Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([O:12]C/C=C(/CCC=C(C)C)\C)=[O:11])=[O:7])([CH3:3])[CH3:2].II.[Mg].IC1C=CC=CC=1C(C)C>IC1C=CC=CC=1C(C)C.C(OCC)C.C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[C:6]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])[CH3:2]
Reactant: CC(C)=CCC/C(C)=C/COC(=O)c1ccccc1C(=O)c1ccccc1C(C)C
Agent: CC(C)c1ccccc1I
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)c1ccccc1C(=O)c1ccccc1C(=O)O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 28.1 %

Procedure:
Geranyl 2-(2'-isopropylbenzoyl)benzoate (2) Magnesium (0.46 g, 19 mmol) and a crystal of iodine were placed in a dry round bottom flask which was heated to activate the magnesium. Diethyl ether was added to cover the magnesium (50mL) and several drops of 2-iodoisopropyl benzene in diethyl ether were added to start the preparation of the Grignard reagent. When the latter was underway, a solution of 2-iodoisopropyl benzene (4.18 g, 17 mnol) in diethyl ether (20 mL) was added over 20 minutes. The reaction mixture was stirred for another 15 minutes and then refluxed for 20 minutes. Phthalic anhydricie (3.11 g, 21 mmol) in toluene (50 mL) was added dropwise to the Grignard reagent at room temperature. The reaction temperature was raised to 60° C. and the diethyl ether removed by evaporation. The reaction was allowed to stir at 60° C. for 6 hours. The reaction mixture was poured on ice and 10% HCl (lOOmL) and extracted twice with diethyl ether. The organic phase was washed twice with a 10% Na2CO3 solution (200 mL). The aqueous phase was acidified with acetic acid (120 mL) and extracted twice with diethyl ether (200 mL). The organic phase was washed three times with NaHCO3 (100 mL) and then twice with water. The ether phase was dried over Na2SO4, filtered and concentrated. The yield was 1.43 g (purity: 94.6%, isolated yield: 31%) of 2-(2isopropylbenzoyl)benzoic acid. For esterification, a solution of the thus obtained acid (3.77 g, 10 mmol), geraniol (1.4 g, 9 mmol) and 4-dimethylaminopyridine (DMAP, 0.244 g, 2 mmol) in pyridine (15 mL) was prepared under anhydrous conditions. 1,3-Dicyclohexylcarbodiimide (DCC, 2.06 g, 10 mmol) was added and the reaction was stirred under a stream of nitrogen gas for 52 hours. The reaction mixture was partitioned between IM HCl and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated under vacuum. The ester product was purified by flash column chromatography (SiO2, 7:1 cyclohexane:ethyl acetate; isolated yield: 0.7 g, 48%) to give the following analytical data:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.N1C=CC=CC=1.O>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[OH:11][C:12]1[C:13]([O:20][CH3:21])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: COc1c(O)cccc1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1c(O)cccc1C=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of titanium (IV) chloride (11.1 g) in THF (50 mL) was added dropwise under ice-cooling a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (4.26 g) and 3-hydroxy-2-methoxybenzaldehyde (3.0 g) in THF (50 mL) at 0° C., and then a solution of pyridine (4.00 g) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 hr, and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.50 g) as a yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:28]=[O:29])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C=O)ccc2c1
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (4 g, 0.01 mol, 1.0 equiv) in dry THF (30 mL) at −78° C. under N2 atmosphere was added n-BuLi (2.5 M, 12 mL, 3.0 equiv) dropwise and stirred for 30 min. Then DMF (7.3 g, 0.1 mol, 10 equiv) was added and stirred for another 1 h, then quenched with water, extracted with ethyl acetate and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (PE:EA=20:1) to give compound the title compound (2.2 g, 64%) as a yellow liquid. ESI-MS (M+1)+: 287.0. 1H NMR (400 MHz, CDCl3) δ: 10.10 (s, 1H), 8.26 (s, 1H), 7.91-7.88 (m, 2H), 7.78-7.76 (m, 1H), 7.24-7.167 (m, 2H), 1.03 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([SH:11])=[N:9][CH:10]=1)=[O:5])[CH3:2].[CH2:12](N(CC)CC)C.IC.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[C:8]([S:11][CH3:12])=[N:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(S)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CI
Product: CCOC(=O)c1cnc(SC)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
To a solution of 2-mercapto-3H-imidazole-4-carboxylic acid ethyl ester (1.0 g, 5.8 mmol) in 15 mL of DCM was added triethylamine (NEt3) (1.0 mL, 7.2 mmol) and iodomethane (0.4 mL, 6.4 mmol) and the mixture stirred for 3 h at RT. The mixture was cooled in an ice bath, NEt3 (1.0 mL, 7.2 mmol) and SEM-Cl (1.2 mL, 6.4 mmol) was added, the mixture stirred for 3 hours at RT and then an additional portion of NEt3 (0.5 mL, 3.6 mmol) and SEM-Cl (0.6 mL, 3.2 mmol) was added and the mixture stirred for 8 h at RT. The mixture was diluted with 50 mL of DCM and washed with NaHCO3 (2×60 mL) and brine (60 mL) and dried over Na2SO4. Flash chromatography of the residue on Si gel with 30% EtOAc/hexanes gave the title compound as a colorless oil (1.0 g, 55%). Mass spectrum (ESI, m/z): Calcd. for C13H24N2O3SSi, 317.1 (M+H). found 316.7.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:27]1[CH:42]=[CH:41][CH:40]=[CH:39][C:28]=1[C:29](ON1C(=O)CCC1=O)=[O:30])[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:27]1[CH:42]=[CH:41][CH:40]=[CH:39][C:28]=1[C:29]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:30])[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccccc1C(=O)ON1C(=O)CCC1=O
Reactant: NCCS(=O)(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)NCCS(=O)(=O)O
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-{2-[2,2,2-trifluoro-N-(4-tetradecenyl)acetamido]benzoyloxy}succinimide as a solution in 45 ml. of ethanol. After 24 hours, the mixture is treated with 20 ml. of 2.0 M sodium hydroxide and 25 ml. of water. After stirring for 10 minutes, the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[CH:28]([CH3:32])[NH:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=[C:18]([O:33][CH3:34])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([C:21]5[C:16]([O:15][CH3:14])=[N:17][C:18]([O:33][CH3:34])=[CH:19][CH:20]=5)[CH:23]=4)[CH:28]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ccc(-c2ccc3c(c2)CCNC3C)c(OC)n1
Product: COc1ccc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(2,6-Dimethoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>CC(C)=O>[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:3]=[C:2]=[S:1])=[O:9]
Reactant: N#C[S-]
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccnc1Cl
Reaction time: 0.08 h

Procedure:
A mixture of 1.512 g (9.5 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. The resulting residue was then dissolved in 10 ml of acetone to obtain an acetone solution of 2-chloronicotinoyl chloride. 804 mg of ammonium thiocyanate was then dissolved in 15 ml of acetone. To the solution thus obtained was then added dropwise the acetone solution of 2-chloronicotinoyl chloride with stirring in 5 minutes. The reaction mixture was then stirred over a 40° C. oil bath for 5 minutes. The resulting insoluble matters were then removed by filtration to obtain an acetone solution of 2-chloronicotinoyl isothiocyanate. To the solution thus obtained was then added dropwise a mixture of 1.685 g of 5-(N-ethylamino)-1-methyl-1H-benzimidazole and 10 ml of acetone with stirring in 5 minutes. The reaction mixture was further stirred for 6 hours, and then poured into about 1,000 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The compound thus obtained was suspended in 30 ml of toluene, and then heated under reflux for 2 hours. After allowed to cool, the reaction mixture was collected by filtration, and then recrystallized from a mixture of ethanol and ether to obtain 1.171 g of 2-[N-ethyl-N-(1H-1-methylbenzimidazol-5-yl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one hydrochloride.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[CH2:7]([O:9][CH2:10][CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[N:14]=[C:13]1[NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:8].[C:28](=[O:31])([O-:30])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[C:5]([OH:4])(=[O:9])[C:28]([OH:30])=[O:31].[CH2:7]([O:9][CH2:10][CH2:11][N:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[N:14]=[C:13]1[NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][O:4][CH2:5][CH3:6])[CH2:26][CH2:27]1)[CH3:8]
Reactant: CCOCCn1c(NC2CCNCC2)nc2cccnc21
Reactant: O=C([O-])[O-]
Reactant: CCOCCCl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOCCN1CCC(Nc2nc3cccnc3n2CCOCC)CC1
Product: O=C(O)C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
A mixture of 1.08 parts of 1-chloro-2-ethoxyethane, 2.9 parts of 3-(2-ethoxyethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 1.06 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70° C. The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in methanol. The salt was filtered off and dried, yielding 0.7 parts (12.9%) of 3-(2-ethoxyethyl)-N-[1-(2-ethoxyethyl)-4-piperidinyl]-3H-imidazo[4,5-b]pyridin-2-amine ethanedioate(1:2); mp. 176.1° C. (compound 44).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>ClCCl.C(OCC)(=O)C>[CH3:21][C:22]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)[CH:8]=1)=[O:30]
Reactant: Cc1nnc(-c2cccc(N)c2)o1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(-c3nnc(C)o3)c2)c1
Yield: 7.4 %

Procedure:
To a solution of 7.05 g (0.04 mol) of 3-(5-methyl-1,3,4-oxadiazol-2-yl)benzenamine and 10 ml of triethylamine in 300 ml of dichloromethane is added 11 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride (U.S. Pat. No. 4,285,951). The mixture is worked up, the crude product slurried in ethyl acetate and filtered through silica gel. The solvent is evaporated to give 1.2 g of 5-(2,5-dimethylphenoxy)-2,2-dimethyl-N-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]pentanamide after recrystallization from 2-propanol; mp 90°-92° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[F:14][C:15]1[C:25]2[O:24][CH2:23][CH2:22][CH2:21][O:20][C:19]=2[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH:28]=O.C[Si]([C:34]#[N:35])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>C1COCC1>[F:14][C:15]1[C:25]2[O:24][CH2:23][CH2:22][CH2:21][O:20][C:19]=2[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH:28]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][CH:9]=1)[C:34]#[N:35]
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: COc1cc(C=O)c(F)c2c1OCCCO2
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Product: COc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)c(F)c2c1OCCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 185 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 239 mg of 6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-carbaldehyde, 250 mg of MS3A and 0.28 ml of trimethylsilyl cyanide to a solution of 65 mg of Yb(OTf)3 in 4 ml of THF under a nitrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the celite was washed with ethyl acetate. The organic layer was concentrated under reduced pressure to give (6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile (crude product).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C:10]1[C:14]([C:15](OC)=[O:16])=[CH:13][N:12]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:22][CH:21]=2)[N:11]=1)([CH3:9])[CH3:8].O>O1CCCC1>[CH:7]([C:10]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:24][CH:25]=2)[N:11]=1)([CH3:9])[CH3:8]
Reactant: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(C(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Lithium aluminium hydride (0.58 g) was added to a solution of methyl 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-carboxylate (9.02 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and [3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]methanol (8.20 g, yield: 97%) was obtained from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[S:15][C:14]=1[NH2:22].[SH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:23][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:22][C:14]1[S:15][C:16]2[C:21]([N:13]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: Nc1nc2cccnc2s1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Sc1ccccn1
Product: c1ccc(Sc2ccc3ncnc(Nc4nc5cccnc5s4)c3c2)nc1

Procedure:
The compound of Example 10 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, thiazolo[5,4-b]pyridin-2-yl-amine and 2-mercaptopyridine.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:7]=[C:8](N)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[ClH:15].N([O-])=O.[Na+].[S:20](=[O:22])=[O:21]>>[F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:7]=[C:8]([S:20]([Cl:15])(=[O:22])=[O:21])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: Cl
Reactant: O=S=O
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Agent: O=N[O-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 5 °C
Yield: 79 %

Procedure:
Under ice-cooling, thionyl chloride (4 mL) was added dropwise to water (24 mL) over 30 min. The mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Under ice-cooling, {3-[(trifluoromethyl)sulfonyl]phenyl}amine (1.0 g) was added to concentrated hydrochloric acid (6 mL) and the mixture was stirred. An aqueous solution (2 mL) of sodium nitrite (0.34 g) was added dropwise while maintaining the inside temperature at not higher than 5° C. and the mixture was further stirred for 15 min. The mixture was gradually added at 5° C. to a mixture of the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (10 mg). Under ice-cooling, the mixture was further stirred for 30 min, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:3) to give the title compound as a pale-yellow oil (yield 1.08 g, 79%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].O.[C:14]1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO>[OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:14])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](O)Cc1ccccc1
Yield: 561.6 %

Procedure:
A solution of commercially available (S)-2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1 g) in methanol (125 mL) was refluxed with removal of water using 3A molecular sieves for 17 h. The solution was concentrated and dissolved in ether. The ether solution was washed with saturated sodium bicarbonate, brine and concentrated to provide the title compound as a white solid (5.32 g, 98%): NMR (CDC13); δ 7.36-7.20 (m, 5H), 4.47 (ddd, J=5, 6, 7 Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5, 14 Hz, 1H), 2.97 (dd, J=7, 14 Hz), 2.69 (d, J=6Hz, 1H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20].C([BH3-])#N.[Na+]>CCO.CCOC(C)=O>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[CH:18]=[N:17][CH:16]=[C:15]2[Br:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c(Br)cncc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Brc1cncc2c(NCc3ccccc3)cccc12
Temperature: 90 °C

Procedure:
Under argon, benzaldehyde (584 μl, 5.75 mmol) is added to a solution of 8-amino-4-bromoisoquinoline (Intermediate 23.2, 1.11 g, 5 mmol) in absolute EtOH (60 ml). The mixture is heated at 90° C. for 24 h. It is cooled to 0° C. and then sodium cyanoborohydride (NaBH3CN, 3.3 g, 50 mmol) is added in small portions. The stirring is maintained for 2 h at room temperature. The reaction mixture is diluted with AcOEt (600 ml) and is then washed with water. The organic phase is dried over Na2SO4 and then evaporated. The residue is purified on silica gel, eluting with an AcOEt/petroleum ether (1/4) mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[N:28]1([CH2:34][CH2:35][NH:36][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: NCCN1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NCCN2CCCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 69.5 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with 2-piperidin-1-yl-ethylamine (48 mg, 1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 82 mg (70%) of the titled compound as a yellow solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:26]=3[CH2:27][CH2:28][CH3:29])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>CO>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:25]2[C:26]([CH2:27][CH2:28][CH3:29])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:37])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:23]=[N:24]2)=[CH:31][CH:32]=1
Reactant: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)OC)ccc3c2)cnn1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(C(=O)NCc2ccc3cc(OCC(=O)O)ccc3c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
1 N NaOH (335 μL, 0.335 mmol) was added under nitrogen to a solution of [6-({[1-(4-chloro-phenyl)-5-propyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (150 mg, 0.305 mmol), prepared in the previous step, in 25 mL of MeOH plus 10 mL of water at room temperature. After the addition the reaction was stirred at room temperature for 20 h (overnight). The reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure to remove the MeOH. The solid present was collected by filtration and dried under reduced pressure to give the title compound (138 mg, 94%) as a pink solid, mp 203-204° C.