystallization of the residual product from cyclohexane gives 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, m.p. 76°-78° C.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:14][C:13]([NH2:15])=[N:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[N:22]1[CH:27]=[CH:26][C:25]([C:28](=O)[CH2:29][C:30]([O:32]CC)=O)=[CH:24][CH:23]=1>C(O)C>[N:22]1[CH:23]=[CH:24][C:25]([C:28]2[N:15]=[C:13]3[NH:14][CH:9]([C:6]4[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=4)[CH2:10][CH2:11][N:12]3[C:30](=[O:32])[CH:29]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC1=NCCC(c2ccncc2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncc2)nc2n1CCC(c1ccncc1)N2
Reaction time: 0.08 h
Yield: 21.2 %

Procedure:
A suspension containing 1.0 g (4.01 mmoles) of 6-(4-pyridinyl)-1,4,5,6-tetrahydro-2-pyrimidinamine dihydrochloride in 30 ml of ethanol was treated with 1.94 g (14.05 mmoles) of potassium carbonate and allowed to stir for 5 min. 1.0 g (4.01 mmoles) of ethyl 3-(pyridin-4-yl)-3-oxopropionate were added and the resulting mixture was heated at reflux temperature for 18 h. The cooled solution was evaporated to remove solvent and the residue was dissolved in water and extracted with dichloromethane. The organic extracts were washed with a saturated solution of aqueous sodium chloride, dried and the solvent evaporated under reduced pressure. The crude product thus obtained was purified using silica gel chromatography eluting with a gradient of dichloromethane/methanol/concentrated aqueous ammonia solution in the proportions 95/5/0.5 to 80/20/2. 0.26 g (21%) of pure product was obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:15]1.CC1C=CC(S(=O)([S:44][CH2:45][CH2:46][CH2:47][O:48][Si](C(C)(C)C)(C)C)=O)=CC=1>O1CCCC1>[OH:48][CH2:47][CH2:46][CH2:45][S:44][C:21]1[C:18]2[C:19](=[O:20])[N:14]([CH3:13])[N:15]=[C:16]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:17]=2[S:23][C:22]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)SCCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(Cc3ccccc3)sc12
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Cc1nn(C)c(=O)c2c(SCCCO)c(Cc3ccccc3)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexanes (2.5M, 1.3 ml) was added to a solution of diisopropylamine (0.45 ml) in tetrahydrofuran (6 ml) at 0° C. under nitrogen. After 30 minutes, 5 ml of the resulting solution was added to a solution of 5-methyl-7-(2-methylpropyl)-2-phenylmethylthieno[2,3-d]pyridazin-4(5H)-one (example 15, 0.50 g) and S-[3-{[(1,1-dimethylethyl)dimethylsilyl]oxy}propyl] 4methylbenzenesulfonothioate, (J. Med. Chem. 1995, 38, 2557., 0.85 g) in tetrahydrofuran (10 ml) at −78° C. under nitrogen. The reaction mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride solution (25 ml) and extracted with ethyl acetate (50 ml). The organic extracts were washed twice with saturated aqueous ammonium chloride solution, twice with saturated sodium hydrogen carbonate solution, then with brine, dried, filtered and evaporated. The residue was dissolved in acetonitrile (20 ml) and treated with 40% hydrofluoric acid (1 ml). After 16 hours, saturated sodium hydrogen carbonate solution (50 ml) was added and the mixture was extracted with ethyl acetate (50 ml). The organic extracts were washed with brine, dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:2 then 1:1) to give the title compound (0.51 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([NH2:11])[CH2:9][NH2:10]>N1C=CC=CC=1>[NH2:10][CH2:9][CH2:8][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCN
Reactant: Brc1ccccn1
Solvent: c1ccncc1
Product: NCCNc1ccccn1

Procedure:
2-Bromopyridine (15.8 g), ethylene diamine (30 g) and pyridine (10 ml) were heated together under reflux for 3 hr. The mixture was stripped to remove the excess of ethylene diamine and the residue taken up in water. The pH was adjusted to 14 and extracted with chloroform. The extracts were dried (K2CO3), stripped and the residue distilled at reduced pressure to give 2-(2-aminoethylamino) pyridine, 8.24 g (60%) bp 80° C., 0.01 mm Hg. (ii) A mixture of sodium hydride (0.53 g) and 2-(aminoethylamino)pyridine (2.74 g) in DMSO (30 ml) was heated slowly to 85° C. under nitrogen. After the evolution of hydrogen had ceased the solution was cooled to room temperature and benzyl bromide (2.37 ml) added dropwise keeping the temperature below 30° C. After a further 1 hr, water (200 ml) was added, the mixture extracted with ether and the extract washed with 2N hydrochloric acid. The pH of the aqueous layer was adjusted to 4.5 and extracted with chloroform. The pH was further raised to 14 and extracted with ether. After drying (K2CO3) and stripping, the final ether extract gave 2-[N-(2-aminoethyl)-N-benzylamino]pyridine (2.58 g) as an oil which was used without further purification.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)[N:18]=1.[Br:38]Br>CCCCCC.O1CCCC1>[Br:38][C:22]1[C:17]([F:16])=[N:18][C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)=[CH:20][N:21]=1
Reactant: BrBr
Reactant: CCCCCCCCOc1ccc(-c2cncc(F)n2)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(Br)c(F)n2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
3.50 g (24.8 mmol) of 2,2,6,6-tetramethylpiperidine and 15.50 ml (24.80 mmol) of 1.6 M n-butyllithium solution in hexane are stirred at 0° C. for 0.5 hour in 80 ml of tetrahydrofuran, 250 ml of tetrahydrofuran are added, and the mixture is cooled to -78° C. 5.00 g (16.5 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyrazine in 150 ml of tetrahydrofuran and, after the mixture has been stirred for one hour, 0.85 ml of bromine are subsequently added dropwise at -78C. The reaction mixture is stirred overnight, during which it warms to room temperature, and is partitioned between ether and aqueous sodium chloride solution, the aqueous phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from the solvent, and the residue is purified by chromatography (silica/hexane: ethyl acetate = 9:1). 4.68 g of 2-bromo-3-fluoro-5-(4-octyloxyphenyl)pyrazine are obtained. ##STR16## 1d
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>O1CCCC1.O>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C(F)(F)F)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(C(F)(F)F)c1C(=O)O
Yield: 80.1 %

Procedure:
A solution of 5-methyl-3-trifluoromethylisoxazole-4-carboxylic acid ethyl ester (2.0 g) and sodium hydroxide (1.1 g) in tetrahydrofuran/water (20 ml/20 ml) was heated at reflux for 18 hours. The tetrahydrofuran was removed in vacuo and the aqueous residue washed with ethyl acetate (50 ml), acidified to pH2 with conc. hydrochloric acid and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml), separated, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a peach-coloured solid (1.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1I)[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([NH:36][C:37](=[CH2:42])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:33]([NH:36][C:37](=[CH:42][C:25]1[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:24]=1[O:23][CH2:22][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COc1cc(C#N)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(C)=O

Procedure:
5.72 g (10.4 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-(5-cyano-2-iodophenoxy)pentanoate was stirred together with 3.0 g (21 mmol) of methyl 2-acetamidoacrylate, 2.0 g (6.6 mmol) of tris(2-methylphenyl)phosphine, 270 mg (1.1 mmol) of palladium (II) acetate and 3.54 g (35 mmol) of triethylamine in 50 ml of DMF at 100° C. for 5 hours. The solvent was evaporated, and the residue was treated with ethyl acetate as the extracting solvent by an ordinary method and then purified by the silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][C:14]1[C:18]([S:19](Cl)(=[O:21])=[O:20])=[C:17]([CH3:23])[O:16][N:15]=1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[S:19]([C:18]1[C:14]([CH3:13])=[N:15][O:16][C:17]=1[CH3:23])(=[O:21])=[O:20]
Reactant: CNCCC#Cc1ccccn1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Product: Cc1noc(C)c1S(=O)(=O)N(C)CCC#Cc1ccccn1
Yield: 17.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 3,5-dimethylisoxazole-4-sulfonyl chloride (79 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 17 mg of N,3,5-trimethyl-N-(4-(pyridin-2-yl)but-3-ynyl)isoxazole-4-sulfonamide as a brown oil (Yield: 17%).
Reaction SMILES: F[C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[CH:16][C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)C>[F:22][C:17]1[CH:16]=[C:3]2[C:2](=[C:19]([F:20])[C:18]=1[F:21])[N:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4]2=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(OC)cc2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
A mixture of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate (0.4 g), p-anisidine (0.15 g) and ethanol (4 ml) is stirred at room temperature for 30 minutes. After the reaction, the solvent is distilled off under reduced pressure. To the residue is added anhydrous dioxane (10 ml) and thereto is further added portionwise 60% sodium hydride (60 mg). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into saturated aqueous ammonium chloride, and the mixture is extracted with dichloromethane to give ethyl 6,7,8-trifluoro-1-(4-methoxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.37 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[S:9]1[CH2:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].C(N(CC)CC)C>C(#N)C>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:11]1[C:12](=[O:14])[CH2:13][S:9][C:10]1=[O:15]
Reactant: BrCCCCCCBr
Reactant: O=C1CSC(=O)N1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CSC(=O)N1CCCCCCBr
Temperature: 25 °C
Yield: 69.4 %

Procedure:
36.6 g of 1,6-dibromohexane, 5.9 g of 2,4-thiazolidinedione and 7.1 g of triethylamine were added to 125 ml of acetonitrile and the mixture was heated with stirring under reflux for 8 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure and the residue was poured into water. The mixture was extracted with methylene chloride and the methylene chloride layer was washed with saturated brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1→4:1) to obtain 9.8 g of the title compound as pale yellow oil (yield: 70%).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)C.CN(C=O)C.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>O>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Agent: CN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2 ml of trimethylamine were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.4 g of 4-cyanobenzoyl chloride. After completion of addition, the reaction mixture was stirred at 40° to 50° C. for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 1.9 g of 5-[4-(4-cyanobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 266°-269° C., colorless granules.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:47]2[CH:48]=[CH:49][C:44]([S:41]([CH3:40])(=[O:43])=[O:42])=[CH:45][CH:46]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)OS(=O)(=O)c1ccc(C)cc1)n2S(=O)(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Yield: 50.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (1.1 g, 1.94 mmol), 4-(methanesulfonyl)phenylboronic acid (775 mg, 3.88 mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.194 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 2.5 mL, 5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The resulting mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine (540 mg, 54%) as a light yellow solid: LC/MS m/e calcd for C28H28N2O6S2 [M+H]+ 553.67, observed 553.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[C-:23]#[N:24].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2cccc(Br)c2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
A mixture of toluene-4-sulfonic acid 4-(3-bromophenyl)butyl ester (2.3 g, 6 mmol) and powdered sodium cyanide (0.65 g, 13 mmol) in DMSO was heated up to 80° C., stirred for 1.5 hours and monitored by NMR. When the reaction was complete, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of this residue on silica gel (ISCO) using (hexanes/EtOAC 9.5/0.5) as the eluting solvent gave 5-(3-bromo-phenyl)pentanenitrile as a colorless oil (1.12 g, 78% yield). m/e (M)+ 237; 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.63-2.65 (m, 2H), 2.75-2.78 (m, 2H), 2.35-2.38 (m, 2H), 2.60-2.63 (m, 2H), 7.05-7.10 (m, 2H), 7.25-7.28 (m, 2H).