Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.[N:14]1([CH2:19][CH2:20]O)[CH:18]=[CH:17][N:16]=[CH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[N:14]1([CH2:19][CH2:20][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]3)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Cc1cc2c(cc1O)CCCC2=O
Reactant: OCCn1ccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1OCCn1ccnc1)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Under N2, a solution of 2.08 g (11.8 mmol) of 6-hydroxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone in 25 mL of THF was treated with 1.46 g (13.9 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and 3.1 g (11.8 mmol) of triphenylphosphine. The solution was cooled in ice and treated with a solution of 1.9 mL (11.8 mmol) of diethyl azodicarboxylate in 5 mL of THF. The solution was allowed to stir at room temperature overnight. The mixture was diluted with EtOAc and washed twice with H2O, twice with saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under pressure left the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (95/5) gave the product which was recrystallized from EtOAc/hexane to give 1.05 g (32.9% yield) of the product as a tan solid, mp 118-120° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 271 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4]>C1COCC1.O>[CH3:1][NH:2][S:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)(=[O:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
A solution of MeNH2 (10 mL of a 2N solution in THF) and 10 mL of H2O was treated with a solution of 3-nitrobenzene sulfonyl chloride (884 mg, 4 mmole) in 4 mL of THF. The reaction was stirred for 2 hours, diluted with H2O and extracted with Et2O. The extracts were washed with H2O, 0.1N HCl, aqueous NaHCO3, dried, and the solvent removed, and gave the titled product, 608 mg (70%). MS (ESI) 217 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[C:30](=[O:47])[N:31]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]([CH3:38])=[N:33]2>CN(C=O)C>[O:46]=[C:40]1[CH:39]([N:31]2[C:30](=[O:47])[C:29]3[C:34](=[CH:35][CH:36]=[CH:37][C:28]=3[CH2:27][NH:26][C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=3)[N:33]=[C:32]2[CH3:38])[CH2:44][CH2:43][C:42](=[O:45])[NH:41]1
Reactant: Cc1ccc(CC(=O)O)cc1F
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1ccc(CC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1F
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of (3-fluoro-4-methyl-phenyl)-acetic acid (0.25 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.27 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-Dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamide as a yellow solid (500 mg, 74% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.10 min (99.3%); mp, 264-266° C.; 1HNMR (DMSO-d6)2.15-2.20 (m, 4H, CHH and CH3Ar), 2.57-2.91 (m, 6H, CHCH2, CH3), 3.51 (s, 2H, ArCH2), 4.73-4.78 (m, 2H, CH2NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 6.99-7.72 (m, 6H, Ar), 8.34 (t, J=6 Hz, 1H, CH2NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.76 (d, JC-F=3 Hz), 20.73, 23.27, 30.59, 41.60, 41.72, 56.48, 115.43 (d, JC-F=22 Hz), 117.69, 121.98 (d, JC-F=17 Hz), 124.82 (d, JC-F=7 Hz), 124.83, 125.59, 131.23 (d, JC-F=5 Hz), 133.80, 136.12 (d, JC-F=8 Hz), 140.64, 148.44, 154.80, 160.38 (d, JC-F=242 Hz), 160.91, 169.49, 169.90, 172.58. LCMS MH=451; Anal Calcd For C24H23N4O4F: C, 63.99; H, 5.15; N, 12.44; F, 4.22. Found: C, 63.61; H, 5.19; N, 12.33; F, 4.20.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][Si](C=[N+]=[N-])(C)C.CCCCCC.[N+](=C)=[N-]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:16])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 97 %

Procedure:
To a solution of 4-chloro-3-nitrocinnamic acid in a mixture of methanol/DCM (1:1, v/v, 0.09 M), a 2 M solution of trimethylsilyl diazomethane in hexane (4 eq) was slowly added until the yellow color persisted, indicating an excess of diazomethane. The resulting mixture was evaporated. PE was added to the residue and the resultant precipitate was filtered and dried under vacuo to afford the title compound (97%) as a solid. 1H NMR (400 MHz; DMSO-d6, 300 K) δ 3.75 (s, 3H), 6.86 (d, J 16, 1H), 7.73 (d, J 16, 1H), 7.84 (d, J 8.4, 1H), 8.08 (d, J 8.4, 1H), 8.48 (s, 1H); MS (ES+) m/z 242 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25]>O1CCCC1.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a degassed solution of 1-bromo-4-trifluoromethylbenzene (17.7 g, 78.6 mmol) in tetrahydrofuran (140 mL) was added in the following order: copper(I) iodide (447 mg, 2.35 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.65 g, 2.35 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (14.4 g, 94.3 mmol). The resulting mixture was degassed one more time, cooled in an ice bath and a solution of propargyl alcohol (5.29 g, 94.3 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 55° C. and then stirred at this temperature for 3 h and subsequently at ambient temperature overnight. The mixture was diluted with ether (200 mL), washed with 5% hydrochloric acid (60 mL), water (3×50 mL) and saturated aqueous solution of sodium hydrogen carbonate (30 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane) yielding 3-(4-trifluoromethylphenyl)prop-2-yn-1-ol.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Br:18])[CH:11]=1)[C:6]([CH3:9])([OH:8])[CH3:7])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C.C1N=CN([C:52](N2C=NC=C2)=[O:53])C=1>[NH4+].[Cl-].C1COCC1.O>[Br:18][C:12]1[CH:11]=[C:10]([C@@H:5]2[C:6]([CH3:9])([CH3:7])[O:8][C:52](=[O:53])[NH:1][CH2:4]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc([C@@H](CN=[N+]=[N-])C(C)(C)O)cc1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CNC(=O)OC2(C)C)cc1Br
Temperature: 60 °C
Yield: 79.6 %

Procedure:
To a 25 mL round bottom flask containing (S)-4-azido-3-(3-bromo-4-methoxyphenyl)-2-methylbutan-2-ol (38 mg, 0.12 mmol) were added PPh3 (48 mg, 0.18 mmol), THF (2 mL) and water (0.2 mL). The resulting reaction mixture was heated to reflux for 2 hrs. Volatiles were removed under vacuum. To the residue was added 2 mL THF, DIEA (0.063 mL, 0.36 mmol) and CDI (39 mg, 0.24 mmol). The resulting reaction mixture was heated at 60° C. for 3 hrs. It was then diluted with 10 mL saturated NH4Cl and extracted with 15 mL EtOAc. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on a Combiflash prepacked silica gel column which was eluted with EtOAc to give 30 mg of the desired product (intermediate N). 1H NMR (500 MHz, CDCl3): δ 7.41 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.76 (s, 1H), 3.90 (s, 3H), 3.65 (t, J=11.4 Hz, 1H), 3.46 (br, 1H), 3.0 (br, 1H), 1.34 (s, 3H), 1.32 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@H:29]3[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31][CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) with tert-butyl trans-4-aminocyclohexylcarbamate as in previous examples gave tert-butyl trans-4-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}cyclohexylcarbamate in 88% yield: mp (CH2Cl2/hexanes) 218-221° C.; 1H NMR (DMSO-d6) δ 8.10 and 7.97 (2d, J=8.3, 8.1 Hz, 1H), 7.87 and 7.72 (2t, JHF=53.1, 53.0 Hz, 1H) 7.83 and 7.77 (2d, J=7.7, 8.10 Hz, 1H), 7.38 (q, J=8.3 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.75-6.70 (m, 1H), 3.98 and 3.97 (2s, 3H), 3.97 (m, 4H), 3.71-3.69 (m, 4H), 1.98-1.91 (m, 2H), 1.85-1.82 (m, 2H), 1.40-1.22 (m, 4H), 1.38 (s, 9H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.6; H, 6.5; N, 19.3%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH:12]([OH:14])[CH3:13].C[N+]1([O-])CCOCC1.CC#N>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: CC(O)c1cc(C(F)(F)F)ccc1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)c1cc(C(F)(F)F)ccc1Br

Procedure:
1-(2-Bromo-5-trifluoromethyl-phenyl)-ethanol (0.914 g, 3.40 mmol), N-methylmorpholine N-oxide (0.731 g, 6.24 mmol), and tetrapropylammonium perruthenate (0.109 g, 0.31 mmol) were combined in CH2Cl2 (18 mL) and MeCN (0.9 mL) and stirred at room temperature for 30 minutes. Once no starting material was seen by analytical LCMS, the mixture was filtered through Celite and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:20]([CH3:22])[CH3:21])=[N:13][C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:22][N:20]([CH3:21])[C:12]1[N:11]=[C:10]([CH3:23])[C:9]([OH:8])=[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:13]=1
Reactant: CCCCCc1nc(N(C)C)nc(C)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCc1nc(N(C)C)nc(C)c1O
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution containing 150 mg (0.48 mmol) of 5-(benzyloxy)-N,N,4-trimethyl-6-pentylpyrimidin-2-amine in 5 mL of methanol were added 5 mg of 20% palladium hydroxide on carbon (Degussa typy E101 NE/E). The reaction mixture was stirred at 23° C. under hydrogen atmosphere for 15 min. The reaction mixture was filtered through celite and the filtrated was concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (8×3 cm). Elution with 2:1 hexane-ethyl acetate afforded the expected product as white solid: yield 60 mg (56%); mp: 61-62° C.; silica gel TLC Rf 0.50 (2:1 hexanes-ethyl acetate); 1H NMR (methanol-d4) δ 0.89 (t, 3H, J=5.6 Hz), 1.33 (m, 4H), 1.66 (quint, 2H, J=7.2 Hz), 2.26 (s, 3H), 2.62 (dd, 2H, J=7.6, 7.6 Hz) and 3.05 (s, 6H); 13C NMR (methanol-d4) δ 12.93, 17.53, 22.16, 27.00, 31.21, 31.43, 36.49, 138.01, 155.64, 157.33 and 159.44; mass spectrum (APCI), m/z 224.1769 (M+H)+ (C12H22N30 requires 224.1763).
Reaction SMILES: CC(C)C[NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[N:15]=[N:16][N:17]=[C:7]2[C:6]=1[N+:18]([O-])=O>[Pt].C(O)C>[N:15]1[N:8]2[C:9]3[C:14]([C:5]([NH2:4])=[C:6]([NH2:18])[C:7]2=[N:17][N:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC(C)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Agent: [Pt]
Solvent: CCO
Product: Nc1c(N)c2nnnn2c2ccccc12

Procedure:
N-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a]quinolin-5-amine (1.0 g, 3.5 mmole, Example 15), ethanol (100 mL) and Pt/C were placed in a Paar apparatus. The mixture was hydrogenated at 50 psi (3.44×105 Pa). The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was recrystallized from ethyl acetate to provide 0.35 g of N5-methylpropyl)tetrazolo[1,5-a]quinoline-4,5-diamine as off white needles, m.p. 148-150° C. Analysis: Calculated for C13H16N6: %C, 60.92; %H, 6.29; %N, 32.79; Found: %C, 60.94; %H, 6.25; %N, 32.93.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[Cl:21][CH2:22][C:23]([N:25]=[C:26]=[O:27])=[O:24].CN(C1C=CC=CN=1)C.O>ClCCl>[CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:26]([NH:25][C:23]([CH2:22][Cl:21])=[O:24])=[O:27])[C@H:10]1[O:18][CH3:19])[CH3:8]
Reactant: O=C=NC(=O)CCl
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of fumagillol (314 mg) in dichloromethane (5 ml), chloroacetyl isocyanate (160 mg) was added dropwise with ice-cooling, followed by addition of dimethylaminopyridine (130 mg) and stirring at 0° C. for 2 hours. The reaction mixture was treated with water and extracted with dichloromethane. The organic layer was washed with saturated saline and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. The eluate with n-hexane-ethyl acetate (3:1) was concentrated under reduced pressure, to give 318 mg (yield: 71%) of O-chloroacetylcarbamoyl fumagillol as a colorless powder.
Reaction SMILES: [OH-].[Na+].[C:3]([C:8]1([CH3:17])[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[CH:9]1[C:15]#[N:16])([O:5][CH2:6][CH3:7])=[O:4].[OH:18]OS([O-])=O.[K+].S(=O)(=O)(O)O>O>[C:3]([C:8]1([CH3:17])[CH2:12][CH:11]([CH3:13])[C:10](=[O:14])[C:9]1([C:15]#[N:16])[OH:18])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)C1(C)CC(C)C(=O)C1C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1(C)CC(C)C(=O)C1(O)C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
29.5 g (77.5 mmol) of borax and 24.8 g (0.62 mol) of sodium hydroxide are dissolved in 310 ml of water and treated while cooling (17° C.) with 65 g (310 mmol) of 3-carboethoxy-2-cyano-3,5-dimethylcyclopentanone (prepared from ethyl methacrylate and sodium cyanide according to H. Stetter et al, Liebig's Annalen d. Chem. 1979, 944-949). 132.2 g (403 mmol) of Caroat dissolved in 428 ml of water are added dropwise at 13° C. to 19° C. within 25 minutes and the mixture is stirred at room temperature for 3 hours. For the working-up, the mixture is acidified with 30 ml of sulphuric acid (2:1) and extracted four times with ethyl acetate. The organic phase is dried over sodium sulphate, concentrated and dried in a high vacuum for 2 hours. There are obtained 69.8 g (100%) of 3-carboethoxy-2-cyano-2-hydroxy-3,5-dimethylcyclopentanone in the form of a diastereomeric mixture; nD20 =1.4658.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:11][CH:10]=1)[CH3:6])[CH3:2].C([BH3-])#N.[Na+].Cl>C(O)C>[CH2:1]([O:3][NH:4][CH:5]([CH3:6])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCON=C(C)CCc1ccc(OC(C)CC)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCONC(C)CCc1ccc(OC(C)CC)cc1
Reaction time: 2 h

Procedure:
To 4-[4-(1-methylpropoxy)phenyl]-2-butanone O-ethyloxime (2.63 g, 10.0 mmol) in 30 ml of ethanol is added sodium cyanoborohydride (2.00 g, 38.1 mmol) and methanolic 2N HCl is added throughout the reaction to maintain pH at 3. The reaction temperature is maintained at 15°-20°. After ca. 2 hours, the solvent is removed under vacuum. The mixture is made basic by the addition of 10% sodium hydroxide, followed by water and ether, and is extracted with ether. The combined organic phases are washed with water and with brine, dried and filtered and the solvent is removed in vacuo to give N-ethoxy-1-methyl-3-[4-(1-methylpropoxy)phenyl]propylamine, MS m/e 265 (M ).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][C:32]3[NH:33][CH:34]=[CH:35][N:36]=3)[CH2:24][C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:39]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:1]1([N:7]([CH3:39])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:31][C:32]3[NH:33][CH:34]=[CH:35][N:36]=3)[CH2:24][C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC2CCCCC2)cc1)Cc1ncc[nH]1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCCNS(=O)(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The compound (69.5 mg) obtained in Example 102-5 was treated with an anion-exchange resin (Amberlite IRA-410), and the treated product was dissolved in anhydrous methanol (2.7 ml). The solution was added with a 36% formaldehyde aqueous solution (0.025 ml). Subsequently, the solution was added with sodium cyanoborohydride (20.7 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 20 hours. After the reaction, the solution was added with a 1 mol/l sodium hydroxide aqueous solution (1.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate. The solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (34.8 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[N+:20]([O-])=O)=[C:6]([CH3:23])[CH:5]=1.C(O)(=O)C>[Fe].O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=2[NH2:20])=[C:6]([CH3:23])[CH:5]=1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2[N+](=O)[O-])c(C)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N)c(C)c1
Temperature: 50 °C

Procedure:
A mixture of 4-(2-nitro-4,5-dimethylphenoxymethyl)-3-methylbenzoic acid methyl ester prepared in Reference Example 1 (7.21 g), acetic acid (88 ml) and water (8.8 ml) was stirred at 50° C. To the reaction solution, iron powder (6.11 g) was gradually added, and the mixture was stirred for 1 hour at 50° C. After cooling, the mixture was filtered and the filtrate was concentrated and azeotroped with toluene. To the residue, ethyl acetate-water (100 ml-100 ml) was added and the mixture was filtrated over Celite (registered trademark). The organic layer was washed, dried, concentrated under reduced pressure to give the title compound (4.66 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[C:15]([Br:30])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2Cc3c(CO)csc3C2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CC2Cc3c(sc(Br)c3CO)C2C1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of the product from Example 17, step c) (199 mg, 0.79 mmol) in CHCl3 (3 ml) and AcOH (3 ml) was added NBS (156 mg, 0.88 mmol). The reaction mixture was stirred for 30 minutes, quenched with saturated NaHCO3 (10 ml), and extracted with EtOAc (20 ml). The EtOAc layer was dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product that was purified by silica-gel preparative TLC (hexanes:EtOAc-3:1) providing the subtitle compound (99.6 mg, 36%). 1H NMR (300 MHz, CDCl3, ppm) 1.22 (t, J=7 Hz, 3H); 2.42 (br s, 1H); 2.63-2.78 (m, 1H); 2.95-3.18 (m, 2H); 3.30-3.48 (br m, 1H); 3.50-3.72 (br m, 2H); 3.75-3.88 (br m, 2H); 4.08 (q, J=7 Hz, 2H); 4.52 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24]>ClCCl>[ClH:24].[F:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]([C@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:23])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)Nc2ccc(F)cc2)C1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
To a cooled solution of (S)-3-(4-fluoro-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (0.34 g, 1.05 mmol) in dichloromethane (5 mL) was added dropwise 5.2 mL of HCl 4N (dioxane solution) and the solution was stirred at R.T. for 45 min. The solvent was evaporated under reduced pressure to give the title compound as a white solid (0.252 g).