Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(C2CCN(C(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2CCNC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.8 %

Procedure:
To a stirred solution of tert-butyl 3-(5-methylpyridin-2-yl)pyrrolidine-1-carboxylate (260 mg, 1.0 mmol) in dry CH2Cl2 (3 mL) was added TFA (2 mL, 20% in CH2Cl2) dropwise at 0° C. The reaction mixture was stirred at rt for 3 h. TLC showed the disappearance of starting material. The reaction mixture was concentrated under vacuum to afford crude 5-methyl-2-(pyrrolidin-3-yl)pyridine (170 mg, 96%), which was used for the next step without purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:25][CH:26]=3)=[CH:18][CH:19]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:25][CH:26]=3)=[CH:18][CH:19]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1cc(CC(=O)O)c(OCc2ccc(OCc3csc(-c4ccccc4)n3)nc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A mixture of methyl [1-methyl-3-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (496 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (432 mg, yield 90%), which was then recrystallized from ethanol-hexane. melting point: 156–157° C.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]2[N:5]=[C:4]([SH:17])[N:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH2:18]([S:17][C:4]1[N:3]=[C:2]([OH:1])[N:7]2[N:8]=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]2[N:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#CCCCCc1cnn2c(O)nc(S)nc12
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: N#CCCCCc1cnn2c(O)nc(SCc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound (3) (5.3 g, 21,3 mmol) in N-methylpyrrolidinone (30 mL) was degassed in vacuum for 5 min. Benzyl bromide (2.28 mL, 19. 1 mmol) and DIEA (4.4 mL, 25 mmol) were added and the reaction mixture was stirred at room temperature under vacuum for 30 min. Sol-vent was removed under reduced pressure and the residue was diluted with EtOAc. The acetate solution was washed with 1 M HCl followed by brine. Organic extract was dried over anhydrous Na2 SO4, filtered, and concentrated. The residue was triturated in a mixture solvent of hexane, ether and EtOAc, and filtered to give 5-(2-benzylsulfanyl-4-hydroxy-pyrazolo[1,5-a][1,3,5]triazin-8-yl)-pentanenitrile (4) as a solid (6.0 g. 93%).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][CH2:12][N:13]2[CH2:43][CH2:42][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:18]([CH2:27][C:28]4[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=4)[C:31]([O:33]C(C)(C)C)=[O:32])[C:17]3=[O:41])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl>O1CCOCC1>[N:1]1([CH2:10][CH2:11][CH2:12][N:13]2[CH2:43][CH2:42][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:18]([CH2:27][C:28]4[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=4)[C:31]([OH:33])=[O:32])[C:17]3=[O:41])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4ncc5ccccc54)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4ncc5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 3-((8-(3-(1H-indazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.16 g, 0.27 mmol) was added 4M solution of HCl in dioxane (2.5 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.12 g, 79%); 1H NMR (DMSO-d6): δ 1.97 (d, 2H, J=14.4 Hz), 2.32-2.36 (m, 2H), 2.92-2.98 (m, 2H), 3.19 (br, 2H), 3.45-3.70 (m, 4H), 4.54 (t, 2H, J=6.8 Hz), 4.63 (s, 4H), 6.79 (t, 1H, J=7.6 Hz), 7.02 (d, 2H, J=8.4 Hz), 7.14-7.22 (m, 3H), 7.42 (t, 1H, J=6.8 Hz), 7.48-7.57 (m, 2H), 7.73-7.79 (m, 2H), 7.87-7.88 (m, 2H), 8.11 (s, 1H), 10.65 (br, 1H), 13.03 (br, 1H); MS for C31H33N5O3 m/z 524.06 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[I:22]N1C(=O)CCC1=O.O>CN(C)C=O>[I:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(I)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (0.700 g, 2 mmol) is initially charged in 10 ml of dimethylformamide. N-Iodosuccinimide (0.750 g, 3.3 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 16 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 8:2). This gives 0.25 g of product (24.5% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]([NH2:32])[CH2:29][O:30][CH3:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:33])[C@@H:28]([NH:32][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:29][O:30][CH3:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)O
Agent: Cl
Product: COC[C@H](NC(=O)[C@H](COC(F)F)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
The compound of Formula II(b)(ii) was prepared as an off-white foam in a similar manner as the compound of Formula II(a)(ii), described above, from the compound of Formula IV(a), (S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionic acid and the compound of Formula V(b), (S)-2-amino-3-methoxy-propionic acid benzyl ester, hydrochloride salt.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:23]([C:26]1[CH:43]=[CH:42][C:29]([C:30]([O:32][C:33]([CH2:40][CH3:41])([C:36]([F:39])([F:38])[F:37])[C:34]#[CH:35])=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C1COCC1>C(OCC)(=O)C.[Cu](I)I>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][C@@:33]([C:34]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=5)=[CH:10][C:11](=[O:15])[O:12]4)=[CH:7][CH:6]=3)[CH:35]=2)([C:36]([F:37])([F:38])[F:39])[CH2:40][CH3:41])=[O:31])=[CH:42][CH:43]=1)([O-:25])=[O:24]
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: [N-]=[N+]=NCc1ccc2c(-c3cccc(F)c3)cc(=O)oc2c1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-(3-fluorophenyl)-2H-chromen-2-one (30 mg, 0.1 mmol) and 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (S-isomer, the second, slower eluting enantiomer from step 2) (27 mg, 0.1 mmol) in THF (5 mL) N,N-diisopropylethylamine (79 uL, 0.45 mmol) and copper iodide (26 mg, 0.14 mmol) were added. After overnight stirring, the reaction was diluted with ethyl acetate, filtered and washed with water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2 5:95) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.5 (s, 1H), 8.42 (d, 2H), 8.31 (d, 2H), 7.7-7.6 (m, 1H), 7.51 (d, 1H), 7.4-7.25 (m, 5H), 6.42 (s, 1H), 5.89 (s, 2H), 3.1-2.98 (m, 1H), 2.91-2.8 (m, 1H), 1.14 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:2]=1.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[CH3:17].[CH3:2][NH:1][CH3:6]
Reactant: O=C1CCCCC1=Cc1cccnc1
Agent: CNC
Product: CN(C)C(c1cccnc1)C1CCCCC1=O
Reaction time: 36 h

Procedure:
Treatment of II with the appropriate secondary amine, such as dimethylamine, N-methyl-ethylamine, or N-methyl-benzylamine, at moderate temperatures, conveniently room temperature, either with or without an inert solvent, for a period of time sufficient to allow a practical amount of conversion to occur, conveniently about 24 to about 48 hours, gives the corresponding 2-[(disubstituted amino)(3-pyridyl)methyl]cyclohexanone (III). The product may, if desired, be used for further synthesis without treatment other than removal of unreacted amine. For example, if 2-(3-pyridylmethylene)cyclohexanone is treated with dimethylamine at room temperature, conveniently in a pressure bottle, as the boiling point of dimethylamine is less than room temperature, for about 36 hours, 2-[(dimethylamino)(3-pyridyl)methyl]cyclohexanone (IIIa) is obtained from which the more volatile dimethylamine may be removed by evaporation in vacuo. Treatment of III with a carbonyl reducing agent such as THF-borane in an inert solvent, conveniently tetrahydrofuran (THF), initially at reduced temperature, conveniently about 0° to about 10° C., then at moderate temperature, conveniently ambient temperature, followed by work-up by standard techniques, conveniently decomposing the reaction complex with water initially at reduced temperature, typically at about 5° C., then at ambient temperature, followed by evaporation of the THF followed by alternate partitioning between aqueous base and diethyl ether and aqueous acid and diethyl ether, gives I. Separation of I, if desired, may be accomplished by standard techniques. Chromatography on alumina is a convenient technique. For example, IIIa may be treated, in tetrahydrofuran solution, by adding it dropwise to a solution of THF-borane, cooled to about 0° to about 10° C. and maintained at this temperature during the addition period. The reaction mixture may be permitted to warm to ambient temperature, then recooled and treated with an excess of water. After standing for some time at room temperature, conveniently about 60 hours, the tetrahydrofuran may be evaporated and the residue partitioned between diethyl ether and dilute aqueous sodium hydroxide. The organic phase may then be treated with dilute aqueous mineral acid. The aqueous layer may then be made base and partitioned with diethyl ether. The organic phase may then be dried and the solvent evaporated. The residue so obtained may then be chromatographed on grade III alumina to give 2-[(dimethylamino) (3-pyridyl)methyl]cyclohexanol (Ia).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:8][CH2:9][OH:10])[CH2:6][CH3:7])[CH3:4].Cl[C:12]1[C:25]2[C:16](=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[N:18]3)[N:15]=[C:14]([CH3:26])[CH:13]=1>C1COCC1>[CH2:3]([N:5]([CH2:6][CH3:7])[CH2:8][CH2:9][O:10][C:12]1[C:25]2[C:16](=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[CH:20][CH:19]=[N:18]3)[N:15]=[C:14]([CH3:26])[CH:13]=1)[CH3:4]
Reactant: CCN(CC)CCO
Reactant: Cc1cc(Cl)c2ccc3cccnc3c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)CCOc1cc(C)nc2c1ccc1cccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 5.25 g, 131.1 mmol) in anhydrous THF (90 mL) a solution of N,N-diethyl-2-hydroxyethylamine (15.30 g, 131.1 mmol) in anhydrous THF (60 mL) was slowly added. The mixture was stirred at room temperature for 20 minutes and a solution of 4-chloro-2-methyl-[1,10]phenanthroline(6.00 g, 26.2 mmol) in anhydrous THF (90 mL) was slowly added. The reaction mixture was refluxed for 18 hours and then allowed to cool down to room temperature, quenched with 1N HCl and evaporated. The residue was redissolved in 1N NaOH (150 mL) and extracted with methylene choride (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was washed with hexane and purified by flash chromatography (SiO2, MeOH/DCM, 1:40) to yield the pure product as an orange oil (5.1 g, 63%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=2)[C:22]1=[O:34])(=O)C.Br[C:36]1[N:37]=[C:38]([NH:44][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CO.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.O1CCOCC1>[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:34])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:36]3[N:37]=[C:38]([NH:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=3)[C:6]=1[CH2:5][OH:4])[CH2:29]2)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: Cn1cc(Br)nc(Nc2cccnc2)c1=O
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: [K+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)nc(Nc2cccnc2)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 103f (298 mg, 0.643 mmol), 112a (150 mg, 0.536 mmol), sodium carbonate (170 mg, 1.61 mmol), 1,4-dioxane (5 mL) and water (1 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (62 mg, 0.054 mmol) was added. After heating at 100° C. for 3 h, the reaction mixture was cooled to room temperature and partitioned between water (40 mL) and methylene chloride (100 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×50 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in a mixture of methanol (5 mL), and potassium carbonate (500 mg, 3.62 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was partitioned between water (20 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 112 in 27% yield (70 mg) as an off-white solid: mp 149-150° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.14 (d, 1H, J=2.0 Hz), 8.44 (m, 1H), 8.18 (dd, 1H, J=5.0, 1.5 Hz), 7.73-7.71 (m, 2H), 7.63-7.59 (m, 2H), 7.52 (t, 1H, J=8.0 Hz), 7.48 (s, 1H), 7.44 (dd, 1H, J=8.0, 1.5 Hz), 7.30 (dd, 1H, J=7.5, 4.5 Hz), 4.93 (s, 2H), 4.88 (t, 1H, J=5.0 Hz), 4.44 (d, 2H, J=5.0 Hz), 3.56 (s, 3H), 1.37 (s, 9H); MS (ESI+) m/z 496.2 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][CH2:8][N:9]([CH3:52])[S:10]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=1)[C:16]([NH:18][C:19]1[S:20][C:21]2[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=2[C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41]C)=[O:40])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)=[O:25])=[O:17])(=[O:12])=[O:11])(C)(C)C.FC(F)(F)C(O)=O.ClCCl.[OH-].[Na+]>C(O)C>[C:6]([CH2:7][CH2:8][N:9]([CH3:52])[S:10]([C:13]1[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=1)[C:16]([NH:18][C:19]1[S:20][C:21]2[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=2[C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:43][CH:44]=2)=[CH:29][CH:28]=1)=[O:25])=[O:17])(=[O:12])=[O:11])([OH:53])=[O:5]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)c4)sc4c3CCCC4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: ClCCl
Product: CN(CCC(=O)O)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
A mixture of 200 mg of methyl 4-{2-[4-({[2-({3-[(3-tert-butoxy-3-oxopropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 2.0 mL of trifluoroacetic acid, and 2.0 mL of dichloromethane was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and to the obtained crude product were added 0.50 mL of a 5.0 M aqueous sodium hydroxide solution and 2.0 mL of ethanol, followed by heating and refluxing overnight. The reaction mixture was concentrated under reduced pressure and to the obtained residue were added water and citric acid (500 mg), followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol). The crude product was washed with ethyl acetate to obtain 135 mg of 4-{2-[4-({[2-({3-[(2-carboxyethyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoic acid as a colorless crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:17][CH:16]=4)[N:12]=3)=[CH:6][CH:7]=2)=[CH:32][CH:31]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Oc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Product: Clc1ccc(COc2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2)cc1
Yield: 30 %

Procedure:
In substantially the same manner as in Working Example 131, 2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole was allowed to react with 4-chlorobenzylchloride to give 2-[4-(4-chlorobenzyloxy)phenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 30%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 151-152° C.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
100 g of crude methyl cinnamate and 926.8 g of 2.8% caustic soda were placed in a 2-liter flask equipped with a thermometer and a stirrer, and the solution was then stirred at 80° C. for 30 minutes to carry out hydrolysis. An active carbon treatment was omitted. Then, 100 g of toluene was added to this aqueous solution, followed by stirring at 80° C. for 30 minutes. After the stop of the stirring, the solution was allowed to stand and separate and the resultant toluene layer was then removed. The resultant aqueous layer was placed in a 2-liter flask equipped with a thermometer and a stirrer and then maintained at 40° C., and 137.1 g of 25% sulfuric acid was added dropwise to precipitate the crystals of cinnamic acid. After the addition of sulfuric acid had been over, the temperature of the solution was lowered to 20° C., followed by filtering through Nutsche. The resultant filter cake was washed with 1000 g of water, and then vacuum-dried at 50° C. to obtain 87.6 g of cinnamic acid. The purity of cinnamic acid was 97.4%, and the contents of palladium, copper and manganese were 5 ppm or less, 290 ppm, 240 ppm, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[C:20]4[C:26]3[N:27]=[N:28][N:29]([C:31]4[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=4)[CH:30]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[C:20]4[C:26]3[N:27]=[N:28][N:29]([C:31]4[CH:39]=[CH:38][C:34]([C:35]([N:52]5[CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[O:36])=[CH:33][CH:32]=4)[CH:30]=3)[N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6cc(F)cc(F)c6)ccc5=O)cc34)nn2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6cc(F)cc(F)c6)ccc5=O)cc34)nn2)cc1)N1CCOCC1
Temperature: 10 °C

Procedure:
4-[4-(5-{[3-(3,5-difluorophenyl)-6-oxopyridazin-1(6H)-yl]methyl}-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzoic acid (218 mg; 0.22 mmol; 1.0 eq.) was added in one portion to a suspension of 1,1′-carbonyldiimidazole (97 mg; 0.60 mmol; 2.7 eq.) in DMF (20 mL). The reaction suspension was heated at 10° C. for 20 min then morpholine (100 μl; 1.15 mmol; 5.2 eq.) was added in one portion. The reaction mixture was heated at 100° C. for 16 h. It was allowed to cool to RT, poured into HCl (1N solution) and extracted with EtOAc. Combined organic phases were washed sequentially with an aqueous saturated solution of NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to give the title compound a a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.42 (s, 1H), 9.38 (s, 1H), 8.48 (s, 1H), 8.23-8.08 (m, 3H), 7.75-7.64 (m, 4H), 7.61 (d, J=8.6 Hz, 1H), 7.57-7.48 (m, 1H), 7.42-7.28 (m, 1H), 7.13 (d, J=9.8 Hz, 1H), 5.51 (s, 2H), 3.64 (s, 8H). HPLC (Condition A): Rt 3.78 min (purity 97.7%). MS (ESI−): 593.7.