Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH:22]1([N:26]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@@H:12]1[C:17]([N:29]1[CH2:30][CH2:31][CH2:32][N:26]([CH:22]2[CH2:23][CH2:24][CH2:25]2)[CH2:27][CH2:28]1)=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CC(N2CCCNCC2)C1
Reactant: O=C(O)C1CC(O)CN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C([C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1)N1CCCN(C2CCC2)CC1
Reaction time: 3 h
Yield: 45.2 %

Procedure:
A solution of cis-D-hydroxyproline (221.1 mg, 1.687 mmol) in CH2Cl2 (15 mL) was treated with diisopropylethylamine (0.60 mL) and chlorotrimethylsilane (0.60 mL). The mixture was stirred for 2 hours, cooled to 0° C. and treated with benzyl chloroformate (0.250 mL). The reaction was stirred for 15 h at rt and then extracted with 1 N NaOH/Et2O. The aqueous layer was acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried and concentrated to give 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.270 g), which was used directly in the next step. A solution of 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (0.2377 g) in acetonitrile (20 mL) was treated with cyclobutyl-[1,4]diazepane dihydrochloride (0.2411 g), triethylamine (0.400 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.4780 g). After 3 h, the reaction mixture was extracted with 1 N NaOH/CH2Cl2, and the organic layer was dried and concentrated. Purification by FCC provided the desired product (0.1628 g, 24% over two steps). MS (ESI): mass calcd. for C22H31N3O4, 401.50; m/z found, 402.3 [M+H]+.
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@@H:9]2[C:14]3[C:15]([OH:30])=[C:16]4[C:23](=[O:24])[C:22]5[C:25]([OH:29])=[CH:26][CH:27]=[CH:28][C:21]=5[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[C@@H:12]([C:31]([O:33][CH3:34])=[O:32])[C@@:11]([OH:39])([CH2:35][C:36]([CH3:38])=[O:37])[CH2:10]2)C[C@H](N(C)C)[C@@H]1O[C@@H]1O[C@@H](C)[C@@H](O[C@@H]2O[C@@H](C)C(=O)CC2)[C@@H](O)C1.S([O-])([O-])(=O)=O.[Na+].[Na+]>Cl>[CH3:38][C:36]([CH2:35][C@:11]1([OH:39])[C@H:12]([C:31]([O:33][CH3:34])=[O:32])[C:13]2[CH:18]=[C:17]3[C:19](=[O:20])[C:21]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[C:22]=4[C:23](=[O:24])[C:16]3=[C:15]([OH:30])[C:14]=2[C@@H:9]([OH:8])[CH2:10]1)=[O:37]
Reactant: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O[C@H]2C[C@H](N(C)C)[C@H](O[C@H]4C[C@H](O)[C@H](O[C@H]5CCC(=O)[C@H](C)O5)[C@H](C)O4)[C@H](C)O2)C[C@]1(O)CC(C)=O)C(=O)c1c(O)cccc1C3=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@@H]1c2cc3c(c(O)c2[C@@H](O)C[C@]1(O)CC(C)=O)C(=O)c1c(O)cccc1C3=O
Yield: 61 %

Procedure:
A solution of 100 mg of sulfurmycin A in 20 ml of 0.1 N hydrochloric acid was heated at 90° C. for 60 minutes. The mixture was cooled and extracted with 40 ml of ethyl acetate. The ethyl acetate layer obtained was dehydrated over sodium sulphate and concentrated in vacuo to give 45 mg. of a yellow powder. Crystallisation from n-hexane/chloroform gave 32 mg of sulfurmycinone (yellow needles).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+].C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>O1CCCC1.CO.[C].[Pd].O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2Cc1ccccc1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
1-benzyl-5-nitro-2,3-dihydro-1H-indole (100 mg, 0.39 mmol) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and ammonium formate (124mg, 1.96 mmol, 5 equivalent) and palladium carbon (10%) of a catalytic amount were added. Then, the solution was stirred at 40° C. for 10 minutes to complete the reduction. After completing the reaction, the solution was filtered through celite, concentrated under reduced pressure, dissolved again in ethyl acetate (10 ml), washed with water and salt solution, dried over anhydrous magnesium sulfate, concentrated again under reduced pressure and then, dried completely under a high-degree vacuum. Afterward, the obtained residue was dissolved with dichloromethane (2.0 ml), cooled to 0° C., blended with triethylamine (0.055 ml, 0.39 mmol) and mesyl chloride (0.031 ml, 0.40 mmol) and then, stirred at the same temperature for 30 minutes to complete the reaction. After pouring water (2.0 ml) again at room temperature, dichloromethane layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. Finally, the residue was purified through flash column chromatography (an eluent:ethyl acetate/n-hexane=1/2, v/v). As a result, the present compound (90 mg, productive yield 76%) was obtained.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:33]1([N:39]=[C:40]=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C(#N)C>[CH:33]1([NH:39][C:40]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C=NC1CCCCC1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2Cc3c(CNC(=O)NC4CCCCC4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.4 g, 2.9 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.6 g, 1.9 mmol) in acetonitrile (100 mL). The mixture was heated for 30 minutes, then cooled to room temperature. Cyclohexyl isocyanate (0.4 g, 2.9 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solid was stirred with water (25 mL) to give 0.9 g of crude product. The crude product was recrystallized from methanol to give 1-cyclohexyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.12 g, 16%) as a white solid: mp 309-311° C.; 1H NMR (DMSO-d6) δ 0.97-1.75 (m, 10H), 1.99-2.04 (m, 1H), 2.32-2.64 (m, 3H), 2.86-2.98 (m, 1H), 4.27-4.51 (m, 4H), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 5.86 (d, J=7.9 Hz, 1H), 6.26 (t, J=5.5 Hz, 1H, NH), 7.47-7.62 (m, 3H, Ar), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.64, 24.44, 25.29, 31.16, 33.32, 46.09, 47.50, 47.85, 51.47, 121.36, 128.18, 130.26, 131.61, 136.28, 139.77, 157.20, 168.09, 170.97, 172.82; Anal. calcd. for C21H26N4O4: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.18; N, 6.58; N, 13.99.
Reaction SMILES: [CH:1]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:17])[C:13]([C:18]([OH:20])=[O:19])=[CH:12][CH2:11]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Ni]>[CH:1]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:17])[CH:13]([C:18]([OH:20])=[O:19])[CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)C1=CCc2cc(C3CCCCCC3)c(Cl)cc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: O=C(O)C1CCc2cc(C3CCCCCC3)c(Cl)cc21

Procedure:
A solution of 1 g of 5-cycloheptyl-6-chloro-ind-1-ene-1-carboxylic acid in 40 ml of absolute ethanol is hydrogenated with 100 mg of Raney nickel at room temperature and normal pressure until 1 equivalent of hydrogen has been taken up. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo and the residue is crystallised from ether/petroleum ether. 5-Cycloheptyl-6-chloro-1-indanecarboxylic acid, thus obtained, melts at 138°-140°C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.[CH3:24][N:25]([CH3:36])[S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>CN(C)C(=O)C.O.N1(C2C=CN=CC=2)CCCC1>[CH3:24][N:25]([CH3:36])[S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:4](=[O:5])[C:3]([OH:7])([CH3:8])[C:2]([F:10])([F:9])[F:1])=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 37.7 %

Procedure:
To a cooled (-10° C.) solution of α-trifluoromethyl lactic acid (0.69 g) in dry N,N-dimethylacetamide (5 ml) was added thionyl chloride (0.33 ml) dropwise over 2 minutes. The mixture was stirred at -10° C. for 90 minutes, then treated successively with 4-pyrrolidinopyridine (13 mg), di-isopropylethylamine (0.76 ml), and 4-(N,N-dimethylaminosulfonyl)aniline (0.88 g). The reaction mixture was stirred at 22° C. for 48 hours, then diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with 1N HCl, brine, dried and the solvent evaporated. The crude product was purified by chromatography (12:1 CH2Cl2 : ethyl acetate) and recrystallised from methyl-t-butyl ether/hexane to give the title compound as a colourless crystalline solid (0.56 g); mp 139°-141° C.; MS: m/z=341(M+1); NMR (250 MHz): 1.60 (s,3), 2.58 (s,6), 7.58 (s,1), 7.69-7.73 (d,2), 8.03-8.06 (d,2). Analysis for C12H15F3N2O4S: Calculated: C, 42.35; H, 4.44; N, 8.23; Found: C, 42.21; H, 4.54; N, 8.15.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:21]([CH2:22][CH2:23][CH3:24])=[CH:20][C:19]3[C:18]([CH3:26])([CH3:25])[CH2:17][CH2:16][C:15]([CH3:28])([CH3:27])[C:14]=3[CH:13]=2)=[CH:6][CH:5]=1>C(OCC)(=O)C>[CH2:22]([C:21]1[C:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][CH:6]=2)=[CH:13][C:14]2[C:15]([CH3:28])([CH3:27])[CH2:16][CH2:17][C:18]([CH3:25])([CH3:26])[C:19]=2[CH:20]=1)[CH2:23][CH3:24]
Reactant: CCCc1cc2c(cc1C=Cc1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Solvent: CCOC(C)=O
Product: CCCc1cc2c(cc1CCc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C

Procedure:
4-[(3-n-Propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid methyl ester (2.7 mmol) in THF (25 mL) was treated with methyltriphenylphosphonium bromide/sodium azide (1.2 g, 3.1 mmol) and the solution was allowed to stir at ambient temperature for 3 h. The reaction was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The organic solution was separated and washed with water and brine, dried (MgSO4), filtered, and concentrated to give a yellow oil. The crude product was crystallized (CH2Cl2/hexanes) to give 4-[(3-n-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl] benzoic acid methyl ester as white crystal (78%): TLC (20% ethyl acetate: 80% hexanes) Rf 0.8; mp 120-121° C.; 1H-NMR (400 MHz, CDCl3) δ7.94 (½ABq, J=8.0 Hz, 2H, ArH), 7.33 (½ABq, J=8.0 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 7.08 (s, 1H, ArH), 5.80 (s, 1H, olefinic), 5.30 (s, 1H, olefinic), 3.90 (s, 3H, OCH3), 2.24 (t, J=8.0 Hz, 2H, CH2), 1.70 (s, 4H, 2CH2), 1.39 (m, 2H, CH2), 1.30 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 0.73 (t, J=7.5 Hz, 3H, CH3), Anal. (C27H34O2) C, H. The ester was hydrolized using the standard conditions of Example 1 to yield 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]benzoic acid (102). Crystallization gave white crystals (83%): TLC (10% MeOH-90% CHCl3) Rf 0.5; mp 263-265° C. 1H-NMR (400 MHz, CDCl3) δ8.00 (½ABq, J=8.0 Hz, 2H, ArH), 7.09 (s, 1H, ArH), 7.08 (s, 1H, ArH), 5.81 (s, 1H, olefinic), 5.31 (s, 1H, olefinic), 2.23 (t, J=8.0 Hz, 2H, CH2), 1.70 (s, 4H, 2CH2), 1.39 (m, 2H, CH2), 1.30 (s, 6H, 2CH3), 1.26 (s, 6H, 2CH3), 0.73 (t, J=7.5 Hz, 3H, CH3), FAB-MS m/z 377 (MH+); Anal. (C26H32O2) C, H.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:15](OC)=[O:16])[C:8](=[CH:13][CH:14]=1)[C:9](OC)=[O:10])[CH:2]=[CH2:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([CH2:9][OH:10])=[C:7]([CH2:15][OH:16])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)c(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1ccc(CO)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl 4-(allyloxy)phthalate [prepared according to Inouye, M.; Tsuchiya, K.; Kitao, T. Angew. Chem. 1992, 104, 198-200 (See also Angew. Chem., Int. Ed. Engl, 1992, 204-205)] (9.9 g, 38 mmol) was dissolved in THF (40 mL) and cooled to 0° C. before the dropwise addition of lithium aluminium hydride (1M in THF, 77 mL, 77 mmol) over 10 min. The mixture was then allowed to stir at room temperature for 3 h before being quenched cautiously by the addition of water (1.4 mL) followed by 2M NaOH (1.4 mL). Excess MgSO4 was then added followed by water until a granular precipitate formed (ca. 5 mL). The mixture was then filtered and evaporated to a brown oil (7.1 g, ca. 95%). 1H NMR showed the material to be of ca. 85% purity. It was used directly in the next stage without further purification; δH (CDCl3, 400 MHz) 2.63 (1H, brs), 2.91 (1H, brs), 4.52 (2H, m), 4.67 (4H, m), 5.26 (1H, dd), 5.38 (1H, dd), 5.97-6.09 (1H, m), 6.80 (1H, dd), 6.92 (1H, d), 7.22 (1H, d).
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.[CH3:25][C:26]1[NH:30][N:29]=[CH:28][C:27]=1[C:31]([NH:33][NH2:34])=[O:32].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.CCO>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:34][NH:33][C:31]([C:27]3[CH:28]=[N:29][NH:30][C:26]=3[CH3:25])=[O:32])=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: Cc1[nH]ncc1C(=O)NN
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]ncc1C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in EtOAc:EtOH (15 mL, 2:1) and cooled to −60° C. where 5-methyl-1H-pyrazole-4-carbohydrazide (0.24 g, 1.0 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.69 mL, 1.5 eq.) was added dropwise followed by DIPEA (2 mL, 8 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-5-methyl-1H-pyrazole-4-carbohydrazide (0.2 g, yield: 42%).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][O:52][C:53]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=4)=[O:54])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][O:52][C:53]([O:55][CH2:56][C:57]3[CH:58]=[CH:59][C:60]([N+:63]([O-:65])=[O:64])=[CH:61][CH:62]=3)=[O:54])[CH2:48][CH2:49]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h

Procedure:
135.75 mg of trifluoroacetic acid and 6.18 ml of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 26.00 g of (2S,4S)-4-(4-methoxybenzylthio)-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 14) in 38.8 ml of anisole, and the resulting mixture was stirred at the same temperature for 1.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with diethyl ether by repeated decantation and dried under reduced pressure to give 32.5 g of the title compound as a powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:21])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CCO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]([OH:21])[CH2:16][CH2:17][O:18]3)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCOc2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)OCCC3O)cc1
Yield: 28.7 %

Procedure:
Crude 7-(4'-nitrophenyloxy)-4-chromanone (1.9 g) in EtOH (150 mL) was reduced with NaBH4 (250 mg) at room temperature overnight. The crude product was purified through a column of silica gel (EtOAc:CH2Cl2, 2:8) to give pure 7-(4'-nitrophenyloxy)-4-chromanol (550 mg). This compound (550 mg) was converted to the chloride with thionyl chloride (0.28 g) in CH2Cl2 (30 mL) at 0° C. for 1 hour and then at room temperature for 3 hours. Work-up yielded crude 4-chloro-7-(4'-nitrophenyloxy)-chroman (500 mg). This was heated with N-cyclohexylpiperazine (0.9 g) at 130° C. for one hour. The mixture was then diluted with water (35 mL), made basic with K2CO3 and extracted with EtOAc. The residue from evaporation of the dried organic layer was purified through a column of TLC-grade silica gel (35 g). The desired product was recrystallized rom acetonitrile, m.p. 67-68° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[CH:18]=[C:19]([CH2:29][NH2:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH2:29][C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[C:17]([CH3:16])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)ccc1OCC(F)(F)F
Agent: Cl
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)(F)F
Yield: 99 %

Procedure:
The title compound is prepared in 99% yield (460 mg, white solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (350 mg, 1.26 mmol) and (3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)methanamine hydrochloride (353 mg, 1.38 mmol, Amine-34) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH2:34][CH2:35][NH2:36])[CH:31]=[CH:32][CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:19])[NH:36][CH2:35][CH2:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Cl)c4)cc3)c(Cl)cc21
Reaction time: 48 h
Yield: 91.5 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (48.8 mg, 0.130 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 2-(3-chlorophenyl)ethylamine (22.2 mg, 0.143 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (29.8 mg, 0.155 mmol), and 1-hydroxy-7-azabenzotriazole (5.29 mg, 0.0389 mmol) at ambient temperature. After 48 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (61.1 mg, 0.119 mmol, 91.7% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=3)[CH2:20][CH2:19]1
Reactant: CN1CCNCC1
Reactant: COC(=O)Cc1ccc2ncc(Br)cc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2ncc(N3CCN(C)CC3)cc2c1
Yield: 56 %

Procedure:
A solution of methyl 2-(3-bromoquinolin-6-yl)acetate (1.0 g, 3.57 mmol), 1-methylpiperazine (0.429 g, 4.28 mmol), Pd2(dba)3 (65 mg, 0.071 mmol), BINAP (133 mg, 0.214 mmol) and Cs2CO3 (1.628 g, 5.00 mmol) in 10 mL of toluene was heated at 100° C. for 18 h. After cooling, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography in silica gel eluting with a EtOAC/hexane gradient to afford 599 mg (56%) of the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 1H), 7.94 (d, 1H), 7.57 (s, 1H), 7.42 (d, 1H), 7.30 (s, 1H), 3.78 (s, 2H), 3.72 (s, 3H), 3.41-3.33 (m, 4H), 2.65-2.63 (m, 4H), 2.39 (s, 3H). LCMS (method A): [MH]+=300, tR=2.06 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[OH-].[Na+]>CO>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=2)[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccc(OC(F)(F)F)cc2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Yield: 97 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl-5-methyl-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylate (6.0 g, 19.91 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (5.55 g, 19.32 mmol, 97%) was obtained.