Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29]C)=[O:28])[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:21][C:19]([C:22]3[CH:31]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=[N:24][CH:23]=3)([OH:20])[CH3:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COC(=O)c1cncc(C2(C)CO2)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cncc(C(=O)O)c2)CCN(C)C1
Reaction time: 0.17 h
Yield: 5.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (90 mg, 0.466 mmol) in DMF (2 mL), sodium hydride (60%, 33 mg, 1.44 mmol) was added. After stirring for 10 min., methyl 5-(2-methyloxiran-2-yl)nicotinate (1.09 g, 12.4 mmol) was added to the reaction mixture, which was stirred at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc (2×100 mL). The aqueous layer was lyophilized and purified by reverse phase HPLC purification to obtain the 10 mg of 5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-3-carboxylic acid. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.9 (d, 1H), 8.7 (d, 1H), 8.57 (d, 1H), 7.11 (s, 1H), 6.74 (d, 2H), 4.67 (dd, 1H),4.33 (m, 2H), 4.29 (dd, 1H), 3.9 (t, 1H), 3.6 (m, 2H), 3.2 (m, 1H), 3.11 (s, 3H), 2.3 (s, 3H), 1.79 (d, 3H). Separation by chiral HPLC provides enantiomers II-141a-b.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(OC)=NN=NC=1OC.CN1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:44]([O:51][C:52](=[O:56])[CH2:53][CH2:54][NH2:55])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([O:51][C:52](=[O:56])[CH2:53][CH2:54][NH:55][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: COc1nnnc(OC)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCC(=O)NCCC(=O)OCc1ccccc1

Procedure:
4-(t-Butoxycarbonylamino)butyric acid in THF was activated with chlorodimethoxytriazine and N-methylmorpholine and reacted with β-alanine benzyl ester p-toluenesulphonate in the presence of N-methylmorpholine to give N-[4-(1-t-butoxyformamido)butyryl]-β-alanine benzyl ester, m.p. 54°-55° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:45][CH:46]1[C@H:50]2[C@H:51](OC3CCCCO3)[N:52](C(OC(C)(C)C)=O)[C:53]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:54]=3[C:55](=[O:56])[N:49]2[CH2:48][CH2:47]1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[C@H:18]2[C@H:19](OC3CCCCO3)[N:20](C(OC(C)(C)C)=O)[C:21]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:22]=3[C:23](=[O:24])[N:17]2[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:45][CH:46]1[C@@H:50]2[CH:51]=[N:52][C:53]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:54]=3[C:55](=[O:56])[N:49]2[CH2:48][CH2:47]1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[C@@H:18]2[CH:19]=[N:20][C:21]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:22]=3[C:23](=[O:24])[N:17]2[CH2:16][CH2:15]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 63.2 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15c (180 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16c (70 mg, 0.12 mmol, 65%) as a solid: [α]20D=+626° (c=0.17, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.62-1.71 (m, 2H, 14-H), 1.89-1.99 (m, 4H, 13-H, 13′-H), 2.0-2.11 (m, 4H, 2-H, 2′-H), 2.25-2.36 (m, 4H, 1-H, 1′-H), 3.53-3.62 (m, 2H, 3-H, 3′-H), 3.66-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.85 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.01-4.16 (m, 4H, 12-H, 12′-H), 6.78 (s, 2H, 9-H, 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 22.5, 29.6, 46.6, 53.7, 56.1, 68.7, 110.5, 111.6, 120.1, 140.6, 147.8, 150.8, 162.3, 164.6; IR (neat): 3350, 2946, 1600, 1505, 1455, 1433, 1383, 1262, 1217, 1092, 1020 cm−1; MS (FAB) m/z (relative intensity) 625 ([M+2×MeOH]+., 4), 593 ([M+MeOH]+., 12), 547 (M+., 100).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:25](O)=[O:26])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C.O>[CH:32]1([NH:34][C:25]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2/[CH:17]=[CH:18]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:26])[CH2:33][CH2:31]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2/C=C/c2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 176.6 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-[(E)-2-phenylvinyl]-1H-1,2,3-triazole-4-carboxylic acid (264 mg, 0.728 mmol) obtained in Example 106b), HOBt (49.7 mg, 0.364 mmol, 0.5 eq.) and cyclopropylamine (0.068 ml, 0.947 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (3:1, 4 ml), WSC (171 mg, 0.874 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 13 hr. Water (10 ml) was added to the reaction mixture and the mixture was stirred. The precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (258 mg, 0.643 mmol, 88.3%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH3:17])[C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19])#[N:2].[H-].[Na+].[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30]I)(=[O:24])[CH3:23]>CS(C)=O>[C:22]([O:25][C@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][N:10]1[C:11](=[O:18])[C:12]2[N:13]([CH3:17])[CH:14]=[N:15][C:16]=2[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:9]1=[O:19])(=[O:24])[CH3:23]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2CCCCCC#N
Reactant: CC(=O)O[C@H](C)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(CCCCCC#N)c1=O
Reaction time: 0.42 h
Yield: 86.7 %

Procedure:
To a stirring solution of 0.31 g 3-(cyanopentyl)-7-methylxanthine (1.2 mmol) in 20 ml dimethyl sulfoxide was added 30 mg sodium hydride (1.3 mmol). After 25 minutes, 0.34 g of (R)-5-acetoxy-1-iodohexane (1.3 mol) was added and the mixture was stirred for 24 h. The mixture was then quenched with 70 ml water and extracted three times with 30 ml ethyl acetate. The combined extracts were washed two times with 35 ml saturated aqueous sodium chloride solution and dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel) eluting with 5% methanol-ethyl acetate to give 0.42 g (R)-1-(5-acetoxyhexyl)-3-(5-cyanopentyl)-7-methylxanthine (88% yield) as a viscous oil.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([N:32]([CH2:46][CH3:47])[C:33]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=O)=[CH:36]1)=[O:34])[CH3:31]>O1CCCC1>[CH2:46]([N:32]([CH2:30][CH3:31])[C:33]([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=[CH:7][C:6]2[CH:27]=[CH:28][CH:29]=[C:4]([O:3][CH3:2])[CH:5]=2)=[CH:36]1)=[O:34])[CH3:47]
Reactant: COc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCN(CC)C(=O)n1cc(C=O)c2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1cc(C=Cc2cccc(OC)c2)c2ccccc21
Yield: 59.2 %

Procedure:
3-Methoxybenzyltriphenylphosphonium chloride (1.71 g) and 1-diethylcarbamoyl-3-formylindole (1.71 g), which had been synthesized according to the method of Tetrahedron Lett., 1869 (1986)., were reacted in tetrahydrofuran (5 ml) as in the above Production Example 41-1 to give the title compound (0.842 g) as a brown oil (yield: 59.1%). (59-2) 1-Diethylcarbamoyl-3-(3-methoxyphenethyl)indole
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH3:37][S:38]([N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)(=[O:40])=[O:39]
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 1 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.063 g) in CH2Cl2 (6 mL) was added DIEA (0.05 mL) and methanesulfonyl chloride (0.015 mL). After 1 hour, the mixture was concentrated and purified by chromatography (Silica gel: 4% MeOH/CH2Cl2, Chromatotron) afforded the titled compound. (0.069 g). MS (m/z) 546 (MH+). mp 229 CC.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>O1CCOCC1.CO>[NH:14]1[CH2:15][CH2:16][CH:11]([O:10][CH2:9][CH2:8][N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCN2CCCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C1CCN(CCOC2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 4 N HCl solution in dioxane (6 mL) was added to a solution of tert-butyl 4-(2-(piperidin-1-yl)ethoxy)piperidine-1-carboxylate (114)(6.5 g, 20.80 mmol) in MeOH (16 mL) and the reaction mixture was stirred at room temperature for 6 hours. Removal of solvent afforded 1-(2-(piperidin-4-yloxy)ethyl)piperidine as its hydrochloride salt (0.540 g, 12.22%). This salt was then dissolved in methanol (50 ml) and MP-carbonate (14.88 g, 33.61 mmol) was added. The resulting mixture was filtered and the solvent removed to give the desired material a colourless liquid which was used without further purification; 1H NMR (400.132 MHz, CDCl3) δ 1.33-1.47 (2H, m), 1.50-1.71 (3H, m), 1.86-1.96 (4H, m), 2.50-2.67 (6H, m), 3.00-3.14 (4H, m), 3.34 (1H, septet), 3.55 (2H, t), 3.60 (2H, t).
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:15]=2[N+:30]([O-])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(O)=O>CO.[Zn]>[NH2:30][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[CH:19][C:14]=1[NH:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:8][CH2:9]1
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(N[C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(COc2ccc(N)c(N[C@H]3CC[C@@H](C(=O)NC(C)C)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of cis-N-isopropyl-4-(5-(4-methoxybenzyloxy)-2-nitrophenylamino)cyclohexanecarboxamide (452 mg, 1.024 mmol) in MeOH (5 mL) was added AcOH (0.293 mL, 5.12 mmol) and zinc (669 mg, 10.24 mmol), and the resulting mixture was stirred at RT for 3 hours. The mixture was filtered through a pad of Celite® brand filter aid and evaporated to afford cis-4-(2-amino-5-(4-methoxybenzyloxy)phenylamino)-N-isopropylcyclohexanecarboxamide (400 mg).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH2:94]([N:101]1[CH2:106][CH2:105][CH:104]([NH2:107])[CH2:103][CH2:102]1)[C:95]1[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:94]([N:101]1[CH2:106][CH2:105][CH:104]([NH:107][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[CH2:103][CH2:102]1)[C:95]1[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCN(Cc6ccccc6)CC5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA7) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 46) replacing 1-(2-aminoethyl)piperidine with 1-benzyl-4-aminopiperidine. MS (ES+) m/e 700 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:48])[CH:7]([NH:12][C:13](=[O:47])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[S:22][S:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[C:32](=[O:46])[NH:33][CH:34]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:39]([CH:34]([NH:33][C:32]([C:25]1[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:24]=1[S:23][S:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:48])=[O:5])=[O:47])=[O:46])[CH2:35][CH:36]([CH3:38])[CH3:37])([OH:41])=[O:40]
Reactant: COc1ccc(C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c(SSc2cc(OC)ccc2C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)NC(CC(C)C)C(=O)O)c(SSc2cc(OC)ccc2C(=O)NC(CC(C)C)C(=O)O)c1
Yield: 7.9 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-methoxy-phenyldisulfanyl]-4-methoxy-benzoylamino]-4-methyl-pentanoic acid tert-butyl ester (1.2 g, 17.0 mmol) from Example 30, 10 mL dichloromethane, 10 mL trifluoroacetic acid, and 1 mL anisole. The crude product was recrystallized from methanol/water to afford 0.8 g of the title compound, mp 230-231° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH3:18].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)S(O[CH2:36][CH3:37])(=O)=O>C1COCC1>[CH2:36]([C@@H:15]([CH2:16][CH2:17][CH3:18])[C:14]([N:3]1[C@@H:2]([CH3:1])[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4]1=[O:13])=[O:19])[CH3:37]
Reactant: CCCCC(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@H](CC)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a −78° C. stirred solution of the (4S,5R)-4-Methyl-3-pentanoyl-5-phenyl-oxazolidin-2-one (9.20 g, 35.2 mmol) in dry THF (150 mL) was added NaHMDS (42.2 mL, 1.0 M in THF) dropwise. After 1 hour, ethyl trifluoromethanesulfonate (5.93 mL, 45.7 mmol) was added dropwise and the reaction was stirred at −78° C. for an additional 2 hours. The reaction was warmed to −30° C. for 30 minutes and quenched with sat. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (3×40 mL). The organic extracts were combined and washed with brine (2×40 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 8.05 g of crude product.
Reaction SMILES: [S:1]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](NO)=[O:29])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].NC1C2C(=CC=CC=2)C=CC=1CCCCCCC(OCOC)=[O:50].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>>[S:1]([NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:29])=[O:50])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Nc2c(CCCCCCC(=O)NO)ccc3ccccc23)cc1
Reactant: COCOC(=O)CCCCCCc1ccc2ccccc2c1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2c(CCCCCCC(=O)O)ccc3ccccc23)cc1

Procedure:
7-(1-Tosylamino-2-naphthyl)heptanohydroxamic acid Using methoxymethyl 7-(1-amino-2-naphthyl)heptanoate and tosyl chloride, the procedure of Reference Example 50 was otherwise repeated to provide 7-(1-tosylamino-2-naphthyl)heptanoic acid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Br:23][C:24]1[C:25]([CH:34]=O)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:23][C:24]1[C:25]([CH2:34][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cc1Br)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4cc5c(cc4Br)OCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To 10 mL of a chloroform solution containing 130 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one and 109 mg of 7-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde, 25 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 140 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=10:1] to give 113 mg of 1-(2-(4-((7-bromo-2,3-dihydro-1,4-benzodioxin-6-yl)methylamino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:33][C:34]1[CH:35]=[C:36]([C:40](Cl)=[O:41])[CH:37]=[N:38][CH:39]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Br:33][C:34]1[CH:35]=[C:36]([C:40]([NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[N:11][C:10]4[CH:22]=[CH:23][CH:24]=[N:25][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)=[O:41])[CH:37]=[N:38][CH:39]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.7 %

Procedure:
To a solution of 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (300 mg) and triethylamine (0.33 ml) in 1,4-dioxane (10 ml) was added 5-bromo-3-pyridylcarbonyl chloride·hydrochloride (304 mg). The mixture was stirred at room temperature for 15 minutes, then poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The organic solution was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from methanol to give 4-[3-[(5-bromo-3-pyridyl)carbonylamino]phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (256 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]=[S:26]1(=[O:33])[CH2:30][CH2:29][CH:28]([NH:31][NH2:32])[CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][NH:31][CH:28]3[CH2:29][CH2:30][S:26](=[O:33])(=[O:25])[CH2:27]3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC1CCS(=O)(=O)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC1CCS(=O)(=O)C1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask charged with a solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.5 g) in EtOAc (20.0 mL) was treated with 2-(1,1-dioxotetrahydrothiophen-3-yl)hydrazine (0.3 g, 1.2 eq.). The mixture was cooled to −60° C. and treated simultaneously with T3P (50% in EtOAc; 2.0 mL, 2 eq.) and DIPEA (1 mL, 4 eq.). The reaction mixture was stirred for 30 min at −60° C. before being concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.60 g of a solid residue. Purification by column chromatography (SiO2; elution with MeOH:CH2Cl2; desired compound eluted at 5% MeOH in CH2Cl2) afforded 100 mg (yield=15%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(tetrahydrothiophen-1-1-dioxide-3-yl)acrylohydrazide. 1H NMR (400 MHz, CD3OD) δ=9.57 (s, 1H), 8.64 (s, 2H), 8.10 (s, 1H), 7.34-7.36 (d, J=10.4 Hz, 1H), 5.89-5.92 (d, J=10.8 Hz, 1H), 4.01 (m, 1H), 3.04-3.26 (m, 4H), 2.27-2.34 (m, 2H). LCMS for C17H15F6N5O3S [M+H]+ 484.40; found 483.39 (RT 2.63 min, purity: 66.39%).