Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[N:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[N:30][CH:29]=[CH:28][N:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cnccn4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4cnccn4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (629 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight and 1N hydrochloric acid (2.5 ml) was added, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (523 mg, yield: 88%) as colorless crystals. This was recrystallized from ethanol. Melting point: 137–138° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]([F:53])([F:52])[CH2:32][CH2:33][C:34]([C:36]1[CH:37]=[N:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1)=O>C1(C)C=CC=CC=1>[F:30][C:31]([F:53])([F:52])[CH2:32][CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[N:38][CH:37]=1)=[CH:2][O:3][CH3:4]
Reactant: O=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Methoxymethyltriphenylphosphonium chloride (7.4 g, 21.6 mmol) is suspended in anhydrous toluene (25 mL) and potassium tert-butoxide (2.4 g, 21.6 mmol) is added at room temperature in one portion. The mixture is allowed to stir under nitrogen for 1 h. Meanwhile, 4,4,4-Trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butan-1-one (5.0 g, 14.4 mmol) is dissolved in another portion of the toluene (25 mL), and kept at room temperature. The mixture is then cooled to 0° C. with ice water, and then the ketone is transferred by cannula. The reaction is allowed to stir at 0° C. for 10 min, then the ice bath is removed. The reaction is allowed to warm to room temperature and monitored by HPLC. Upon complete conversion, the reaction is carefully quenched with saturated ammonium chloride solution, and diluted with ethyl acetate, then extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The 5-(4,4,4-Trifluoro-1-methoxymethylene-butyl)-2-(4-trifluoromethyl-phenyl)-pyridine (4.1 g, 10.9 mmol) is isolated as a mixture of regioisomers after column chromatography, 76% yield.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:3][CH2:2][CH2:1][NH:7][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)Nc3ccccc3)cc2-c2ccccc2)cc1
Yield: 90 %

Procedure:
The titled compound was prepared in 90% yield from phenyl isocyanate using the procedure detailed for compound 7. mp 171.0-172.1° C. 1H NMR (300 MHz, DMSO-d6): δ 8.43 (s, 1H), 7.79 (d, J=9 Hz, 2H), 7.47-7.36 (m, 9H), 7.29-7.16 (m, 4H), 6.87 (t, J=7 Hz, 1H), 6.57 (s, 1H), 6.23 (t, J=6 Hz, 1H), 3.25-3.14 (m, 2H), 2.69 (t, J=8 Hz, 2H), 1.92-1.78 (m, 2H). MS (ESI) m/z: 476.18 (M+H+). Anal. Calcd for C25H25N5O3S.0.3CH4O: C, 62.63; H, 5.44; N, 14.43. Found: C, 62.63; H, 5.34; N, 14.41.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:8][C:9]([C@H:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[F:23])[C@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12]2)=[O:10])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O.C(OCC)(=O)C>[Cl:22][C:18]1[C:17]([F:23])=[C:16]([C@@H:15]2[C@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[F:33])([C:24]#[N:25])[C@H:13]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH:12][C@H:11]2[C:9]([NH:8][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C1(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2(C(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The ester was taken directly to the hydrolysis step by dissolved in THF (3 mL) and methanol (1 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 3 hours. The mixture was diluted with water and ethyl acetate, the organic phase was separated then concentrated under reduced pressure to rac-1-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-cyclopropanecarboxylic acid (65.2 mg, 67.2%) as an off-white powder. HRMS (ES+) m/z Calcd for C27H27Cl2F2N3O3+H [(M+H)+]: 550.1471. found: 550.1471.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C([O-])([O-])=O.[Na+].[Na+].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](C3CC(=O)N(O)C3=O)=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>O1CCOCC1.C(Cl)Cl>[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32](=[O:33])[NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([Br:2])[CH:4]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: NCc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NCc1cccc(Br)c1)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To 3-bromobenzylamine hydrochloride (16.0 g, 71.9 mmol) was added aqueous 9% Na2CO3 (211 mL) followed by 9-fluorenylmethyloxycarbonyl-N-hydroxysuccinimide (25.5 g, 75.5 mmol) in dioxane (211 mL). This was stirred 30 minutes, then diluted with CH2Cl2 (200 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 1 M HCl, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was purified by recrystallization (ethyl acetate/hexanes) to obtain a fluffy, white solid (24 g, 59 mmol, 82%). 1H NMR (400 MHz, d6-DMSO): δ 7.90 (t, 1H, J=6.2 Hz), 7.88 (d, 2H, J=7.5 Hz), 7.68 (d, 2H, J=7.5 Hz), 7.43 (m, 4H), 7.32 (dd, 2H, J=7.5 Hz, 7.5 Hz), 7.26 (d, 1H, J=7.7 Hz), 7.20 (d, 1H, J=7.3 Hz), 4.35 (d, 2H, J=6.6 Hz), 4.22 (t, 1H, J=6.6 Hz), 4.17 (d, 2H, J=6.2 Hz). ESI/MS: 408 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:30][NH:29][CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:17][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](O)(=O)C.C=O>CO>[CH2:1]([C:8]1[C:9]2[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:19][CH:20]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)cc1
Agent: C=O
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
4-benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (75 mg, 0.19 mmol, Example 41a) was dissolved in methanol (2 mL). Acetic acid (10.83 μL, 0.19 mmol) was added followed by formaldehyde (0.014 mL, 0.19 mmol). The reaction mixture was stirred at room temperature for 15 minutes and MP-CNBH3 was added. The reaction was stirred for 1 h, the MP-CNBH3 was filtered off and the solvent was evaporated under reduced pressure. The crude was dissolved in methanol, filtered and purified by preparative HPLC yielding 4-benzyl-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (23.00 mg, 27%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=C)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:32].[Na+]>[Os](=O)(=O)(=O)=O.O1CCOCC1.O>[CH2:29]([O:28][C:26]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:32])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:27])[CH3:30]
Reactant: C=Cc1ccc(Oc2ccc(N3CCCC3(C(=O)OCC)C(=O)OCC)cn2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
A mixture of 1-[6-(4-Vinyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (4.8 g, 11.3 mmol), sodium metaperiodate (4.8 g, 22 mmol), osmium tetroxide (10 mg) and 2:1 dioxane-water (189 mL) was stirred for 6 hours at ambient temperature. The mixture was quenched with sodium sulfite, diluted with water and extracted 3× with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo affording 1-[6-(4-Formyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup (4.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N2CCCC2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A mixture of methyl 2,4-dichloropyrimidine-6-carboxylate (1.66 g, 8.0 mmol), pyrrolidine (0.66 mL, 8 mmol) and sodium carbonate (1.54 g, 14.0 mmol) in methanol (8 mL) was stirred for 1 h at 20° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was subsequently washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give crude title compound (0.78 g, 40%) as light yellow solid. MS ISP (m/e): 242.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([NH:6][C:7]2[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(OCC)(=O)C>[C].[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:15]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=3)[CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=[O:10])=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCc2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the obtained 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoic acid were added ethyl acetate 1.0 mL, methanol 1.0 mL and 10% palladium-carbon 2.0 mg sequentially, and it was stirred under hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The solvent was removed under reduced pressure after insoluble matter was filtrated to give 2-(4-fluoroanilino)-4-(2-(4-(trifluoromethoxy)phenyl)ethyl)benzoic acid 3.4 mg of a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[CH:19]1([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:24][C:25]([NH:12][C:10]2[S:11][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[C:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Reactant: O=C(Cl)CC1CCCC1
Product: Cc1nc(-c2sc(NC(=O)CC3CCCC3)nc2-c2ccccc2)no1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and cyclopentyl-acetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([NH:36][NH2:37])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH:37][NH:36][C:34]([C:30]2[S:29][CH:33]=[CH:32][CH:31]=2)=[O:35])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)O)s3)c2cc1OC
Reactant: NNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(=O)NNC(=O)c4cccs4)s3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 4-(3-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (41 mg, 0.1 mmol) and thiophene-2-carboxylic acid hydrazide (14.2 mg, 0.1 mmol, Aldrich) in N,N-dimethylformamide (1 ml) was added HATU (38 mg, 0.1 mmol) and diisopropylethylamine (26 μl, 0.15 mmol). The mixture was stirred at ambient temperature overnight. The solvent was reduced in vacuo and water (3 ml) was added. After sonication, the crude was filtered and sent directly for purification with prep-HPLC to afford thiophene-2-carboxylic acid N′-[4-(3-chloro-phenyl)-2-(5,6-dimethoxy benzoimidazol-1-yl)-thiazole-5-carbonyl]-hydrazide (37.9 mg, 70.2%) as a white solid. MS m/z 540 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.[CH3:23][C:24](=O)[CH2:25][CH2:26][C:27](=O)[CH3:28].C(O)(=O)C>C(O)C>[CH3:28][C:27]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=3)[CH:7]=2)[C:24]([CH3:23])=[CH:25][CH:26]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Solvent: CC(=O)O
Solvent: CCO
Product: CCCOc1ccc(-n2c(C)ccc2C)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Yield: 43.9 %

Procedure:
The compound (200 mg, 0.66 mmol) of example 42 and 2,5-hexanedione (76 mg, 0.66 mmol) were dissolved in ethanol (10 ml) and added with glacial acetic acid (0.1 ml), followed by refluxing for 12 h. The reaction mixture was concentrated to dryness, dissolved in CH2Cl2 (10 ml), and washed with saturated NaHCO3 (10 ml) and saturated saline (10 ml), dried and concentrated. The residue was passed through a silica gel column to give the title compound (110 mg, yield: 44%). 1H NMR (CDCl3) δ: 11.20 (1H, br), 8.42 (1H, d), 7.30 (1H, dd), 7.10 (1H, d), 5.93 (2H, s), 4.23 (2H, t), 2.63 (2H, q), 2.59 (2H, q), 2.06 (6H, s), 2.04 (2H, m), 1.24 (3H, t), 1.18 (3H, t), 1.15 (3H, t).
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([OH:22])=O)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.[NH2:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.O>[F:6][C:7]1[CH:8]=[C:9](/[CH:18]=[CH:19]/[C:20]([NH:23][CH:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:22])[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: NC1CCc2ccccc21
Reactant: O=C(O)/C=C/c1ccc(-n2ccnc2)c(F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(-n2ccnc2)c(F)c1)NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a DMF (4.0 mL) solution of (E)-3-[3-fluoro-4-(1H-imidazol-1-yl)phenyl]acrylic acid (100 mg), TEA (167 μL), 1-aminoindane (83.0 μL) and PYBOP (448 mg) were added one by one, and the reaction solution was agitated at room temperature overnight. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate=1:1→ethyl acetate), and 95.0 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([N:23]2[CH2:28][CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25][CH2:24]2)[CH:15]=1)(=[O:13])=[O:12].[OH-].[Na+]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[C:16]([N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH:15]=1)(=[O:12])=[O:13]
Reactant: CCOc1ccc(S(=O)(=O)Nc2ccccc2COC)cc1N1CCN(C(=O)C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(S(=O)(=O)Nc2ccccc2COC)cc1N1CCNCC1

Procedure:
0.074 g of the product was obtained as described in Example 1 by reaction of N-(2-methoxymethyl-phenyl)-4-ethoxy-3-[4-(2,2,2-trifluoro-acetyl)piperazin-1-yl]-benzenesulfonamide with aqueous sodium hydroxide.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:38])[F:37])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:32]([CH3:33])=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[CH3:34])=[O:21])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([C:36]([F:39])([F:37])[F:38])=[C:19]([CH:35]=2)[C:20]([NH:22][C:23]2[C:24]([CH3:34])=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][C:32]=2[CH3:33])=[O:21])[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc2C(F)(F)F)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O)CC3)ccc2C(F)(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.2 %

Procedure:
To a solution of methyl 4-[[5-[4-[tert-butyl(dimethyl)silyl]oxy-1-piperidyl]-2-(trifluoromethyl)benzoyl]amino]-3,5-dimethyl-benzoate (0.10 g, 177.08 μmoles) in THF (4 ml) is added Bu4NF 1.0 M in THF (1.0 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 6 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 40-60% ethyl acetate in hexanes to afford the title compound as a light yellow solid (0.06 g, 81.5%). Mass spectrum (m/z): 451.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[CH:15][S:16][CH:17]=2)=[C:9]([F:18])[CH:8]=1)=O.Cl.[NH:23]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[N:29][CH:30]=1)[NH2:24]>C(O)C>[F:18][C:9]1[CH:8]=[C:7]([C:5]2[N:23]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[N:29][CH:30]=3)[N:24]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[CH:15][S:16][CH:17]=1
Reactant: NNc1ccc(S(N)(=O)=O)nc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)c(F)c1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)c(F)c2)cn1
Yield: 23 %

Procedure:
A suspension of 4,4,4-trifluoro-1-(3-fluoro-4-(1,3-thiazol-4-yl)phenyl)-1,3-butanedione (503 mg, 1.59 mmol) and 5-hydrazino-2-pyridinesulfonamide hydrochloride (392 mg, 1.74 mmol) in ethanol (22 ml) was stirred at reflux for 28 h. After cooling, the solvent was removed and the residue was added water, extracted with ethyl acetate. The extracts was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:4/1:3/1:2) to afford 172 mg (23.0%) of the titled compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([Cl:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:2]2[C:3]3[C:10]([CH3:11])=[C:9]([Cl:12])[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1c(Cl)sc2ncnc(Cl)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: Cc1c(Cl)sc2ncnc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12

Procedure:
The title compound was prepared (611 mg, 82%) from 4,6-dichloro-5-methylthieno[2,3-d]pyrimidine (425 mg, 1.94 m. mol) and tert-butyl 4-aminopiperidine-1-carboxylate (582 mg, 2.9 m. mol) by following the general procedure described for Preparation 9. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 5.25 (d, 1H), 4.35 (m, 1H), 4.30 (m, 2H), 3.00 (m, 2H), 2.55 (s, 3H), 2.15 (m, 2H), 1.45 (s, 9H), 1.35–1.55 (m, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:68])[C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[C:64]([F:67])([F:66])[F:65])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:63][C:61]1[CH:60]=[CH:59][C:58]([C:64]([F:66])([F:65])[F:67])=[C:57]([CH:62]=1)[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[CH:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1)=[O:68]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 56.1 %

Procedure:
DIPEA (223 mg, 0.3 mL, 1.72 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-4-carboxylic acid (65 mg, 0.34 mmol) in DMF (5 mL). HOBT (51 mg, 0.38 mmol) and EDCI (165 mg, 0.86 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (140 mg, 0.38 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 96 mg (53.3% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 96.77%. 1H NMR (CDCl3): δ 8.42 (d, 2H), 8.04 (s, 1H), 7.8-7.64 (m, 3H), 7.52-7.42 (t, 2H), 7.4-7.3 (t, 1H), 7.1 (d, 1H), 7.0-6.9 (bs, 1H), 4.34-4.18 (m, 2H), 4.04-3.84 (m, 1H), 3.8-3.5 (m, 4H), δ 3.44 (t, 1H), 3.3-3.2 (m, 2H).