Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[O:18][C:19]=1[CH3:20])[CH:6]=[CH:7][CH:8]=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:30]2[S:26][C:27](=[O:32])[NH:28][C:29]2=[O:31])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[O:18][C:19]=1[CH3:20]
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccco2)oc1C
Product: COc1cc(CCCC2SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 9 %

Procedure:
According to the same manner as that described in Example 13, 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]cinnamaldehyde was condensed with 2,4-thiazolidinedione, and the resulting product was subjected to catalytic hydrogenation to give 5-[3-[3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]propyl]-2,4-thiazolidinedione (yield: 9%). This product was recrystallized from chloroform-diethyl ether. Colorless prisms, mp: 109-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[NH2:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2ccccc2Br)Nc2ccc(C#N)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1ccccc1C1CC(C)(C)c2cc(C#N)ccc2N1)C(=O)O
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of 2-(2-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (120.1 mg, 33.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 364.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: COc1ccc(Cl)cc1
Reactant: Nc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1ccc(Nc2ccc(F)cc2)cc1
Temperature: 110 °C
Yield: 96.2 %

Procedure:
Following general procedure E, a mixture of 4-chloroanisole (123 μL, 1.0 mmol), 4-fluoroaniline (114 μL, 1.2 mmol), NaOt-Bu (115 mg, 1.2 mmol), 10 (0.08 mg, 0.01 mol %), 1 (0.05 mg, 0.01 mol %), and Bu2O (1 mL) was heated to 110° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-30% EtOAc/hexanes) to provide the title compound as a white solid (209 mg, 94%), mp 59-60° C. 1H NMR (300 MHz, CDCl3) δ: 7.03-6.86 (m, 8H), 5.41 (s, 1H), 3.81 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 159.0, 155.8, 155.2, 141.4, 136.8, 121.4, 118.0, 117.9, 116.2, 115.9, 115.0, 55.8 ppm. IR (neat, cm−1): 3391, 3007, 1508, 1314, 1243, 1221, 1027, 814, 772, 591. Anal. Calcd. for C13H12FNO: C, 71.87; H, 5.57. Found: C, 71.89; H, 5.62.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][N:18]1[C:22]([CH2:23][NH:24][C:25]2[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=2[CH3:31])=[CH:21][C:20]([CH3:33])=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][N:18]1[C:22]([CH2:23][NH:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=2[CH3:31])[O:32][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)=[CH:21][C:20]([CH3:33])=[N:19]1
Reactant: Cc1cc(CNc2cc(O)ccc2C)n(C)n1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CNc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 72.4 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (210 mg, 0.64 mmol), 3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}-4-methylphenol (220 mg, 0.96 mmol), potassium carbonate (220 mg, 1.6 mmol) and N,N-dimethylformamide (1.5 mL) was stirred under microwave irradiation at 150° C. for 40 min. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (200 mg, 72%) as a brown solid.
Reaction SMILES: N1C=CC=C1[C:6]1[CH2:12][CH2:11][CH2:10][CH:9]=[C:8]([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:7]=1[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21].O1CCCC1>O>[C:8]1([C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:7]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])=[CH:6][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CC(C)COC(=O)C1=CCCCC(c2ccc[nH]2)=C1C(=O)OCC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COC(=O)C1=CCCCC=C1C(=O)OCC(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a four-necked two litter flask purged with nitrogen, 165.4 g (455.0 mmol) of diisobutyl 3-pyrrolylcyclohepta-2,7-diene-1,2-dicarboxylate obtained in Reference Example 2 and 1,158 mL of tetrahydrofuran were charged. Thereto, 500.0 mL (containing 455.0 mmol of borane-tetrahydrofuran complex) of a tetrahydrofuran solution (concentration: 0.91M) of a borane-tetrahydrofuran complex was added dropwise over 1.5 hour. The mixture was stirred for 6 hours at room temperature. The reaction mixture was provided with water, and the resultant mixture was subjected to toluene extraction. The extraction liquid was washed with water, and was dried over anhydrous magnesium sulfate. The dried liquid was filtered, and volatile matters contained therein were distilled away under reduced pressure to obtain orange colored oil. The oil was purified with silica-gel column chromatography (developing solvent: mixed solvent of 4 parts by volume of hexane with one part by volume of ethyl acetate), thereby obtaining 105.0 g (yield: 78.0%) of diisobutyl cyclohepta-2,7-diene-1,2-dicarboxylate as pale yellow oil with a purity of 99.6% determined by a gas chromatography measurement, its NMR and GCMS data being shown below:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([C:23](Cl)=[O:24])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>>[CH2:1]([NH:4][C:23]([C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][Br:5])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:24])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1c from n-propylamine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:18]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:21][C:10]1=2.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:18]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:19][C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:21][C:10]1=2)(=[O:4])=[O:3]
Reactant: OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
A mixture of methanesulfonyl chloride (0.38 mL) in methylene chloride (20 mL) is added dropwise to a mixture of 9-(2-hydroxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (VIII, EXAMPLE3, 1.05 g) and triethylamine (0.5 mL) in methylene chloride (25 mL). After a few minutes, the reaction mixture is diluted with water and extracted with methylene chloride. The organic layer is dried (sodium sulfate) and concentrated, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[NH:7][C:6]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:7][C:6]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(=O)[nH]c1C(=O)c1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)nc1C(=O)c1ccccc1
Reaction time: 24 h

Procedure:
A slurry of 2-benzoyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (1.00 g), benzyl bromide (1.88 ml) and silver carbonate (1.64 g) in toluene (50 ml) was stirred at room temperature in the dark under nitrogen for 3 days. More silver carbonate (0.82 g) was added and the slurry was stirred as before for 24 h. A final portion of silver carbonate (0.82 g) was added, and the mixture was stirred as before for 3 days. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane, yielding 2-benzoyl-6-benzyloxynicotinic acid methyl ester as a pale brown solid (1.14 g). 1H NMR (400 MHz, CDCl3) δ3.69 (3H, s), 5.39 (2H, s), 6.92 (1H, d, J=8.8 Hz), 7.30 (3H, m), 7.37 (2H, m), 7.45 (2H, t, J=7.7 Hz), 7.59 (1H, t, J=7.4 Hz), 7.78 (2H, d, J=7.8 Hz), 8.25 (1H, d, J=8.7 Hz); MS (ES+) m/e 348 [MH]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:26])=[C:8]([C:16]([C:18]2[CH:19]=[N:20][N:21]([CH2:24][CH3:25])[C:22]=2[OH:23])=[O:17])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:33](=[O:40])([O:38][CH3:39])[O:34][CH:35](Cl)[CH3:36].O>CC(=O)CC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:33](=[O:40])([O:38][CH3:39])[O:34][CH:35]([O:23][C:22]1[N:21]([CH2:24][CH3:25])[N:20]=[CH:19][C:18]=1[C:16](=[O:17])[C:8]1[CH:9]=[CH:10][C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:7]=1[CH3:26])[CH3:36]
Reactant: COC(=O)OC(C)Cl
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Solvent: O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2C)c1OC(C)OC(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
5-Hydroxy-1-ethylpyrazol-4-yl 3-(2-methoxyethoxy)-2-methyl-4-(methylsulfonyl)phenyl ketone (300 mg) was dissolved in 2-butanone (10 mL), and potassium carbonate (130 mg) and tetrabutylammonium bromide (15 mg) were added. After stirring at room temperature for 10 minutes, 1-chloroethyl methyl carbonate (purity: 85%, 270 mg) was added at room temperature, followed by heating and refluxing for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into water and then extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and a saturated sodium chloride aqueous solution, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography with n-hexane:ethyl acetate=1:1, to obtain the desired product (180 mg) as slightly yellow solid. The NMR spectrum data of this product are as follows.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C:19]1[CH:24]=[C:23](F)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[NH2:18][C:19]1[CH:24]=[C:23]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:20]=1[NH:29][C:30](=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: Sc1cccc2cnccc12
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])c(F)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(=O)Nc1cc([N+](=O)[O-])c(Sc2cccc3cnccc23)cc1N
Temperature: 90 °C
Reaction time: 6 h
Yield: 12.7 %

Procedure:
5-Isoquinolinethiol 500 mg (3.1 mmol) was dissolved in DMF 20 ml, potassium carbonate 1.29 g (9.3 mmol) and N1-(2-amino-4-fluoro-5-nitrophenyl)butane amide 750 mg (3.1 mmol) were added, and the mixture was heated with stirring at 90° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate-ether was added to the resulting residue to crystallize. The crystals were collected and washed with methanol to obtain N1-[2-amino-4-(5-isoquinolylsulfanyl)-5-nitrophenyl]butanamide 150 mg (12.9%).
Reaction SMILES: [C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].C([O-])(=O)C>CO>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7]
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCC(=O)[O-]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(C)(CO)[C@H](O)C(=O)NCCC(=O)O

Procedure:
The concentration of the D-pantothenate formed is then determined in the culture supernatant centrifuged off by means of High Performance Liquid Chromatography [column: Reversed Phase MZ-Aqua Perfect (diameter 4,6 mm), mobile Phase 25 mM acetate buffer with 10% methanol, flow rate 1 ml/min, RI detector].
Reaction SMILES: CO[CH:3]([NH:7][C:8]([NH2:10])=[O:9])[C:4]([OH:6])=O.[C:11]1([C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14])[OH:12].NC(N)=O>Cl>[OH:12][C:11]1[CH:18]=[C:17]([CH:3]2[NH:7][C:8](=[O:9])[NH:10][C:4]2=[O:6])[CH:16]=[CH:15][C:13]=1[OH:14]
Reactant: Oc1ccccc1O
Reactant: COC(NC(N)=O)C(=O)O
Agent: Cl
Agent: NC(N)=O
Product: O=C1NC(=O)C(c2ccc(O)c(O)c2)N1
Reaction time: 18 h
Yield: 44 %

Procedure:
One mole (148.12 g) of α-methoxyhydantoic acid, 1.25 moles (137.64 g) of catechol, 1 mole (60.06 g) of urea and 300 ml of concentrated HCl (36 percent volume) were placed into the 2-liter flask of Preparation 1, and are stirred at 60° C. to 65° C. for 18 hours. The heterogeneous solution is filtered and is recrystallized from ethanol to give the title compound, with a melting point of 212° C.-214° C., in a yield of 44 percent.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:13][CH3:14])=[N:7][C:8]([NH2:12])=[C:9]([Cl:11])[CH:10]=1)=[O:4].[OH-].[Na+].O>CO>[NH2:12][C:8]1[N:7]=[C:6]([O:13][CH3:14])[C:5]([C:3]([OH:4])=[O:2])=[CH:10][C:9]=1[Cl:11]
Reactant: COC(=O)c1cc(Cl)c(N)nc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nc(N)c(Cl)cc1C(=O)O
Temperature: 25 °C

Procedure:
A solution of methyl-6-amino-5-chloro-2-methoxypyridine-3-carboxylate (0.32 g) in MeOH (5 mL) was treated with 2.5N NaOH (0.6 mL) and H2O (5 mL) and the reaction stirred at room temperature until the reaction was complete by TLC. The MeOH was removed by rotary evaporation and the residue carefully acidified with 5N HCl to give the title compound which was collected and dried (0.15 g).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:17]4=[N:18][CH:19]=[CH:20][C:21](Br)=[C:16]4[CH:15]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].Br[C:34]1[C:35]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=2)=[N:36][N:37]([CH2:39][CH3:40])[CH:38]=1>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:14]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:17]4=[N:18][CH:19]=[CH:20][C:21]([C:34]5[C:35]([C:41]6[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[CH:43][CH:42]=6)=[N:36][N:37]([CH2:39][CH3:40])[CH:38]=5)=[C:16]4[CH:15]=3)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(-c3cc4c(Br)ccnc4n3S(=O)(=O)c3ccccc3)cc2C1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc4c(c2)CN(C(C)=O)CC4)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reaction time: 4.5 h

Procedure:
Following the procedure described for Intermediate 32 with 2-acetyl-7-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1,2,3,4-tetrahydroisoquinoline. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea and stirring for 4.5 hours provided the title compound. ESMS [M+H]+: 688.6.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:2]=1.BrN1C(=[O:18])CCC1=O.C1N2CN3CN(C2)CN1C3.Cl>C(Cl)(Cl)Cl.C(Cl)Cl.O>[CH:11]([C:1]1[CH:2]=[C:3]([CH2:7][C:8]([OH:10])=[O:9])[CH:4]=[CH:5][CH:6]=1)=[O:18]
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1cccc(CC(=O)O)c1
Yield: 62 %

Procedure:
To a solution of 2-(m-tolyl)acetic acid in chloroform (30 mL) was added N-bromosuccinimide (2.37 g, 13.32 mmol). The mixture was heated to reflux for 8 hours and the solvent was removed in vacuo. The residue was dissolved in ethanol (30 mL) and water (30 mL) and hexamethylenetetramine (5 g, 35.7 mmol) was added. The mixture was heated to reflux for 4 hours. Concentrated HCl (5.9 mL) was added cautiously to the mixture at reflux. The mixture was heated to reflux for 30 minutes and then allowed to cool. Water (30 mL) and DCM (30 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was taken up into saturated aqueous sodium bicarbonate solution, and washed with DCM (2×15 mL). The aqueous phase was acidified with 2M aqueous HCl. The mixture was extracted with DCM (2×15 mL) and the combined organic fractions were passed through a hydrophobic frit. The solvent was removed in vacuo to afford a mixture of the title compound as an off-white solid (1.35 g, 62%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 7.84-7.79 (m, 2H), 7.60-7.48 (m, 2H), 3.75 (s, 2H). LCMS (Method 1): [MH+]=165 at 2.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13]O)=[CH:4][C:3]=1[F:21].N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].S(Cl)([Cl:36])=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH2:12][CH2:13][Cl:36])=[CH:4][C:3]=1[F:21]
Reactant: CCOC(=O)c1cn(CCO)c2cc(Cl)c(F)cc2c1=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(CCCl)c2cc(Cl)c(F)cc2c1=O
Yield: 80 %

Procedure:
27 g of the foregoing ester product were added, portionwise, to an agitated and cooled solution of pyridine (8.1 cm3) in thionyl chloride (54 cm3). The addition was carried out at such a rate that the temperature of the mixture remained between 0° and 5° C. After returning to room temperature, the solution was heated for 1 hour under reflux and the excess of reagent was then removed by distillation under reduced pressure. The residue was added, with agitation, to 100 cm3 of iced water. The suspension obtained was neutralised by the addition of 10% aqueous Na2CO3. The precipitate obtained was filtered off, washed with water and recrystallised from ethanol (480 cm3). 22.4 g of 7-chloro-1-(2-chloroethyl)-3-ethoxycarbonyl-6-fluoro-4-oxo-1,4-dihydro-quinoline, m.p. 222° C., were obtained; yield 80%.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[CH2:26][NH:25][CH2:24][CH2:23][NH:22]2)=[C:17]([CH3:27])[CH:16]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:25]1[CH2:24][CH2:23][NH:22][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=2[CH3:27])[CH2:26]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(F)ccc1[C@H]1CNCCN1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of benzylchloroformate (376 μL) in dry DCM (20 mL) was added drop-wise to a solution of the 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine dihydrochloride (700 mg) and TEA (1.1 mL) in DCM (30 mL) previously cooled to 0° C. under a nitrogen atmosphere. The mixture was stirred at r.t. for 2 hrs, then washed with brine. The organic layer was dried, concentrated in vacuo and the residue was purified by flash chromatography (from CH/AcOEt 1:1 to AcOEt 100%) to give the title compound (750 mg) as colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:23])=[C:4]([C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:1][C:2]1[C:3]([CH3:23])=[C:4]([C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:12])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)c1ccc(C(=O)c2c(C)c(O)c3ccccn23)cc1
Reactant: COc1cccc(CBr)c1
Product: COC(=O)c1ccc(C(=O)c2c(C)c(OCc3cccc(OC)c3)c3ccccn23)cc1

Procedure:
This compound is obtained according to the same procedure as that of Example 86, by O-alkylation of methyl 4-[(1-hydroxy-2-methylindolizin-3-yl)carbonyl]benzoate with 3-methoxybenzyl bromide. A yellow powder is obtained which melts at 106° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48].O>C1(C)C=CC=CC=1>[Br:48][CH2:26][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CO)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)methanol (472 mg) and triphenylphosphine (675 mg) in toluene (10 mL) was added carbon tetrabromide (635 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (434 mg) as a colorless oil.