Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:16][CH:17]=O)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:21]([O:25][C:26]([N:28]1[CH2:35][CH:34]2[O:36][CH:30]([CH2:31][NH:32][CH2:33]2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCl.O>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]2[O:36][CH:34]([CH2:33][N:32]([CH2:17][CH2:16][N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:19]=[CH:20][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:31]2)[CH2:35]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CN(C)C(=O)N(CC=O)CCOc1ccc(C#N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Reaction time: 1 h
Yield: 102.5 %

Procedure:
1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethyl-1-(2-oxoethyl)urea (4.5 g; see Preparation G above) was taken in dichloromethane (100 mL). 9-Oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (2.9 g, 0.013 mol; see WO 01/28992), followed by glacial acetic acid (1.47 g, 0.0245 mol), was added, and reaction mixture was stirred for 1 h. NaBH3CN (1.54 g, 0.024 mol) was added at 0° C., and stirring was continued overnight at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation, followed by purification by column chromatography, yielded the title compound (6.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.CCN(CC)CC.Cl.[NH2:21][OH:22]>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8]/[C:9]/2=[N:21]\[OH:22])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1)/C(=N/O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To the solution of 6-methoxy-2,3-dihydro-1H-inden-1-one (6.5 g, 40 mmol) in 100 mL of MeOH was added Et3N (11.1 mL, 80 mmol) and hydroxylamine hydrochloride (3.9 g, 56 mmol). The mixture was stirred at rt for 2 h. The mixture was evaporated and redissolved in EtOAc, the organic phase was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give (E)-6-methoxy-2,3-dihydro-1H-inden-1-one oxime (intermediate 16) (6.6 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]([CH3:20])=[C:13]1[C:21](O)=[O:22].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[CH3:34].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[N:15]([CH3:19])[C:14]([CH3:20])=[C:13]1[C:21]([NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[CH3:34])=[O:22]
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1C
Reactant: Cc1n[nH]c2ccc(N)cc12
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
The product from Example 45, Step 2 (215 mg, 0.649 mmol, 1.00 equiv), 5-amino-3-methylindazole (96 mg, 0.649 mmol, 1.0 equiv), and EDC (149 mg, 0.779 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.109 mL, 0.779 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (0-80% EtOAc in Hexanes) to provide 70 mg (23%) of the title compound as a white solid. MS (ES+) m/e 461 [M+H]+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[C:8]1([S:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCCCSc1ccccc1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(5-chloropentyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 411.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH:27](/B(O)O)=[CH:28]/[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.O>C(OCC)(=O)C.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>[O:11]=[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:27]=[CH:28][CH3:29])[CH:10]=2)[CH2:6][N:7]1[C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:26])[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:16][CH:17]=1
Reactant: C/C=C\B(O)O
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Br)cc3C2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC=Cc1ccc2c(c1)C(=O)N(c1ccc(C(C)C(=O)OC(C)(C)C)cc1)C2
Temperature: 120 °C
Yield: 79.5 %

Procedure:
A mixture of tert-butyl 2-(4-(6-bromo-1-oxoisoindolin-2-yl)phenyl)propanoate (0.200 g, 0.48 mmol), cis-1-propene-1-boronic acid (0.413 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.554 g, 0.48 mmol), and cesium carbonate (0.470 g, 1.44 mmol) in 5:2 DME/water (7 mL) was heated in a microwave reactor for 20 min at 120° C. The mixture was cooled to room temperature, then diluted with ethyl acetate (8 mL). The reaction mixture was concentrated and purified by flash chromatography (silica, gradient 1-20%, ethyl acetate/hexanes) afforded tert-butyl 2-(4-(1-oxo-6-(prop-1-enyl)isoindolin-2-yl)phenyl)propanoate (0.144 g, 77%) as a yellow solid: mp 125-130° C.; 1H NMR (500 MHz, CDCl3) δ 7.96-7.80 (m, 2H), 7.75-7.65 (m, 1H), 7.54-7.34 (m, 4H), 6.53-6.33 (m, 1H), 5.93-5.87 (m, 1H), 4.84-4.80 (m, 2H), 3.66-3.60 (m, 1H), 1.94-1.91 (m, 3H), 1.47-1.45 (m, 3H), 1.41 (s, 9H) [6:4 mixture of olefin isomers determined by NMR]; ESI MS m/z 378 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][OH:11])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH2:10][OH:11])[S:3][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[S:22])#[N:8]
Reactant: Cc1c(CO)sc(N)c1C#N
Reactant: O=C(N=C=S)c1ccccc1
Product: Cc1c(CO)sc(NC(=S)NC(=O)c2ccccc2)c1C#N

Procedure:
Prepared as in example 1a from 2-amino-5-(hydroxymethyl)-4-methylthiophene-3-carbonitrile (Example 9b) and benzoyl isothiocyanate as a yellow solid. MS 332 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[I:10]I>CO.OO>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([I:10])[C:3]=1[NH2:9]
Reactant: II
Reactant: Cc1ccc(N)c(F)c1
Agent: OO
Solvent: CO
Product: Cc1cc(F)c(N)c(I)c1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
A solution of 2-fluoro-4-methylphenylamine (1.25 g, 10 mmol) in 5 mL of methanol was treated with a solution of iodine (1.27 g, 5 mmol) in a mixture of 25 mL of methanol and 3 mL of hydrogen peroxide over a period of 15 minutes at room temperature. After 18 hours, the reaction mixture was quenched with 30 mL of saturated aqueous sodium thiosulfate and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with two 30 mL portions of saturated sodium bisulfite solution, three 50 mL portions of water, dried over sodium sulfate, and concentrated in vacuo. Chromatography on SiO2 (10% ethyl acetate in hexanes) gave 1.1 g of the title product as a light brownish oil (44% yield).
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:34])[CH:32]=[CH2:33]>C(Cl)Cl>[C:31]([O:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[CH:22]=[CH:23][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)=[CH:14][CH:15]=1)(=[O:34])[CH:32]=[CH2:33]
Reactant: OCCc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 0 °C
Yield: 86 %

Procedure:
To a 1 L three-neck round bottom flask equipped with mechanical stirrer were charged 2-[4-(4-phenoxyphenoxy)phenyl]ethanol (61.2 g, 0.2 mol), anhydrous triethylamine (60 mL, 0.42 mol), and anhydrous methylene chloride (300 mL). The solution was cooled in an ice/salt bath under dry air blanket for 15 mins. Acryloyl chloride (22 mL, 0.27 mol) was added into the vigorously stirred cold solution through an addition funnel over 60 min and the addition rate was adjusted to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was stirred in the ice/salt bath for additional two hours followed by quenching with the addition of 2M HCl (300 mL). The mixture was extracted with ethyl acetate (300 mL×3) and the combined organic layer was washed with DI water (200 mL×3), aqueous sodium bicarbonate (200 mL×2), and dried over MgSO4. Filtration and removal of solvents under reduced pressure gave the crude product as light brown oil which was purified on silica gel using Hexanes/Ethyl acetate (9/1, v/v) as eluent to give P3E2EA as a white powder (62 g, 86%).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:14])=[O:13])[CH:6]=[CH:7][CH:8]=1.[N+:21](C1C=C(NC2C=CC=CC=2C(O)=O)C=CC=1)([O-:23])=[O:22]>>[N+:21]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:14])=[O:13])[CH:6]=[CH:7][CH:8]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1Nc1cccc(C(F)(F)F)c1
Product: O=C(Cl)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Yield: 77 %

Procedure:
The following compound is obtained using the same procedure as that used for procurement of 2-(3-trifluoromethylphenylamino)-benzoyl chloride except that an equivalent amount of 2-(3-nitrophenylamino)-benzoic acid is used in place of the 2-(3-trifluoromethylphenylamino)-benzoic acid of the reference example from 2-(3-nitrophenylamino)-benzoic acid: 2-(3-Nitrophenylamino)-benzoyl chloride ##STR9## Yield: 77% of theory, melting point: 141°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-])=O)=[CH:20][C:19]=4[Cl:28])=[C:11]3[C:10]([CH3:29])=[N:9]2)=[CH:5][CH:4]=1>CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[C:19]([Cl:28])=[CH:20][C:21]([NH2:25])=[C:22]([F:24])[CH:23]=4)=[C:11]3[C:10]([CH3:29])=[N:9]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4cc(F)c([N+](=O)[O-])cc4Cl)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4cc(F)c(N)cc4Cl)ccnc32)cc1
Yield: 41 %

Procedure:
Prepared by process from Example 92, Step B, substituting 1-(4-methoxybenzyl)-4-(2-chloro-5-fluoro-4-nitrophenoxy)-3-methyl-1H-pyrazolo[3,4-b]pyridine (0.850 g, 1.92 mmol). The reaction mixture was dilute with EtOAc (250 mL) and saturated Na2CO3 (50 mL) was added. The solution was filtered through celite and the filtrate was dried over sodium sulfate and concentrated to provide the product (0.325 g, 35%). The crude material was used in the next step without purification.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Al](C)C.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24](=[NH:25])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[N:22][CH:23]=1
Reactant: Cc1ccc(C#N)nc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (10 mmol) in toluene (60 ml) at 0° C., trimethylaluminum (2M solution in toluene, 10 ml, 20 mmol) is added over 10 minutes. The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. A solution of 5-methyl-2-cyanopyridine (20 mmol) in toluene (100 ml) is added over 10 minutes and the mixture is heated to 85°-90° C. After 24 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride and methanol and later with methanol. The combined filtrates are concentrated and the resulting solid is stirred with a mixture of hexane and ethyl acetate (1000 ml) and filtered. The product obtained is used in the next reaction without further purification.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[NH2:12][C:13]1[C:14]([NH:18][C:19]([NH:21][C:22]2[C:26]([Cl:27])=[CH:25][S:24][C:23]=2[Cl:28])=S)=[CH:15][S:16][CH:17]=1.[OH-].[Na+].Cl>C1COCC1.O.C(OCC)(=O)C>[ClH:10].[Cl:28][C:23]1[S:24][CH:25]=[C:26]([Cl:27])[C:22]=1[NH:21][C:19]1[NH:18][C:14]2=[CH:15][S:16][CH:17]=[C:13]2[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cscc1NC(=S)Nc1c(Cl)csc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Clc1csc(Cl)c1Nc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 108.4 mg of p-toluenesulfonyl chloride in 5 ml of anhydrous THF was added dropwise to a mixture prepared from a solution of 157 mg of N-(4-amino-3-thienyl)-N′-(2,4-dichlorothienyl)thiourea in 15 ml of THF and a solution of 51.08 mg of NaOH in 2 ml of water. The resulting dark solution was stirred at room temperature for 2 hours, the solvent was distilled off and the residue was admixed with water. After extraction with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate. After the solvent had been distilled off, the residue was purified by column chromatography on silica gel using a mixture of 20 parts by volume of ethyl acetate, 10 parts by volume of n-heptane, 3 parts by volume of glacial acetic acid as an eluent, which was then distilled off under reduced pressure. A viscous amorphous product was obtained which was dissolved in ethyl acetate and made strongly acidic using hydrogen chloride gas-saturated diethyl ether. The crystallization of the amorphous hydrochloric acid salt was brought about by scratching. M.p.: >300° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>O1CCCC1>[CH3:24][S:21]([O:1][N:2]=[C:3]([C:12]#[N:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C#N)=NO)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)=NOS(C)(=O)=O)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
α-(Methylsulfonyloxyimino)-4-methoxybenzyl cyanide was prepared in the following manner. Thus, 51.0 g (0.29 mole) of α-hydroxyimino-4-methoxybenzyl cyanide and a solution prepared by dissolving 44.0 g (0.43 mole) of triethylamine in 400 ml of tetrahydrofuran were introduced into a reaction vessel to form a uniform solution which was chilled to and kept at -5° C. Into the solution in the reaction vessel were added dropwise 36.5 g (0.32 mole) of mesyl chloride over a period of 2 hours under agitation. The reaction mixture in the vessel was agitated at -5° C. for 3 hours and then at about 10° C. for additional 2 hours. The reaction mixture was freed from tetrahydrofuran as the solvent by distillation under reduced pressure at 30° C. to give 73.6 g of a solid residue as a crude product which was purified by repeating recrystallization from acetonitrile to give 47.5 g of a white crystalline product having a melting point of 116° C., which could be identified to be the target compound from the results of the analysis described below. The above mentioned yield of the product corresponds to 64.5% of the theoretical value.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:19][CH:20]=1)[CH3:13]
Reactant: CCc1cccc(N)c1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCc1cccc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-ethylaniline to yield 2-[(3-ethylphenyl)amino]phenylacetic acid.
Reaction SMILES: C(O)C(N)(CO)CO.Cl.[CH3:10][C:11]([C@@H:45]([OH:57])[C:46]([NH:48][CH2:49][CH2:50][C:51]([NH:53][CH2:54][CH2:55][SH:56])=[O:52])=[O:47])([CH2:13][O:14][P:15]([O:18][P:19]([O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])([OH:21])=[O:20])([OH:17])=[O:16])[CH3:12].C[O:59][C:60]1C(O)=C(OC)[CH:63]=[C:62](/C=C/C(O)=O)[CH:61]=1>FC(F)(F)C(O)=O.C(#N)C>[C:60]([S:56][CH2:55][CH2:54][NH:53][C:51](=[O:52])[CH2:50][CH2:49][NH:48][C:46](=[O:47])[C@H:45]([OH:57])[C:11]([CH3:10])([CH3:12])[CH2:13][O:14][P:15]([OH:17])(=[O:16])[O:18][P:19]([OH:21])(=[O:20])[O:22][CH2:23][C@H:24]1[O:28][C@@H:27]([N:29]2[C:33]3[N:34]=[CH:35][N:36]=[C:37]([NH2:38])[C:32]=3[N:31]=[CH:30]2)[C@H:26]([OH:39])[C@@H:25]1[O:40][P:41]([OH:44])([OH:43])=[O:42])(=[O:59])/[CH:61]=[CH:62]/[CH3:63]
Reactant: COc1cc(/C=C/C(=O)O)cc(OC)c1O
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/C(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
The assay mixture contained 50 mM Tris-HCl (pH 7.5), 1 mM CoA ester, and about 1 μg cell free extract. Reactions were allowed to proceed at room temperature and were stopped by adding 1 volume 10% trifluoroacetic acid (TFA). The reaction mixtures were purified prior to MALDI-TOF MS analysis using Sep Pak Vac C18 50 mg columns (Waters, Inc.). The columns were conditioned with 1 mL methanol and then equilibrated with two washes of 1 mL 0.1% TFA. The sample was applied to the column, and the flow through was discarded. The column was washed twice with 1 mL 0.1% TFA. The sample was eluted in 200 μL 40% acetonitrile, 0.1% TFA. The acetonitrile was removed by centrifugation in vacuo. Samples were prepared for MALDI-TOF MS analysis by mixing 1:1 with 110 mM sinapinic acid in 0.1% TFA, 67% acetonitrile. The samples were allowed to air dry.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[N:16]=[C:15]([C:17]3[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:13][C:12]=1[CH:43]=[CH:44][CH2:45][CH2:46][OH:47])[NH:6]2>CC(N(C)C)=O.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[CH:13][C:12]=4[CH2:43][CH:44]([CH2:45][CH2:46][OH:47])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(C=CCCO)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(CCO)C4)cc12
Reaction time: 3 h
Yield: 33.3 %

Procedure:
A solution of (Z and E)-5-(6-(4-fluoro-1H-indol-2-yl)-5-(4-hydroxybut-1-en-1-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (300 mg, 0.457 mmol) in DMAc (9 mL) was added K3PO4.3H2O (606 mg, 2.28 mmol) under N2. It was put into a pre-heated oil-bath at 110° C. for 3 hours. The mixture was diluted with H2O and it was extracted with EtOAc (500 mL×5). The combined organic phase was washed with brine, and dried over Na2SO4. The crude product was purified with Prep-HPLC to give the pure product of 5-(11-fluoro-6-(2-hydroxyethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 7.97 (s, 1H), 7.88˜7.92 (m, 2H), 7.63 (s, 1H), 7.60 (s, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.09˜7.22 (m, 5H), 6.72 (t, J=8.4 Hz, 1H), 5.83 (s, 1H), 5.02 (d, J=6.4 Hz, 1H), 3.43˜3.55 (m, 4H), 3.35 (s, 3H), 3.10 (d, J=24.0 Hz, 1H), 2.94 (d, J=4.4 Hz, 3H), 2.61 (s, 3H), 1.78 (d, J=5.2 Hz, 2H). MS (M+H)+: 657.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:23])[NH:7][C:6]=1[CH:24](OC)[O:25]C)=[O:4].Cl>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:23])[NH:7][C:6]=1[CH:24]=[O:25])=[O:4]
Reactant: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C(OC)OC)=C2C(=O)OC)c1
Agent: Cl
Solvent: CC(C)=O
Product: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C=O)=C2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
The mixture of 4.3 g (0.011 mol) of 3,5-dimethoxycarbonyl-1,4-dihydro-6-methyl-2-dimethoxymethyl-4-(3 -ethynylphenyl)pyridine obtained in Example 14, 5 ml of 6N hydrochloric acid and 50 ml of acetone was stirred for 4 hours at room temperature. After completing the reaction, acetone was distilled away, water was added to the residue. Then pH of the solution was adjusted to 7.5 with saturated solution of sodium hydrogencarbonate. The solution was extracted with ethyl acetate several times. All organic layers thereof were mixed, and were washed with water, dehydrated and concentrated. Then, the residue was purified by subjecting to silica gel column chromatography [eluent: benzene-ethyl acetate (5 : 4)] and recrystallized from ethyl acetate to give 2.4 g of the desired compound as yellow prism crystals (yield: 64.9%).