Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH:15]=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:17]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[S:20])[NH2:18].CN(C)C=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH:15]=[N:18][NH:17][C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)=[S:20])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: O=Cc1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(NC(=S)NN=Cc2csc(-c3ccc(Cl)c(Cl)c3)c2O)cc1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-formylthiophene (52 mg, 0.19 mmol) synthesized in Reference Synthetic Example 26 and 4-hydrazinocarbonothioylaminobenzoic acid (40 mg, 0.19 mmol) were stirred with dimethylformamide (1.9 mL) and concentrated hydrochloric acid (0.1 mL) at room temperature for 14 hours. Water was added to the reaction solution, and the precipitated solid was recovered by filtration and dried. The crude product was stirred with chloroform at room temperature and recovered by filtration to give the desired product as a pale yellow solid (58 mg, yield 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[C:26]([F:31])=[CH:27][C:28]([F:30])=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)[C:9]([C:11](O)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[NH:25][C:24]5[C:26]([F:31])=[CH:27][C:28]([F:30])=[CH:29][C:23]=5[N:22]=4)=[CH:16][CH:15]=3)[C:9]([C:11]([NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(C(=O)O)c(-c3ccc(Nc4nc5cc(F)cc(F)c5[nH]4)cc3)c12
Reactant: CC(C)(C)N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn2ncnc(N)c2c1-c1ccc(Nc2nc3cc(F)cc(F)c3[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a suspension of 4-amino-5-{4-[(5,7-difluoro-1H-benzimidazol-2-yl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (75.0 mg, 0.178 mmol) in DMF (3 mL) was added tert-butylamine (0.021 ml, 0.196 mmol), benzotriazolyloxytris(dimethlyamino)phosphonium PF6 (86.6 mg, 0.196 mmol), and 4-methylmorpholine (0.039 ml, 0.356 mmol). The reaction was stirred for 3 hr at rt and then purified directly by HPLC using 25-85% acetonitrile in water to afford the desired product (75.3 mg, 89%). 1H-NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.02 (s, 1H), 7.80-8.02 (m, 3H), 7.38 (dd, J=6.7, 2.0 Hz, 2H), 7.00 (dd, J=8.9, 2.2 Hz, 1H), 6.85 (ddd, J=10.7, 10.7, 2.4 Hz, 1H), 6.54 (s, 1H), 4.96-5.21 (br s, 1H), 1.16 (s, 9H); ES-MS m/z 477.1 (MH)+; HPLC RT (Method B) 2.54 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[C@:37]1([O:55][C@H:54]([C:56]([O:58][CH3:59])=[O:57])[C@@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]1[O:40][C:41](=[O:43])[CH3:42])[OH:38])([O-:29])=[O:28]>C(Cl)(Cl)(Cl)Cl>[N+:27]([C:30]1[CH2:35][C:34](=[CH:36][Br:1])[CH:33]=[CH:32][C:31]=1[C@:37]1([O:55][C@H:54]([C:56]([O:58][CH3:59])=[O:57])[C@@H:49]([O:50][C:51](=[O:53])[CH3:52])[C@H:44]([O:45][C:46](=[O:48])[CH3:47])[C@H:39]1[O:40][C:41](=[O:43])[CH3:42])[OH:38])([O-:29])=[O:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)[C@H]1O[C@](O)(c2ccc(C)cc2[N+](=O)[O-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1O[C@](O)(C2=C([N+](=O)[O-])CC(=CBr)C=C2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.5 %

Procedure:
N-bromosuccinimide (117.2 mg, 0.66 mmol) and benzoyl peroxide (159 mg, 0.66 mmol) were added to a solution of methyl 1-(2-nitro-4-methylphenyl)-2,3,4-tri-O-acetyl-β-D-glucopyranuronate (206 mg, 0.44 mmol) in carbon tetrachloride (20 ml). The mixture was refluxed for 5 hours and stirred at room temperature for 12 hours. The reaction mixture was evaporated under reduced pressure, and purified by column chromatography on silica gel (ethyl acetate-hexane, 2:3) to give 47 mg of methyl 1-(2-nitro-4-bromomethylene-phenyl)-2,3,4-tri-O-acetyl-β-D-glucopyranuronate in 20% yield. 1H NMR (300 MHz, DMSO-d6) δ1.98-2.02 (m, 9H, CH3), 3.64 (s, 3H, OCH3), 4.73 (s, 2H, CH2), 4.77 (s, 1H, sugar-H), 5.09-5.13 (m, 2H, sugar-H), 5.47 (t, J=9 Hz, 1H, sugar-H), 5.76 (d, J=7.7 Hz, 1H, sugar-H), 7.43 (d, J=8.7 Hz, 1H, ArH), 7.76 (d, J=8.7 Hz, 1H, ArH), 8.02 (s, 1H, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13]O>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:13][C:12]1([CH3:16])[CH2:15][O:10][CH:8]([C:4]2[S:5][CH:6]=[CH:7][C:3]=2[O:2][CH3:1])[NH:11]1
Reactant: COc1ccsc1C(=O)O
Reactant: CC(C)(N)CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccsc1C1NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
50.2 g (0.32 moles) of 3-methoxy-2-thiophene carboxylic acid are refluxed in 300 ml of thionyl chloride for 2 hours, the reaction solution is evaporated in vacuo, the crystalline residue (56 g) is dissolved in 250 ml of methylene chloride and added dropwise with stirring to a solution of 57 g (0.64 moles) of 2-amino-2-methyl-1-propanol in 200 ml of methylene chloride at 0° C. within 1/2 hour. After 12 hours of stirring at room temperature, the solution is concentrated under vacuum, cooled, the precipitate is aspirated, washed well with water, dried, 135 ml of thionyl chloride are added slowly with cooling, and the solution is stirred at room temperature for 12 hours. Then it is evaporated in vacuo, the residue is dissolved in water, extracted with ether, the aqueous phase is made alkaline with aqueous 2N sodium hydroxide and extracted several times with methylene chloride. The combined methylene chloride phases are dried with sodium sulfate and evaporated in vacuo. Yield: 57.0 g (84%), m.p. (petroleum ether) 97°-98° C.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:13][C:14]([F:21])([F:20])[C:15](=[CH2:19])[C:16]([OH:18])=[O:17]>>[F:13][C:14]([F:21])([F:20])[C:15](=[CH2:19])[C:16]([O:18][CH:2]([O:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)[CH:1]([CH3:10])[CH3:8])=[O:17]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: OCC12CC3CC(CC(C3)C1)C2
Product: C=C(C(=O)OC(OCC12CC3CC(CC(C3)C1)C2)C(C)C)C(F)(F)F
Yield: 67 %

Procedure:
By following the same procedures as in Examples 1-1-1 to 1-1-3 aside from using 1-adamantanemethanol instead of 2-adamantanol and 2-(trifluoromethyl)acrylic acid instead of methacrylic acid, 1-[(1-adamantyl)methoxy]-2-methylpropyl 2-(trifluoromethyl)acrylate was produced (four step yield 67%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1(=O)[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>ClCCl>[C:13]1(=[O:18])[N:1]([CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:16](=[O:17])[CH:15]=[CH:14]1
Reactant: CN(CCCN)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: CN(CCCN1C(=O)C=CC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Aminopropyl)-N-methylaniline [S. L. Shapiro et al., J. Am. Chem. Soc., 81, 3081 (1958)](8.3 g) was dissolved in dichloromethane (50 ml). Maleic anhydride (6 g) was added portionwise under ice-cooling and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and then acetic anhydride (20 ml) was added. The resulting mixture was allowed to stand at room temperature for 2 days. The reaction mixture was stirred at 60° C. for 2 hours and further at 100° C. for 2 hours. The mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was neutralized with an aqueous sodium bicarbonate, washed with saturated brine and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (4:1). The desired compound thus obtained was recrystallized from the same solvent to obtain the compound as yellow needles (4.1 g).
Reaction SMILES: [CH2:1]([C@@:4]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C@@:4]1([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(OC)cc2)C(=O)O1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(O)cc2)C(=O)O1
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-1,3-oxazinan-2-one (1.5 g, 4.07 mmol) in CH2Cl2 (40 mL) was added BBr3 (3 g, 12.2 mmol) at −78° C. The mixture was stirred at this temperature for 2 h. The solution was washed with satd aq NaHCO3 and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-hydroxyphenyl)ethyl)-1,3-oxazinan-2-one (1.2 g, 83%), which was used for the next step without further purification.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[N:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])(=O)C.[Na+].[N:19]#[C:20]Br.[OH-].[Na+]>C(O)(=O)C.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([C:20]([NH2:19])=[N:13][N:12]=3)[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#CBr
Reactant: NNc1ccc(-n2ccnc2)nn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nnc2ccc(-n3ccnc3)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
(6-Imidazol-1-ylpyridazin-3-yl)hydrazine (500 mg) were initially charged in a mixture of acetic acid (4 ml) and water (8 ml) with addition of sodium acetate (232 mg) at RT while stirring. Thereafter, the mixture was cooled to 0° C. and cyanogen bromide (330 mg) was introduced in portions. After stirring for 2.5 h, the mixture was left to stand overnight. After cooling to 0° C., the mixture was alkalized with 10 M sodium hydroxide solution and extracted repeatedly with EA. The combined EA phases were dried over sodium sulfate, filtered and concentrated. 66 mg of the title compound were isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:15]([CH3:17])[CH3:16])[C:10]=2[CH:11]=[C:12]([OH:14])[CH:13]=1)=[O:4].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:15]([CH3:17])[CH3:16])[C:10]=2[CH:11]=[C:12]([O:14][CH2:21][CH2:20][N:19]([CH3:23])[CH3:18])[CH:13]=1)=[O:4]
Reactant: COC(=O)c1cc(O)cc2c1ccn2C(C)C
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCN(C)C)cc2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a cooled (0° C.) mixture of 6-hydroxy-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (700 mg, 3 mmol), 2-dimethylamino-ethanol (320 mg, 3.60 mmol) and PPh3 (948 mg, 3.60 mmol) in THF (10 mL) was added DEAD (620 mg, 3.60 mmol) and stirred for 16 h at RT. Reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography by eluting with 2% MeOH in chloroform to afford the title compound (550 mg, 60%) as colorless gum. LCMS (ES+): m/z=305.36[M+H].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4].[CH3:26][Si:27]([CH3:44])([CH3:43])[C:28]#[C:29][Sn](CCCC)(CCCC)CCCC>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:29]#[C:28][Si:27]([CH3:44])([CH3:43])[CH3:26])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1C#C[Si](C)(C)C
Temperature: 130 °C
Yield: 21.2 %

Procedure:
4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylic acid methyl ester (0.8 g, 2.061 mmol), trimethyl((tributylstannyl)ethynyl)silane (1.596 g, 4.12 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.145 g, 0.206 mmol) were combined in 1,2-dichloroethane (2 mL) and heated in a CEM microwave reactor at 130° C. for 15 min. The cooled reaction mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (0.196 g, 21.1% yield). 1H NMR (CDCl3) δ 9.03 (s, 1H), 8.4 (br s, 1H), 7.67 (m, 1H), 7.24 (m, 1H), 4.0 (s, 3H), 3.99 (d, 3H), 2.29 (s, 3H), 0.36 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=2[CH3:34])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=3[CH3:34])[CH2:24][CH2:23]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3Cl)CCCCC2)CC1

Procedure:
Example 134 was prepared from 1-(2-chloro-4-fluorophenyl)cyclo hexanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, 1H, J=8.9, 6.3 Hz), 7.32 (s, 1H), 7.23–7.18 (m, 2H), 7.06 (dd, 1H, J=8.5, 3.0 Hz), 7.01–6.92 (m, 2H), 5.99–5.93 (m, 1H), 3.24 (q, 2H, J=5.9 Hz), 2.85–2.79 (m, 3H), 2.59–2.50 (m, 1H), 2.44 (septet, 1H, J=7.0 Hz), 2.41–2.37 (br, 1H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.07–2.01 (m, 2H), 1.81–1.69 (m, 4H), 1.61–1.37 (m, 10H), 1.17 (d, 6H, J=7.0 Hz); ESMS m/e: 556.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[CH3:26][C@@H:27]1[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:29]4[CH2:28][C@H:27]([CH3:26])[O:31][C:30]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: C[C@H]1CNC(=O)O1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4C[C@H](C)OC4=O)cc3F)CC2)c(C)c1
Yield: 52.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (615 mg) described in Preparation Example 60 and (S)-5-methyloxazolidin-2-one (243 mg) described in Preparation Example 42, the title compound (337 mg) was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:19]=[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[C:21]([OH:34])=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:23]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[C:51]([OH:58])[CH:50]=1)(=[O:48])=[O:47].[K+].[Br-]>>[OH:58][C:51]1[CH:50]=[C:49]([S:46]([O:34][C:21]2[C:20]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=3)=[CH:19][C:18]([C:16](=[O:17])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:23][C:22]=2[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)(=[O:48])=[O:47])[CH:57]=[CH:56][C:52]=1[C:53]([OH:55])=[O:54]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as an white foam (0.541 g, 78%) from 2′-Hydroxy-3,3″-bis-trifluoromethyl-[1,1′;3′1″]terphenyl-5′-carboxylic acid (8-phenyl-octyl)-amide and 4-chlorosulfonyl-2-hydroxy-benzoic acid using a procedure similar to step 3 of Example 179. 1H NMR (DMSO-d6) δ 11.60 (bs, 2H); 8.70 (t, 1H); 7.94 (s, 2H); 7.88-7.80 (m, 4H); 7.69-7.57 (m, 5H); 7.26-7.10 (m, 5H); 6.68 (dd, 1H); 6.57 (d, 1H); 3.25 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.28 (m, 8H); IR (KBr) 3400, 2950, 2840, 1690, 1640, 1600, 1550, 1460, 1380, 1320, 1280, 1200, 1170, 1120, 1080 cm−1; mass spectrum [(−)ESI], m/z 812 (M−H)−; Anal. Calcd. for C42H37F6NO7S: C, 61.99; H, 4.58; N, 1.72, Found: C, 61.40; H, 4.80; N, 1.68.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]3)[CH:38]=2)[CH:34]=[CH:35][CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([NH:29][CH2:30][C:31]3[CH:32]=[C:33]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH:44]5[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]5)[CH:38]=4)[CH:34]=[CH:35][CH:36]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CC3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
To the solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.0779 g, 0.200 mmol) in DCM (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (0.0837 g, 0.220 mmol), HBTU (0.0910 g, 0.240 mmol), TEA (0.0563 mL, 0.400 mmol) and was stirred at room temperature for 16 hours. The reaction mixture was concentrated on Glas-Col evaporator, purified by Gilson HPLC and concentrated with Biotachi evaporator. The crude product was dissolved in DCM (0.6 mL) and TFA (0.2 mL) was added. The resultant mixture was left at room temperature for 1 hour before being concentrated on Glas-Col evaporator, purified by Gilson HPLC (with 0.1% TFA) and basified with amine cartridge to afford the title compound 0.0329 g (25.24%). LC-MS m/z 652 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.38 (t, J=7.65 Hz, 3H) 1.49 (t, J=7.28 Hz, 5H) 1.72-1.85 (m, 2H) 1.87-2.02 (m, 5H) 2.69 (d, J=6.78 Hz, 2H) 2.94 (td, J=12.80, 2.26 Hz, 2H) 3.05 (q, J=7.53 Hz, 2H) 3.37 (d, J=12.55 Hz, 2H) 3.59 (td, J=11.48, 2.13 Hz, 2H) 3.92 (dt, J=1.80, 3.51 Hz, 2H) 4.19-4.30 (m, 1H) 4.42-4.50 (m, 4H) 4.52 (s, 2H) 7.19 (d, J=7.53 Hz, 1H) 7.27-7.32 (m, 1H) 7.37 (td, J=7.59, 3.14 Hz, 2H) 7.44-7.52 (m, 3H) 7.57 (s, 1H) 8.24 (s, 1H).
Reaction SMILES: C(O[C:5]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:20]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:19][CH:18]=1)=[C:6](C1C=CN=CC=1)[C:7]([O:9][CH3:10])=[O:8])(=O)C.C1(C)C=CC=CC=1.N12C[CH2:50][CH2:49][N:48]=[C:47]1[CH2:46][CH2:45][CH2:44]CC2>CCOCC>[CH2:30]([C:20]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:17](/[CH:5]=[C:6](\[CH2:44][C:45]2[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=2)/[C:7]([O:9][CH3:10])=[O:8])=[CH:18][N:19]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1ncc(C(OC(C)=O)=C(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCc1ncc(/C=C(\Cc2ccncc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 90 °C

Procedure:
A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-2-(4-pyridyl)propenoate (7.5 mmol), toluene (50 mL) and 1,8-diazabicyclo[5,4,0]-undec-7-ene (DBU) (3.4 mL, 22.5 mmol) was heated at 90° C. for 18 hours under argon. The cooled mixture was diluted with ether, and washed with brine, dried and concentrated to 3.1 g (97%) of the title compound. NMR showed that the trans or E isomer was the primary product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1

Procedure:
Methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-3-yl]acrylate (160 mg, 0.34 mmol) was dissolved in ethanol (15 ml). Palladium on carbon (30 mg) was added and the resulting mixture was vigorously stirred under 1 atm hydrogen atmosphere for 24 hours. The reaction mixture was filtered and then, concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (94 mg, 58%) was obtained as needle crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][CH2:12][CH:13]([OH:20])[C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)[CH3:10])=[CH:4][CH:3]=1.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:11]2[CH2:12][CH:13]([C:14]3[N:15]=[C:16]([CH3:19])[S:17][CH:18]=3)[O:20][CH:22]2[C:21]([O:25][CH3:26])=[O:24])[CH3:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C=O
Reactant: Cc1nc(C(O)CNC(C)Cc2ccc(O)cc2)cs1
Product: COC(=O)C1OC(c2csc(C)n2)CN1C(C)Cc1ccc(O)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with methyl glyoxylate, followed by purification of the base on a silica gel column using ether/petroleum ether=8:2 as eluant.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[O:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[O:12][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][CH:21]1[NH:22][CH2:23][CH2:24][N:25]([C:2]2[C:7]([O:8][CH2:9][CH:10]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[O:12][CH2:11]3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:26]1
Reactant: Clc1nccnc1OCC1COc2ccccc2O1
Reactant: CC1CNCCN1
Product: CC1CN(c2nccnc2OCC2COc3ccccc3O2)CCN1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-(2,3-dihydro-1,4-benzodioxin-2-ylmethoxy)pyrazine* (150 mg, 0.54 mmol) and 2-methylpiperazine (293 mg, 2.92 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 118 mg (64%) of the title product. HRMS m/z calcd for C18H22N4O3 (M)+ 342.1692, found 342.1678. Anal. (C18H22N4O3) H, N; C: calcd, 63.14; found, 62.30.