Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cc1
Yield: 97.8 %

Procedure:
A solution of the compound (155 mg, 0.3 mmol) obtained in Example 12-1) and 4 M hydrochloric acid (1,4-dioxane solution, 0.75 mL) in methanol (2 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (119 mg, 98%) as a colorless solid.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([CH2:23][NH:24][C:25]([C:27]4[CH:28]=[C:29]([CH2:33][CH:34]5[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]5)[CH:30]=[CH:31][CH:32]=4)=[O:26])[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3]1.Cl>O1CCOCC1>[CH3:1][C@@H:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([CH2:23][NH:24][C:25](=[O:26])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH:34]5[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]5)[CH:28]=4)[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:3]1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[3-({[(3′-{[(3S)-3,4-dimethyl-1-piperazinyl]methyl}-6-fluoro-3-biphenylyl)methyl]amino}carbonyl)phenyl]methyl)-1-piperidinecarboxylate (250 mg, 0.40 mmol) in 5 mL of 1,4-dioxane was added 4M HCl in 1,4-diozane (5 mL). The mixture was stirred at room temperature for 30 min. After removal of the solvent, the crude was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (200 mg, 95%). LC/MS: m/z, 529 (M+H), 1.27 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>CO.O=[Pt]=O>[O:1]1[C:5]2[CH:6]=[C:7]([C:10]3([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3ccoc3c2)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(O)C1(c2ccc3c(c2)OCC3)CC1
Temperature: 20 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
To a solution of 1-(benzofuran-6-yl)cyclopropanecarboxylic acid (370 mg, 1.8 mmol) in MeOH (50 mL) was added PtO2 (75 mg, 20%) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at 20° C. for 3 d. The reaction mixture was filtered and the solvent was evaporated in vacuo to afford the crude product, which was purified by prepared HPLC to give 1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid (155 mg, 42%). 1H NMR (300 MHz, MeOD) δ 7.13 (d, J=7.5 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.74 (s, 1H), 4.55 (t, J=8.7 Hz, 2H), 3.18 (t, J=8.7 Hz, 2H), 1.56-1.53 (m, 2H), 1.19-1.15 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C@@H:9]([OH:24])[C@H:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1)(=O)C.N1C=CN=C1>C(O)C>[OH:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C@@H:9]([OH:24])[C@H:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc([C@@H]2COc3c(ccc(OC(C)=O)c3C)[C@H]2O)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: COc1ccc([C@@H]2COc3c(ccc(O)c3C)[C@H]2O)cc1

Procedure:
trans-7-Hydroxy-4′-methoxy-8-methylisoflavan-4-ol was prepared from trans-7-acetoxy-4′-methoxy-8-methylisoflavan-4-ol (0.23 g, 0.7 mmol) and imidazole (0.28 g) in ethanol (2.1 ml) as described for cis- and trans-tetrahydrodaidzein. m.p. 162° C. Mass spectrum: 285 M, 5%); 268 (10); 151 (20); 135 (20); 134 (100); 119 (20). 1H NMR (d6-acetone): δ 1.97 (s, 3H, CH3), 3.00 (ddd, 1H, J 3.4 Hz, 7.2 Hz, 10.2 Hz, H3), 3.72 (s, 3H, OMe), 4.20 (dd, 1H J 7.5 Hz, 10.9 Hz, H2); 4.27 (m, 1H, H2), 4.73 (d, 1H, J 6.8 Hz, H4), 6.45 (d, 1H, J 8.3 Hz, H6), 6.85 (d, 2H, J 8.6 Hz, ArH), 7.10 (d, 1H, J 8.7 Hz, H5), 7.18 (d, 2H, J 8.6 Hz, ArH).
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1>CCCCCC>[OH:10][CH:4]([CH:12]1[CH2:13][CH2:14][CH2:15][C:11]1=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1CCCC1
Reactant: CCCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: CCCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of hexanal (100 g) and cyclopentanone (152 g) was added dropwise thereto under stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and then separated. The resulting organic layer was further washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a crude product (188 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 142 g of 2-(1-hydroxyhexyl)cyclopentanone (boiling point: 107-108° C./666 Pa; GC purity: 94%). The remaining 6% was 2-hexylidenecyclopentanone which is a dehydration product.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:18][CH2:10][C:9]1[C:2]([F:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C#N)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1cccc(CBr)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-fluoro-3-methylbenzonitrile (200 mg, 1.5 mmol) in 1,2-dichloroethane (30 ml) was added NBS (266 mg, 1.49 mmol) and AIBN (29 mg, 0.15 mmol) at RT. The reaction mixture was then heated to 80° C., and the reaction mixture was stirred for 2 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT. The volatiles were removed under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 2-3% EtOAc/hexane afforded compound I-6 (250 mg, 1.15 mmol, 78%) as colorless liquid. 1H NMR (500 MHz, CDCl3): δ 7.69-7.65 (m, 1H), 7.62-7.58 (m, 1H), 7.28-7.25 (m, 1H), 4.50 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.CSC(=N)N[N+]([O-])=O.S1C=CCN1CSC[CH2:27][NH:28][C:29]([NH:31][N+:32]([O-:34])=[O:33])=N.CNC(=N[N+]([O-])=O)SC>>[S:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH3:27])=[N:31][N+:32]([O-:34])=[O:33])=[N:7]1
Reactant: N=C(NCCSCN1CC=CS1)N[N+](=O)[O-]
Reactant: NCCSCc1ccsn1
Agent: CNC(=N[N+](=O)[O-])SC
Agent: CSC(=N)N[N+](=O)[O-]
Product: CNC(=N[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reacting 3-[(2-aminoethyl)thiomethyl]isothiazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(2-isothiazolylmethylthio)ethyl]-N'-nitroguanidine and reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-methyl-N"-nitroguanidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:42])[CH:32]=[C:33]([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C1(C2C=C[N+]([O-:55])=CC=2)C=CC=CC=1.[O-]Cl.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([CH:32]2[C:33]([C:38]([F:39])([F:41])[F:40])([C:34]([F:35])([F:36])[F:37])[O:55]2)=[O:42])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Reactant: O=C(C=C(C(F)(F)F)C(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C1OC1(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
At 0° C., to a solution of (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-(trifluoromethyl)but-2-enamide (260 mg, 0.41 mmol) and 4-phenyl pyridine N-oxide (56 mg, 0.33 mmol) in acetonitrile (16 mL) was added NaOCl solution (363 uL, chlorine wt % 10-3%, 1.23 mmol). The reaction mixture was stirred at 0° C. for 10 min, then at room temperature for 1 h. After removal of the solvents in vacuo the residue was diluted with EtOAc (30 mL) and the solution washed with saturated Na2SO3 (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (40 g column, flow rate 20 mL/min) using hexanes/EtOAc (0-10% over 30 min) to give N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide as a diastereomer mixture at a retention time of 27-35 min (243.9 mg, 92% yield). The diastereomeric mixture was separated by Chiral preparative HPLC chiralpak AD 20μ column, 5×50 cm, eluting with 10% IPA/Heptane with flow rate 50 mL/min.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]>[Pd]>[NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C=O
Agent: [Pd]
Product: Nc1ccc(C=O)c(N)c1

Procedure:
In a manner similar to that described for 10-nitro-20(RS)- and 10-nitro-20(S)-camptothecin, a mixture of 2-amino-4-nitrobenzaldehyde is treated with the tricyclic ketone 11 yielding 11-nitro-20(RS)- or 11-nitro-20(S)-camptothecin which in turn is reduced to 11-amino compound camptothecin by palladium/carbon. Alternatively, the 11-amino-20(RS)- or 11-amino-20(S)-camptothecin is obtained by reaction of 2,4-diaminobenzaldehyde with ketone 11.
Reaction SMILES: F[C:2](F)(F)[C:3]([C:5]1[C:10]2[CH:11]([C:13]#[N:14])[CH2:12][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]>N1C=CC=CC=1>[C:3]([C:5]1[C:10]2[CH:11]([C:13]#[N:14])[CH2:12][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: N#CC1Cc2cccc(C(=O)C(F)(F)F)c21
Solvent: c1ccncc1
Product: CC(=O)c1cccc2c1C(C#N)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution composed of 55.94 g of 6-trifluoroacetyl-1-benzocyclobutanecarbonitrile in 600 ml of pyridine is purged with nitrogen for 15 minutes; 30.5 ml of triethylamine, 117.44 ml of butyl vinyl ether, 2.25 g of 1,3-bis-(diphenylphosphino)propane and 1.02 g of palladium acetate are added and the reaction mixture is heated at reflux for 2 hours. 400 ml of 1N hydrochloric acid are then added dropwise in the course of 1 hour and, after stirring for 3 hours at ambient temperature, the reaction mixture is extracted with ether. The organic phases are washed, dried and concentrated to yield a residue, which is purified by chromatography on silica gel (dichloromethane: 100%) allowing the expected product to be isolated.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:31][C:32](=[NH:51])[C:33]1[CH:34]=[CH:35][C:36]2[CH2:42][N:41]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][CH2:39][CH2:38][C:37]=2[CH:50]=1>CN(C=O)C.CCOC(C)=O.CCCCCC.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:31]=[C:32]([C:33]3[CH:34]=[CH:35][C:36]4[CH2:42][N:41]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:40][CH2:39][CH2:38][C:37]=4[CH:50]=3)[N:51]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(C(=N)NO)ccc2C1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(C(=O)OC(C)(C)C)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (302 mg, 1.474 mmol), EDC (339 mg, 1.768 mmol) and HOBT (271 mg, 1.768 mmol) were stirred in DMF (3 ml) for 5 minutes. 1,1-Dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (Preparation 5) (450 mg, 1.474 mmol) was added and the reaction mixture stirred at RT for 1 hour. There was still some 3-cyano-4-[(1-methylethyl)oxy]benzoic acid acid present. Further quantities of EDC (100 mg) and 1,1-Dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (100 mg) were added and the reaction stirred for 1 hour. Then the reaction was heated at 80° C. for 3 hours and left standing overnight. The reaction was then heated at 90° C. for 1 hour. EtOAc (70 ml) was added and the reaction mixture washed with sat. NaHCO3 (50 ml) and water (2×70 ml), dried over anhydrous MgSO4 and evaporated. The crude material obtained was subjected to biotage chromatography (EtOAc/hexane 1:2), yielding a white solid on evaporation. Trituration with ether yielded the title compound (320 mg) as a white solid. NMR (400 MHz, d6DMSO) 1.31 (9H, s), 1.38 (6H, d), 1.69 (2H, br. s), 3.06 (2H, broad s), 3.65 (2H, br. s), 4.44 (2H, s), 4.94-5.03 (1H, m), 7.38-7.43 (1H, m), 7.56 (1H, d), 7.84-7.91 (2H, m), 8.40 (1H, dd), 8.50 (1H, d)
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Si:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][CH2:31][C@@H:32]([C:34]2[CH:45]=[CH:44][C:37]3[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=3[CH:35]=2)[OH:33])[CH3:29])=[CH:23][CH:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1COCC1>[Si:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C@@H:28]([N:30]2[CH2:31][C@@H:32]([C:34]3[CH:45]=[CH:44][C:37]4[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=4[CH:35]=3)[O:33][C:1]2=[O:2])[CH3:29])=[CH:25][CH:26]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC[C@H](O)c1ccc2c(c1)COC(C)(C)O2
Solvent: C1CCOC1
Product: C[C@@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)N1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 36.5 %

Procedure:
1,1′-Carbonyldiimidazole (0.62 g) was added to a solution of (1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.83 g) in THF (8 ml). The mixture was stirred for 18 h at 20° C. and partitioned between Et2O and water. The organic phase was washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography on a Biotage (40 g) eluting with cyclohexane-EtOAc (5:1 then 3:1) to give (5R)-3-[(1S)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.32 g), LCMS RT=4.17 min and (5R)-3-[(1R)-2-(4-{[tent-butyl(dimethyl)silyl]oxy}phenyl)-1-methylethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.36 g) LCMS RT=4.15 min.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH2:34])[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][NH:34][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)=[CH:18][CH:19]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCCc1cccc(Cl)c1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCCc3cccc(Cl)c3)cc2)n1
Yield: 62 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and [2-(3-chlorophenyl)ethyl]amine gave the title compound as a colorless oil (62%). 1H NMR (CDCl3, 300 MHz) δ 7.99 (d, J=8.3 Hz, 2H, 7.37 (d, J=8.3 Hz, 2H), 7.21-6.96 (m, 4H), 3.80 (s, 2H), 2.87-2.78 (m, 2H), 2.77-2.66 (m, 4H), 1.80-1.66 (m, 2H), 1.40-1.10 (m, 16H), 0.80 (t, J=7.2 Hz, 3H). M+(LC/MS(ESI)): 468.4. HPLC (Condition A), Rt: 5.1 min (HPLC purity: 99.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=O.[CH3:25][CH:26]([CH3:33])[CH2:27][C:28](=O)[CH2:29][C:30]#[N:31].CS(O)(=O)=O>C1(C)C=CC=CC=1>[OH:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:28]([CH2:27][CH:26]([CH3:33])[CH3:25])[C:29]([C:30]#[N:31])=[C:16]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1
Reactant: Cc1cccc(C(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc2N)c1
Reactant: CC(C)CC(=O)CC#N
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2c(C#N)c(CC(C)C)nc3ccc(O)cc23)c1
Yield: 56.3 %

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (2.0 g, 6.4 mmol) in diethyl ether (50 ml) was added dropwise 1.0 M solution of m-tolylmagnesium bromide in tetrahydrofuran (30 ml, 30 mmol) under ice-cooling over 30 min. Ice water (250 g) was added to the reaction mixture 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 to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone as a mixture. To a solution of the obtained mixture (1.4 g) of (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}phenyl)(3-methylphenyl)methanone and 5-methyl-3-oxohexanenitrile (0.60 g, 4.7 mmol) in toluene (50 ml) was added methanesulfonic acid (0.38 g, 4.0 mmol), and the mixture was heated under reflux for 6 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the organic layer was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained crude crystals were recrystallized from n-hexane-ethyl acetate to give 6-hydroxy-2-isobutyl-4-(3-methylphenyl)quinoline-3-carbonitrile (0.73 g, yield 36%) as pale-yellow crystals.
Reaction SMILES: ClCCl.[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[N:12][C:13]=1[NH:14][NH:15]C(OC(C)(C)C)=O)=[O:8])[CH3:5].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:4]([O:6][C:7]([C:9]1[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=[N:12][C:13]=1[NH:14][NH2:15])=[O:8])[CH3:5]
Reactant: CCOC(=O)c1c(NNC(=O)OC(C)(C)C)ncn1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(NN)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To 50 ml of a dichloromethane solution containing 3.7 g of 3-benzyl-5-(N′-t-butoxycarbonylhydrazino)-3H-imidazole-4-carboxylic acid ethyl ester, 20 ml of trifluoroacetic acid was added. The resulting mixture was stirred at room temperature for 4 hours, and 100 ml of toluene was added thereto. The mixture was concentrated under reduced pressure. The residue was dissolved in 400 ml of ethyl acetate, and the solution was washed with 200 ml of a 2 N sodium hydroxide solution. The aqueous layer was extracted with 200 ml of ethyl acetate, and the organic layers were combined and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-ethyl acetate) to give the title compound (1.65 g) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24][CH:23]1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCC(=O)N1CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)C(c2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CCC(=O)O)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of 177 mg of ethyl 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoate in 2.0 mL of ethanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring for 2 hours. It was neutralized by addition of 1.00 mL of 1 M hydrochloric acid. It was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 174 mg of 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoic acid as a colorless oily compound. ESI+: 563
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[S:18]([NH2:21])(=[O:20])=[O:19])C1C=CC=CC=1.O>[Pd].CO>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[S:18]([NH2:21])(=[O:19])=[O:20]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 55 °C
Yield: 93.6 %

Procedure:
A mixture of 2-benzylamino-5-nitro-benzenesulfonamide (Example 17ci, 15 g, 48.81 mmol) and 5% palladium on activated carbon powder (wet, nominally 50% water, 6 g) in methanol (500 mL) was heated to 55° C. The mixture was degassed while stirring and the flask was charged with hydrogen gas via balloon. After stirring for 16 h under 1 atmosphere of hydrogen gas, the reaction was filtered through Celite and concentrated in vacuo to afford the desired product, 2,5-diamino-benzenesulfonamide (8.55 g, 45.67 mmol, 93.6% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.56 (2H, bs), 4.98 (2H, bs), 6.58-6.59 (2H, m), 6.87 (1H, d, J=1.6 Hz), 7.00 (2H, s). LC-MS (ESI) calcd for C6H9N3O2S 187.04. found 188.2 [M+H+] (100%).