Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)O
Reaction time: 5 h

Procedure:
A solution containing (2S,4R)-4-fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (700 mg, 2.075 mmol) and Pd/C 10% (221 mg, 2.075 mmol) in THF (6 mL) was placed under a nitrogen atmosphere and stirred for 5 h. The catalyst was removed through a pad of celite and washed with MeOH. Solvents were removed under vacuum to give the desired material as a colorless oil which was used without further purification in the next step. MS (UPLC/MS): 246.2 [M−H]−, 292.2 [M+HCOO−]−, 493.4 [2M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCCCCl
Temperature: 80 °C
Yield: 19.1 %

Procedure:
A mixture of 2-methoxy-5-nitrophenol (16.90 g, 100 mmol), 3-chloropropyl p-toluenesulfonate (29.2 g, 120 mmol) and potassium carbonate (27.0 g, 195 mmol) in 160 mL of N,N-dimethylformamide was heated at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate and filtered. The solution was concentrated in vacuo and recrystallized from hexane and ethyl acetate to give 4.68 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene as a first crop of off-white crystals. A second crop of 11.10 g was obtained from the mother liquor. The remaining solution was concentrated in vacuo and purified by flash column chromatography, eluting with 4:1 hexane:ethyl acetate, to provide 1.31 g of 2-(3-chloropropoxy)-1-methoxy-4-nitrobenzene as off-white crystals, mp 85-87° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.23 (m, 2H), 3.79 (t, J=6 Hz, 2H), 3.92 (s, 3H), 4.21 (t, J=6 Hz, 2H), 7.19 (d, J=9 Hz, 1H), 7.77 (d, J=2 Hz, 1H), 7.92 (dd, J=9, 2 Hz, 1H); MS (ES) m/z246.1, 248.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].[H-].[Na+].[CH3:13][N:14]([CH3:28])[S:15]([NH:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)(=[O:17])=[O:16].Cl>C1COCC1.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][O:6][C:23]1[CH:24]=[CH:25][C:20]([C:19]([NH:18][S:15]([N:14]([CH3:28])[CH3:13])(=[O:17])=[O:16])=[O:27])=[CH:21][CH:22]=1
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dichlorobenzyl alcohol (500 mg, 2.8 mmol) in THF (20 mL) was added sodium hydride (113 mg, 2.8 mmol, 60% dispersion in mineral oil) and stirred at room temperature for 2 hours and then at 50° C. for 30 minutes. Cooled to room temperature and the solvent removed in vacuo to afford an orange solid. This was dissolved in DMSO (5 mL) to which was added a solution of N-[(dimethylamino)sulfonyl]-4-fluorobenzamide (Preparation 11, 580 mg, 2.3 mmol) in DMSO (10 mL) slowly. The dark red solution was heated at 50° C. for 18 h then 120° C. for 2 hours. The mixture was cooled and poured onto water (50 mL) containing 2M HCl (30 mL) and extracted with EtOAc (2×30 mL), washed with 1M HCl (30 mL) and dried over MgSO4, filtered and solvent removed in vacuo to give 1.9 g of crude residue that was purified using reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([CH2:15][C:16]([O:18]CC)=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]([CH2:15][C:16]([OH:18])=[O:17])[CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC1CN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC1CN(C(=O)OCc2ccccc2)C1
Yield: 98.5 %

Procedure:
A solution of 3-ethoxycarbonylmethylazetidine-1-carboxylic acid benzyl ester (0.30 g, 1.1 mmol), and lithium hydroxide monohydrate (0.091 g, 2.2 mmol) in TBF (3 mL) and water (1 mL) was stirred under argon at room temperature for 1 hr. After acidification with 2 M aqueous hydrochloric acid (10 mL), the reaction mixture was extracted with ethyl acetate (3×20 ml). The combined ethyl acetate layers were washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.27 g of the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1.CN(CCN(C)C)C.C([Li])(C)(C)C.[Br:36]C(F)(F)C(F)(F)Br>C1COCC1>[Br:36][C:7]1[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:9][C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:11][C:6]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:22]
Reactant: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCCc1cc(CCCOC)c(Br)c(C(=O)NC2CC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a THF (0.1 M) solution of N-cyclopropyl-3,5-bis(3-methoxypropyl)benzamide (1 eq.) from the previous step and freshly distilled TMEDA (1 eq.) was added at −78° C. t-butyl lithium (1.7 M in pentanes, 1 eq.) dropwise over 10 min. The resulting reaction mixture was then slowly warmed to 0° C. over 1 h and stirred at 0° C. for 1 h. With the now orange reaction solution re-cooled to −78° C., 1,2-dibromotetrafluoroethane was added neat, dropwise over 10 min. The cooling bath was removed and the reaction mixture was stirred at RT for 18 h. The reaction was then quenched with 1 N aq. NaOH and extracted with EtOAc. The combined organic extracts were washed further with 10% aq. HCl, water and brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:26]5[CH2:30][CH2:29][CH2:28][C:27]5=[O:31])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCCC3=O)cn2)CC1
Yield: 2 %

Procedure:
Using (5-bromopyrazin-2-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 243 and pyrrolidin-2-one (25 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (2 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20].[H-].[Na+].[CH:24](OC)=[O:25]>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:11][CH2:12][CH2:13]1)[CH:9]([CH:24]=[O:25])[C:8]2=[O:20]
Reactant: COC=O
Reactant: COCOc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1c(C)c(C)c2c(c1C)C(=O)C(C=O)C1(CCC1)O2
Reaction time: 0.08 h

Procedure:
To a solution of 6-(methoxymethoxy)--5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-4(3H)-one (2.0 g) in 20 mL of THF was added under stirring, NaH (1.38 g). After 5 minutes, 8.5 mL of methyl formate (137.4 mmol) were added dropwise to the mixture. The reaction was allowed to stir at room temperature overnight. The organic phase was washed with 1N HCl and water, dried over anhydrous MgSO4, and concentrated in vacuo to give 6-(methoxymethoxy)-5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-3-carbaldehyde as a yellow paste. This intermediate was used directly for subsequent reactions without further purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[CH2:16]([O:1][CH2:2][C@H:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][C@@H:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: C=C1C[C@@H](CO)[C@H](c2cccc(F)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C1C[C@H](COCc2ccccc2)[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To a solution of (+)-trans-1-hydroxymethyl-4-methylene-2-(3-fluorophenyl)cyclopentane (5.0 g, 26.5 mmol) from Example 1, Step C and benzyl bromide (4.7 mL, 40 mmol) in DMF (130 mL) was added 60% sodium hydride in mineral oil (0.77 g, 32 mmol). The reaction was stirred at room temperature for 24 h was then diluted with ether and slowly quenched into aq. sodium bicarbonate. After three ether extractions, the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by FC (2–5% ethyl acetate in hexanes) to afford the title compound (7.1 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].[Br:27]Br>CCO>[Br:27][C:8]1[CH:7]=[C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:25])[F:26])[CH:11]=[CH:10][C:9]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(O)C(F)(F)F)cc2)CC1
Reactant: BrBr
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(O)C(F)(F)F)cc2Br)CC1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
A 500 mL round-bottomed flask was charged with tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.61 g, 23.0 mmol) and 100 mL of EtOH. To this was added bromine (1.30 mL, 25.3 mmol). After 15 min, the reaction was concentrated and purified via column chromatography (120 g of silica, 0 to 40% EtOAc in hexanes) to give tert-butyl 4-(2-bromo-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (6.50 g) as a tan foam.
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]>O.CCO>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C(C)(C)C)cc3)c(C)o2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
A solution of Na2SO3 (126 mg, 1.0 mmol) and Na2CO3 (106 mg, 1.0 mmol) in water (2 mL) was added to a suspension of 4-tert-butylbenzenesulfonyl chloride (233 mg, 1.0 mmol) in water (5 mL) and the mixture was stirred at 100° C. for 2 h. A solution of chloride 2 (268 mg, 1.0 mmol) in EtOH (5 mL) was added and the mixture stirred at 100° C. for 16 h. The mixture was cooled and diluted with water (40 mL) and stirred for 15 min. The precipitate was filtered, washed with water (5 mL). The residue purified by column chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give benzoate 22 (112 mg, 26%) as a white powder: mp (EtOAc) 190-192° C.; 1H NMR (CDCl3) δ 8.05 (ddd, J=8.6, 1.8, 1.5 Hz, 2H, H-2, H-6), 7.89 (ddd, J=8.6, 1.8, 1.5 Hz, 2H, H-3, H-5), 7.71 (ddd, J=8.6, 2.2, 1.8 Hz, 2H, H-2′, H-6′), 7.51 (ddd, J=8.6, 2.2, 1.8 Hz, 2H, H-3′, H-5′), 4.30 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.32 (s, 3H, CH3), 1.33 [s, 9H, C(CH3)3]; MS m/z 428.5 (MH+, 100%). Anal. calcd for C23H25NO5S: C, 64.62; H, 5.89; N, 3.28. Found: C, 64.70; H, 5.94; N, 3.25%.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([C:8]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:9]=1)[O:6][CH3:7])C.[OH-].[Na+]>CO>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:10]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:8]([CH:5]([O:6][CH3:7])[C:4]([OH:24])=[O:3])=[N:9]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(OC)c1nn(-c2ccc(Cl)cc2)c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C(=O)O)c1nn(-c2ccc(Cl)cc2)c2c1CCCC2
Yield: 84.1 %

Procedure:
A solution of the compound of Example 73 (0.75 g) in methanol (15 ml) was treated with N sodium hydroxide (6 ml) and reacted at room temperature for 15 minutes. The solution was concentrated in vacuo, diluted with water, and acidified. The precipitate was filtered to yield the title compound (0.58 g). An analytical sample (m.p. 185°-186° C.) was obtained from methanol-hexane solution.
Reaction SMILES: [N:1]1([C:7]([C:9]2([C:15]3[CH:31]=[CH:30][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:17][CH:16]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C>C(Cl)Cl>[CH3:34][N:4]1[CH2:3][CH2:2][N:1]([C:7]([C:9]2([C:15]3[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:30][CH:31]=3)[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[O:8])[CH2:6][CH2:5]1
Reactant: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCOCC3)cc2)CCOCC1
Reactant: CC(=O)O
Agent: C=O
Solvent: ClCCl
Product: CN1CCN(C(=O)C2(c3ccc(OCCCN4CCCOCC4)cc3)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
4-(3-{4-[4-(piperazin-1-ylcarbonyl)tetrahydro-2H-pyran-4-yl]phenoxy}propyl)-1,4-oxazepane (45 mg, 0.1 mmol) was dissolved in DCM (3 ml), to which was added formaldehyde (37% w/w in H2O, 12 mg, 0.12 mmol) and acetic acid (8 mg, 0.12 mmol) and was stirred at room temperature for 30 minutes before adding STAB (25 mg, 0.12 mmol). The solution was allowed to stir for a further 45 minutes before washing the solution with saturated sodium bicarbonate (10 ml), followed by brine (10 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound as a white solid (25 mg, 56%). 1H NMR (400 MHz, d6-DMSO) δ 1.76-2.13 (m, 11H), 2.55-2.78 (m, 6H), 3.16-3.39 (m, 8H), 3.50-3.62 (m, 4H), 3.63 (m, 2H), 3.72 (M, 2H), 3.99 (t, 2H), 6.92 (d, 2H), 7.12 (d, 2H). LRMS ESI+ m/z 446 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 93 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H), 3.20-3.28 (m, 4H), 3.76-3.96 (m, 4H), 4.14 (s, 3H), 7.02-7.13 (m, 3H), 7.28 (s, 1H), 7.49-7.63 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@@H:20](O)[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4].CN(C=O)C.S(Cl)([Cl:33])=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[C:11]([N:13]2[C:17](=[O:18])[C@H:16]3[CH2:19][C@H:20]([Cl:33])[CH2:21][N:15]3[C:14]2=[O:23])[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])(=[O:5])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C1[C@H]2C[C@@H](O)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1[C@H]2C[C@H](Cl)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of the title compound of Example 1, Step G (3.3 g, 8 mmol) in 25 mL toluene and 0.02 g DMF was added at 80° C. thionyl chloride (1.31 g, 11 mmol) over a period of 15 minutes. The suspension was stirred at the same temperature for 2 h and at 105° C. for 30 minutes. After cooling to room temperature, the organic layer was washed with water, dried, and the solvent was evaporated under reduced pressure to yield the title compound of Step A, a compound of this invention, in quantitative yield as a crude powdery product melting at 169-170° C. 1H NMR (CDCl3) δ 7.64 (d, 1H), 7.36 (d, 1H), 7.20 (br s, 1H), 4.78 (m, 2H), 4.56 (s, 2H), 4.24 (dd, 1H), 3.62 (dd, 1H), 2.62 (m, 1H), 2.38 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)COCc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(-c3ncc(COCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A mixture of ethyl [(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)methoxy]acetate (0.08 g), 1N aqueous sodium hydroxide solution (0.30 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.04 g, yield 45%) as pale-yellow crystals. melting point 197-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:19](O)[CH3:20]>Cl>[CH2:19]([O:8][C:7](=[O:9])[C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:17]=[CH:18][C:2]([NH2:1])=[CH:3][CH:4]=1)[OH:10])[CH3:20]
Reactant: Nc1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)(c1ccccc1)c1ccc(N)cc1

Procedure:
4.8 g (19.7 mmol) of 4-aminobenzilic acid was dissolved in 200 ml of absolute ethanol (EtOH) saturated with dry HCl gas. The reaction mixture was refluxed for 24 hours then spin evaporated to dryness in vacuum. The residue was dissolved in water and neutralized with NaHCO3, extracted with 2×50 ml of AcOEt, washed with water (2×) and the AcOEt extract filtered through a siliconized filter and dried over MgSO4. The dried solution was filtered and spin evaporated in vacuum. Yellow oil, 2.8 g (52%). SGTLC in acetone Rf 0.8. HPLC Bondapak μC18MeOH/H2O (75:25) pH 4 (formic acid). Elemental Analysis Calc. for C16H17NO3. Calc. C 70.83, H 6.32, N 5.16; Found C 70.77, H 6.47, N 5.04, 5.26.
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C(N(CC)CC)C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of A1 (110.65 mg, 0.5 mmol) in dry dichloromethane (3 mL) at 0° C. was added triethylamine (0.086 mL, 0.55 mmol) and 2-fluorobenzenesulfonyl chloride (66.88 μL, 0.50 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Then dissolved the oil mixture in 2 mL CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using ethyl acetate/hexane (2:5) as the eluent, gave 14a; (105.42 mg, 65.2%). [α]D25: −11.7 (c=0.24, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.82 (dd, J=1.8, 7.8 Hz, 1H), 7.60-7.52 (m, 1H), 7.27-7.21 (m, 4H), 7.16-7.09 (m, 3H), 5.27 (d, J=9 Hz, 1H), 4.41 (m, 1H), 3.20-3.06 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.41, 160.51, 157.15, 136.54, 134.91, 134.80, 129.48, 129.31, 128.18, 126.68, 124.15, 117.04, 116.76, 57.31, 38.36; HRMS (ESI): calcd for: C15H14FNO4S [M+H]+=324.0690, obsd [M+H]+=324.0700.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14]>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: CC(C)C(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)C(=O)Nc1cn2nc(I)ccc2n1
Yield: 73.2 %

Procedure:
Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol), N,N-dimethylacetamide (8.0 mL) and isobutyryl chloride (0.44 mL, 4.23 mmol) as starting materials and in the same manner as in Reference Example 5, the title compound (0.93 g, 73%) was obtained as a dark brown powder.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccc(F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
(2R,4S)-Methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (647 mg, 1.94 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 15 mL, 85.65 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(4-fluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (360 mg, 67%). 1H NMR (600 MHz, DMSO) δ 1.08 (q, 1H), 1.37 (dq, 1H), 1.73-1.81 (m, 2H), 2.44-2.73 (m, 5H), 2.96-3.03 (m, 1H), 5.70 (s, 1H), 7.07-7.14 (m, 2H), 7.21-7.27 (m, 2H). HRMS Calculated for [C15H17FN2O2+H]+: 277.1352. Found: 277.1333