Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@:3]1([OH:25])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[C@H:11]1O[C@@H:10]31)#[CH:2].[ClH:26]>C(O)(=O)C>[C:1]([C@:3]1([OH:25])[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([C@@H:20]([F:22])[CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12](=[CH:13][C:14](=[O:23])[CH2:15][CH2:16]1)[C:11]([Cl:26])=[CH:10]3)#[CH:2]
Reactant: Cl
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Solvent: CC(=O)O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@@]21C
Temperature: 0 °C
Reaction time: 20 h

Procedure:
460 mg. of 17α-ethinyl-6α,7α-epoxy-11β-fluoro-17β-hydroxy-4-androsten-3-one is introduced at room temperature into 25 ml. of glacial acetic acid saturated with gaseous hydrogen chloride. After 20 hours, the solution is poured into ice/water. The thus-precipitated product is vacuum-filtered and worked up as indicated in Example 17. After chromatography of the crude product on silica gel with acetone/hexane, 215 mg. of 17α-ethinyl-6-chloro-11β-fluoro-17β-hydroxy-4,6-androstadien-3-one is obtained as a foamy product. UV: ε282 = 20,600 (methanol).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:25][C:26]([O:28][C:29](C)(C)C)=[O:27])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].ClC(OC)=O.Cl>C(Cl)Cl.C1COCC1.O.O.CCOC(C)=O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C@H:14]([NH:25][C:26]([O:28][CH3:29])=[O:27])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Agent: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-benzyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate (0.52 g, 1.15 mmol) in CH2Cl2 was added TFA (4 mL). The mixture was allowed to stir at room temperature for 2 h. The mixture was concentrated in vacuo to give a colorless oil which solidified on standing. This material was dissolved in THF-H2O and cooled to 0° C. Solid NaHCO3 (0.25 g, 3.00 mmol) was added followed by ClCO2Me (0.25 mL, 3.25 mmol). After stirring for 1.5 h the mixture was acidified to pH˜2 with 6N HCl and then poured into H2O-EtOAc. The layers were separated and the aq phase extracted 2× with EtOAc. The combined org layers were washed (H2O, brine), dried (Na2SO4), filtered, and concentrated in vacuo to give a colorless oil (505.8 mg, 111%, NMR suggested the presence of an unidentified impurity) which solidified while standing on the pump. The material was used as is without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.10 (d, J=12.7 Hz, 1H), 5.06 (d, J=12.7 Hz, 1H), 4.32-4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, J=5.6, 14.7 Hz, 1H), 2.98 (dd, J=9.6, 14.7 Hz, 1H). LC-MS: Anal. Calcd. for C21H22N4O4: 394. found: 395 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH:34]7[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]7)[CH:33]=6)=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[ClH:47]>C(Cl)Cl.O1CCOCC1>[ClH:47].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:18][CH2:19][CH2:20][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH:34]7[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]7)[CH:33]=6)=[CH:25][N:24]=5)[CH2:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCN(C(=O)OC(C)(C)C)CC7)c6)cn5)CCO4)c3n2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCNCC7)c6)cn5)CCO4)c3n2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
(S)-tert-butyl 4-(4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 463 mg (0.74 mmol) was dissolved in methylene chloride 20 ml, and 4 M HCl (excess) dissolved in 1,4-dioxane 20 ml was added and then charged with nitrogen, followed by stirring at room temperature for 18 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methylene chloride and dioxane, thereby giving a yellow solid 493 mg (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([C:14]1[C:22]2[C:17](=[C:18]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[N:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13])[C:5](OC)=[O:6].[BH4-].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([Cl:29])[C:11]=1[C:12]([C:14]1[C:22]2[C:17](=[C:18]([NH:23][C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[N:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1c(Cl)cc(CO)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Temperature: 60 °C
Yield: 2.1 %

Procedure:
To a solution of methyl 3,5-dichloro-4-({7-[(cyclopropylcarbonyl)amino]-1H-pyrrolo[2,3-c]pyridin-3-yl}carbonyl)benzoate (100 mg, 2.31 mmol) in 1,4-dioxane and water (3:1), sodium borohydride (27 mg, 6.944 mmol) was added portion wise over a period of about 15 minutes, followed by heating the reaction mixture at 60° C. until starting material was consumed (approximately 3 hours) The reaction mixture was cooled to room temperature and quenched by the addition of saturated aq. ammonium chloride solution and extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-{3-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropane carboxamide (20 mg, 22%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[CH:12][C:11]([C:29]([OH:31])=O)=[CH:10][CH:9]=2)=[O:5].Cl.CN(C)CCCN=C=NCC.O.O[N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2N=N1.NC1C=CC=CC=1>ClCCl.CS(C)=O.C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[CH:12][C:11]([C:29](=[O:31])[NH:46][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:49]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)c1[nH]c2ccc(C(=O)O)cc2c1CCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: CCOC(=O)c1[nH]c2ccc(C(=O)Nc3ccccc3)cc2c1CCCNC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
A reaction flask equipped with a nitrogen line and a stir bar was charged with a solution of 3-(3-benzyloxycarbonylamino-propyl)-1H-indole-2,5-dicarboxylic acid 2-ethyl ester (64 mg, 0.15 mmol) in dichloromethane (2 mL) and DMSO (1 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (37.5 mg, 0.19 mmol) and 1-hydroxybenzotriazole hydrate (26.5 mg, 0.19 mmol) were added. The reaction mixture was stirred for 0.5 h. Aniline (20.5 microL, 0.23 mmol) was added and stirring continued for 48 h. The reaction mixture was diluted with ethyl acetate and washed in turn with 1N HCl. and saturated sodium carbonate. The organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated and the resulting oil was purified by flash chromatography with 50-100% ethyl acetate/hexane to give 3-(3-benzyloxycarbonylamino-propyl)-5-phenylcarbamoyl-1H-indole-2-carboxylic acid ethyl ester (44 mg, 58%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[C:8]([CH3:23])[C:6]=2[N:7]=1.B(O)(O)[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1>>[OH:21][C@@H:19]([CH3:20])[C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH2:13][CH2:14]1)=[O:22]
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(-c3cccnc3)nc12
Yield: 85.4 %

Procedure:
(S)-1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (60 mg) was reacted with 27 mg of pyridin-3-yl-3-boronic acid via General Procedure A to give 56.2 mg of 206. MS (Q1) 483.3 (M)+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].B>C1COCC1.CO>[CH2:1]([S:3]([C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(CO)cc1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To a stirring solution of 4-(ethylsulfonyl)benzoic acid (500 mg, 2.33 mmol) in THF (5 mL) at 0° C. under argon was added 1 M borane in THF solution (3.5 mL, 3.5 mmol). The reaction mixture was stirred at 70° C. for 20 min. The reaction mixture was then cooled to room temperature, and the THF was removed under reduced pressure. The residue thus obtained was diluted with methanol (5 mL) and stirred for 5 min. Methanol was then removed under reduced pressure. This process was repeated two more times to ensure complete methanolysis of any borane complex. After residual solvent removal under vacuum, 420 mg of the title compound was obtained as a colorless gum. HPLC/MS: retention time=1.373 min, [M+H]+=201.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C:13]2([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]2)(=O)=O)=CC=1.[CH3:20][O-].[Na+]>CO.O>[CH3:20][O:11][CH2:12][C:13]1([CH3:19])[CH2:17][O:16][C:15](=[O:18])[NH:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC(=O)N2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a round bottom flask containing (4-methyl-2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (300 mg, 1.05 mmol) was added under a nitrogen atmosphere 3 ml of sodium methoxide in methanol solution (25% wt). The resulting thick suspension was stirred at ambient temperature for 24 hours, and then heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature, diluted with water, and the pH was adjusted to neutral. The mixture was concentrated, and the resulting solids were extracted with DCM and EtOAc. The combined organic layer was concentrated to afford 4-(methoxymethyl)-4-methyloxazolidin-2-one (129 mg, 85%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL, 1:1) was added 0.460 g of 10% Pd/C and the mixture was stirred under hydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 0.277 g (99% yield) of tert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: 1H NMR (DMSO-d6) δ9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18]C(=O)OC(C)(C)C)[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:18][C@@H:3]([C@H:4]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)/[CH:5]=[CH:6]/[CH3:7])[CH2:2][OH:1]
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CO
Reaction time: 1 h

Procedure:
Tert-butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (0.10 g, 0.28 mmol) was taken up in 3 mL of DCM. 1 mL of TFA was added. The mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was taken up in 5 mL of DCM and 5 mL of 5% aq NaOH. The mixture was partitioned, and the aqueous portion was extracted three times with 5 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure afforded (2S,3S,E)-2-amino-3-(4-(trifluoromethyl)phenyl)hex-4-en-1-ol, which was used without any further purification.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].I[CH3:20]>CN(C)C=O>[CH3:20][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1
Reactant: CI
Reactant: CCOC(=O)N1CCC(OC)(OC)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(OC)(OC)C(OC)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
To a stirred mixture of 35 parts of ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate and 144 parts of N,N-dimethylformamide were added portionwise 8.2 parts of sodium hydride dispersion 50%: exothermic reaction (temp. roses to 30° C.; cooling in a water-bath was necessary to keep the temperature below 30° C.). The whole was stirred for 1.50 hours at about 30° C. and then it is cooled to room temperature. 24.1 Parts of iodomethane were added dropwise (strong exothermic reaction) while the temperature was kept below 30° C. Upon completion, stirring was continued over week-end at room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated, yielding 35.9 parts (95.7%) of ethyl 3,4,4-trimethoxy-1-piperidinecarboxylate as an oily residue (intermediate 64).
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])(=[O:23])=[O:22])=[CH:17][CH:16]=1)(O)=[O:13].ON1C2N=CC=CC=2N=N1.[CH2:45]([NH2:53])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=1[NH:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12](=[O:13])[NH:53][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:16][CH:17]=1)(=[O:22])=[O:23]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDCI (84.4 mg, 0.44 mmol) is added to a solution of the title A compound, followed by methyl 2-(4-carboxy-benzene-sulfonylamino)-benzoate (134.1 mg, 0.40 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt, 59.9 mg, 0.44 mmol) in 1 mL of DMF at RT. The reaction is stirred 1 h after which phenethylamine (50.2 μL, 0.40 mmol) is added. The resulting solution is stirred overnight at RT, followed by addition of 5% aqueous sodium bicarbonate (1 mL) and water (8 mL). A white precipitate is collected by filtration, washed with water, and dried under vacuum to give 2-(4-phenethylcarbamoylbenzenesulfonyl-amino)-benzoic acid methyl ester m.p. 167-168° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:43])([F:44])[F:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2ccccc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2Cl)c1C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 76.1 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-chlorophenyl)isoxazol-4-carboxylic acid (440 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (424 mg, 1.84 mmol), a white solid required compound (633 mg, 1.40 mmol, 76%) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:13][C:14]=1Br.CCOC(C)=O>CN1C(=O)CCC1.O>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[CH:21]=2)=[N:13][C:14]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)n1cc(-c2nc(-n3cccn3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 62.1 %

Procedure:
To a solution of pyrazole (106 mg) in NMP (1.0 ml), was added 60% NaH (52 mg) under ice-bath cooling. After 5 minutes stirring, 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) was added to the mixture. And then the mixture was heated at 100° C. with stirring for 2 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was recrystallized from MeOH and dried in vacuo to give 5-[5-amino-3-phenyl-6-(1H-pyrazol-1-yl)-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (60 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:23])[CH:13]([OH:22])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O.O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:23])[CH:13]([O:22][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(C)(C)C(O)C(C)NC(=O)OCc1ccccc1
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(O[Si](C)(C)C(C)(C)C)C(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-hydroxypentanoate (5.7 g) and 2,6-lutidine (2.27 mL) in THF (80 mL) was added under ice-cooling tert-butyldimethylsilyl trifluoromethanesulfonate (3.44 mL) and, after warming to room temperature, the mixture was stirred for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/1) to give the title compound as a colorless oil (yield: 5.42 g, 70%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([S:14]([NH:17][C:18]2[C:19]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:20]([F:28])[C:21]3[O:25][N:24]=[C:23]([CH3:26])[C:22]=3[CH:27]=2)(=[O:16])=[O:15])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl>C1COCC1>[OH:8][CH2:9][CH2:10][C:11]1([S:14]([NH:17][C:18]2[C:19]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:20]([F:28])[C:21]3[O:25][N:24]=[C:23]([CH3:26])[C:22]=3[CH:27]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1
Reactant: Cc1noc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3(CCO[Si](C)(C)C(C)(C)C)CC3)cc12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1noc2c(F)c(Nc3ccc(I)cc3F)c(NS(=O)(=O)C3(CCO)CC3)cc12
Reaction time: 1 h
Yield: 60.7 %

Procedure:
To a solution of 1-(2-(tert-butyldimethylsilyloxy)ethyl)-N-(7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazol-5-yl)cyclopropane-1-sulfonamide (20 mg, 0.030 mmol) in THF (2 ml) was added HCl (0.10 ml, 1.2 N in H2O, 0.12 mmol). After stirring for 1 h, the reaction was quenched with saturated aqueous NaHCO3 solution (3 ml) and extracted with EtOAc (2×10 ml). The combined organic solution was dried over Na2SO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=75:25) yielded 10 mg (61%) of 1-(2-hydroxyethyl)-N-(7-fluoro-6-(2-fluoro-4-iodophenylamino)-3-methylbenzo[d]isoxazol-5-yl)cyclopropane-1-sulfonamide as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 0.75 (m, 2H), 0.87 (m, 2H), 1.84 (t, J=8 Hz, 2H), 2.57 (s, 3H), 3.38 (m, 2H), 4.52 (s, 1H), 6.59 (m, 1H), 7.34 (d, J=8 Hz, 1H), 7.60 (dd, J=4, 8 Hz, 1H), 7.68 (s, 1H), 7.84 (s, 1H), 9.58 (s, 1H).
Reaction SMILES: FC1C=CC([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C@@H](C3C=CC(OC)=CC=3)C)[CH:15]=2)=[O:9])=CC=1>C(O)(C(F)(F)F)=O>[NH:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:14]1[CH:15]=[C:10]([CH:8]=[O:9])[CH:11]=[N:12][CH:13]=1
Reactant: COc1ccc([C@@H](C)N2CCC[C@H]2c2cncc(C(=O)c3ccc(F)cc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cncc([C@@H]2CCCN2)c1
Yield: 109.1 %

Procedure:
A solution of (4-fluoro-phenyl)-(5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridin-3-yl)-methanone (4) (3.3 g, 8.17 mmole) in 5 mL of TFA is heated at 100° C. in a microwave reactor for 30 minutes. The result solution is concentrated to remove TFA. The residue is diluted with 100 mL of CH2Cl2, and basified by washing with 5 mL of saturated sodium bicarbonate. The organic layer is concentrated and purified by flash column chromatography (CH2Cl2 100% to CH2Cl2 80% MeOH 20% gradient in 30 minutes) to give 4-fluoro-phenyl)-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-methanone (5) (1.57 g, yield 71%) as a light brown viscose liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCC[C@@H]1C[C@H](CC(=O)Oc2ccccc2)OC2(CCCCC2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)Oc2ccccc2)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and phenyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.