Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:9][Si:10]([O:13][CH2:14][CH3:15])([CH3:12])[CH3:11].[Cl-]>>[CH:1]1([NH:7][CH2:9][Si:10]([O:13][CH2:14][CH3:15])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO[Si](C)(C)CCl
Reactant: NC1CCCCC1
Agent: [Cl-]
Product: CCO[Si](C)(C)CNC1CCCCC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
In a 500 ml three-necked flask having a reflux condenser, KPG stirrer and thermometer, 317 g of dry cyclohexylamine were heated to 130° C., and 122 g of (chloromethyl)ethoxydimethylsilane were added in the course of 45 min with stirring. After the end of the addition, stirring was effected for a further 30 min at 130° C. and excess cyclohexylamine was distilled off under reduced pressure. Thereafter, the mixture was cooled to 30° C. and 150 ml of isohexane were added. Thereafter, the suspension was filtered using a pressure filter, and the precipitate was rinsed with two 80 ml portions of isohexane. Filtrate and wash solutions were combined and were freed from the solvent under reduced pressure. The subsequent fractional distillation gave 163 g (yield 95%) of (N-cyclohexyl-aminomethyl)ethoxydimethylsilane with a chloride content of <20 ppm. When 1% of ammonia was added before the distillation of the product and any precipitate which separated out was filtered off, a product having a chloride content of <10 ppm was obtained in the same yield.
Reaction SMILES: CS(O[C@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:19])[CH2:8][C@H:7]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[NH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:6]([N:28]=[N+:29]=[N-:30])[C@@H:11]([CH3:12])[CH2:10]1
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of (+/−)-(1S,2R,4R,6S)-4-(3-aminopyridin-4-yl)-2-((tert-butoxycarbonyl)amino)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.20 M) was added NaN3 (7.0 equiv.). The solution was submerged in a 70° C. oil bath and left stirring under Ar for 4 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated to yield (+/−)-tert-butyl ((1R,2R,3S,5R)-5-(3-aminopyridin-4-yl)-2-azido-3-methyl cyclohexyl)carbamate in 87% yield. LC/MS (m/z)=347.3 (MH+), Rt=0.68 min.
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][C@@H:11]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[OH:15][C@H:13]1[CH2:14][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[C@@H:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
Iodomethane (4.17 ml) was added to (2R,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (15.00 g) in DMF (100 ml) at 0° C. Caesium carbonate (25.4 g) was added in one portion and the resulting mixture stirred at 20° C. for 16 hours. The reaction mixture was diluted with water (150 ml) and extracted with dichloromethane (2×150 ml). The combined organics were washed with brine (100 ml), dried over Magnesium sulphate, filtered and evaporated to dryness to give O1-tert-butyl O2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.83 g) as a yellow oil. 1 NMR Spectrum: (DMSOd6) 1.32 (9H, s); 1.77-1.85 (1H, m); 2.24-2.38 (1H, m); 3.07-3.15 (1H, m); 3.47 (1H, q); 3.63 (3H, t); 4.16-4.23 (2H, m); 4.92-4.98 (1H, m).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[CH2:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH3:12]I>CN(C=O)C.[Ag]=O>[OH:1][C@H:2]1[C@@H:6]([O:7][CH3:12])[CH2:5][C@@H:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1
Reactant: COC(=O)C1C[C@@H](O)[C@@H](O)C1
Reactant: CI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@@H](O)[C@@H](OC)C1
Reaction time: 3 h

Procedure:
Methyl (3S,4R)-3,4-dihydroxycyclopentanecarboxylate (0.481 g, 3 mmol), freshly prepared silver oxide (0.348 g, 1.500 mmol) and methyl iodide (0.375 ml, 6.00 mmol) were combined in DMF and allowed to stir for 3 hrs. The reaction mixture was filtered through celite and washed with 15 ml of ether. The organic filtrate was washed 2× with brine, dried over sodium sulfate and evaporated. Purification by silica gel chromatography eluting with 20-40% acetone hexane gave the title compound. 1H NMR (500 MHz, CDCl3) δ 2.01-2.18 (m, 4H), δ 2.48 (s, br, 1H), δ 2.77 (m, 1H), δ 3.40 (s, 3H) δ 3.6-3.65 (m, 1H), δ 3.71 (s, 3H), δ 4.10 (m, 1H)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:29][C@@H:30]2[C:36](=[O:37])[N:35]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[C:34]3[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=3[O:32][CH2:31]2)[C:24]([O:26]CC)=[O:25])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br.C(O)(=O)C>C(O)(=O)C.C(OCC)C>[C:24]([C@@H:23]([NH:29][C@@H:30]1[C:36](=[O:37])[N:35]([CH2:38][C:39]([OH:41])=[O:40])[C:34]2[CH:46]=[CH:47][CH:48]=[CH:49][C:33]=2[O:32][CH2:31]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:26])=[O:25]
Reactant: CCOC(=O)[C@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of tert-butyl 3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in acetic acid (1.5 ml) is added 30% hydrogen bromide-acetic acid solution (1.5 ml). The resulting mixture is allowed to stand for 0.5 hour at room temperature and then diluted with ethyl ether (100 ml). The supernatant layer is removed by decantation and the precipitate is dissolved in 1N sodium hydroxide solution (10 ml). The solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2 ml), the mixture is chromatographed on MCI gel using water-methanol (1:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to give 3(S)-[1(S)-carboxy-7-(4-piperidyl)heptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.15 g) as colorless powder.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25].Cl.C[O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH2:34][S:35][CH3:36])[NH2:32].N>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:7]2[C:8]([I:10])=[CH:9][C:4]([C:3]([NH:32][C@H:31]([C:30]([OH:37])=[O:29])[CH2:33][CH2:34][S:35][CH3:36])=[O:26])=[C:5]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH:6]=2)[CH:14]=1
Reactant: COC(=O)c1cc(I)c(COc2cccnc2)cc1-c1ccccc1C
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Agent: N
Product: CSCC[C@H](NC(=O)c1cc(I)c(COc2cccnc2)cc1-c1ccccc1C)C(=O)O

Procedure:
The desired compound was prepared by saponification of 4-(3-pyridyloxymethyl)-5-iodo-2-(2-methylphenyl)benzoic acid methyl ester, prepared as in Example 219G, followed by coupling with methionine methyl ester hydrochloride and saponification of the methyl ester as described above. 1H NMR (300 MHz, DMSO-d6) δ 12.68 (1H, bs), 8.45 (1H, d, J=9 Hz), 8.37 (1H, d, J=3 Hz), 8.20 (1H, d, J=4 Hz), 7.93 (1H, s), 7.48 (1H, m), 7.37 (2H, m), 7.30-7.00 (4H, m), 5.20 (2H, s), 4.22 (1H, m), 2.30-2.00 (5H, m), 1.96 (3H, s), 1.80 (2H, m). MS m/e (DCI, NH3) m/e 577 (M+H)+. Anal calcd for C25H25IN2O4S: C, 51.85; H, 4.40; N, 4.84. Found: C, 51.91; H, 4.47; N, 4.69.
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][N:28]([CH2:12][CH2:13][CH:14]2[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][CH2:15]2)[CH2:27][CH2:26]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1(c2ccccc2)CCN(CCC2COc3ccccc3O2)CC1

Procedure:
The mixture of 6.68 of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 3.54 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is refluxed 48 hours. It is filtered, evaporated and the residue recrystallized from isopropanol, to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan melting at 142°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH3:33])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH3:33])[C@H:10]([O:14][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]/[CH:25]=[CH:24]\[CH2:23][CH2:22][CH2:21][CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCC/C=C\CCCCCCCCOS(C)(=O)=O
Product: CCCC/C=C\CCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCC/C=C\CCCC

Procedure:
Compound VI-13 (119 mg, 49.5%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 80.0 mg, 0.414 mmol) and (Z)-tetradec-9-enyl methanesulfonate (Nu-Chek Prep, Inc; 301 mg, 1.04 mmol).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:2]2[C:7]3[CH:8]=[C:9]([S:11]([CH2:21][C:20]4[CH:23]=[CH:24][C:17]([C:16]([F:26])([F:25])[F:15])=[CH:18][CH:19]=4)(=[O:13])=[O:12])[S:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(S(=O)(=O)Cc4ccc(C(F)(F)F)cc4)cc23)CC1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 4-(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.02 g (16% over two steps). Beige solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=6 Hz 1H), 7.53-7.61 (d, J=9 Hz 2H), 7.49 (s, 1H), 7.26-7.36 (m, 4H), 4.51 (s, 2H), 3.49-3.60 (m, 4H), 3.36-3.49 (m, 4H), 1.49 (s, 9H); MS (ESI+) for C24H26F3N3O4S2 m/z 542 (M+H)+. HPLC 71%, RT 4.07 min (ACE3 C8 50×4 mm, 5-50% acetonitrile in 3 min).
Reaction SMILES: CN(C)CCN.[CH2:7]([O:9][N:10]1C(=O)C2=CC=CC=C2C1=O)[CH3:8].C(O)(=O)C.[C:25]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])(=O)[CH2:26][CH2:27][CH3:28]>CCO>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([NH:37][S:38]([C:41]([F:44])([F:43])[F:42])(=[O:40])=[O:39])=[C:30]([C:25](=[N:10][O:9][CH2:7][CH3:8])[CH2:26][CH2:27][CH3:28])[CH:35]=1
Reactant: CCON1C(=O)c2ccccc2C1=O
Reactant: CCCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CCCC(=NOCC)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 22 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-ethoxyphthalimide (287 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-butyryl-4-chlorophenyl)trifluoromethanesulfonamide 29A (330 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1), the solvent evaporated under reduced pressure and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-[4-chloro-2-(1-ethoxyiminobutyl)phenyl]trifluoromethanesulfonamide 193 (82 mg, 22%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 12.10, br s, 1H; 7.67, d, J=8.8 Hz, 1H, 7.47, d, J=2.4 Hz, 1H, 7.32, dd, J=2.4 and 8.8 Hz, 1H, 4.27, q, J=7.2 Hz, 2H, 2.78, m, 2H, 1.59, sextet, 2H; 1.37, t, J=7.2 Hz, 3H, 1.02, t, J=7.6 Hz, 3H. HRMS (M+) 372.0514.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=[O:37])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=2[F:35])[C:12]1=[O:37]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](N)C3CCCCC3)c2=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 11c (300 mg, 0.5 mmol) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by reverse phase HPLC (C-18 column, 15–75% ACN/water) to give compound 11d. MS (CI) m/z 502.2 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]([I:12])=[C:7]([I:11])[C:8]([OH:10])=[O:9].N1C=CC=CC=1.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[I:11][C:7](=[C:6]([I:12])[I:5])[C:8]([O:10][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:9]
Reactant: O=C(O)C(I)=C(I)I
Reactant: c1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Oc1ccccc1)C(I)=C(I)I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 0.3 ml of thionyl chloride in 2 ml of benzene was added dropwise to a mixture of 0.3 g of triiodoacrylic acid, 0.3 ml of pyridine and 3 ml of benzene. The mixture was then stirred at room temperature for 45 minutes, after which the solvent was distilled off under reduced pressure. 5 ml of benzene and 0.3 ml of pyridine were added to the resulting residue, and then 0.3 g of phenol was added, with ice-cooling, after which the mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into an ice-cooled dilute solution of hydrochloric acid and then extracted with diethyl ether. The extract was washed, in turn, with a saturated aqueous solution of sodium bicarbonate, water and then a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous sodium sulphate and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography through silica gel eluted with a 100:12 by volume mixture of hexane and ethyl acetate, to give 0.18 g of the title compound, melting at 83°-84.5° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[Cl:23])[NH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[NH:18][CH3:19].[OH-].[Na+].Cl[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C(=O)(O)[O-].[Na+]>C(OCC)C>[ClH:8].[Cl:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=1[Cl:23])[NH:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[N:18]([CH3:19])[C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28]
Reactant: CN[C@@H]1CCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C(=O)OCC(Cl)(Cl)Cl)[C@@H]1CCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a mixture of 3.03 g. (0.03 mole) of triethylamine and 9.96 g. (0.03 mole) of the free diamine, trans-3,4-dichloro-N-[2-(N-methylamino)cyclopentyl]aniline, released from its hydrochloride salt with sodium hydroxide, in 250 ml. of ethyl ether, there is added 6.36 g. (0.03 mole) of 2,2,2-trichloroethyl chloroformate in 50 ml. of ethyl ether. The mixture is stirred at room temperature for 2 hours. Then 100 ml. of saturated sodium bicarbonate solution is added. The organic layer is dried over magnesium sulfate and concentrated to a yellow oil. This oil is converted to its hydrochloride salt by treatment with excess ethereal hydrochloric acid. This salt is recrystallized from a mixture of 120 ml. of methanol and 400 ml. of ethyl ether. The subtitled salt weighs 11.25 g. (80% yield). The NMR, IR, UV and mass spectral are consistent with the subtitled structure.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.ClCCl.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH4-].[Na+]>C(O)(=O)C>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:18][C:17]2[CH:16]=[C:15]([CH:14]3[C:5]4=[N:4][NH:3][C:2](=[O:1])[C:11]5[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=54)[NH:12][CH:13]3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Reactant: CN1CCNCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a stirred solution of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (150 mg, 0.4 mmol) in dryness dichloromethane (10 mL) was added acetic acid followed by 1-methylpiperazine (121 mg, 1.2 mmol). After the addition, the mixture was stirred at room temperature for 1 h, Then the mixture was cooled to 0° C. Sodium borohydride (130 mg, 0.2 mmol) was added. After the addition, the mixture was stirred at this temperature for 3 hr. Dichloromethane was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 9-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as white solid (22 mg, yield 12%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.31 (s, 3H), 2.36-2.48 (m, 8H), 3.37-3.48 (dd, 2H), 4.30 (dd, 1H), 4.71 (dd, 1H), 7.01 (s, 1H), 7.05 (dd, 1H), 7.17-7.23 (m, 5H), 7.25-7.28 (m, 2H), 7.56 (dd, 1H), 7.61-7.65 (t, 1H); LC-MS (ESI) m/z: 452(M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16](Cl)[N:15]=3)[C@H:10]([CH3:28])[CH2:9]2)=[N:6][CH:7]=1.Br.[CH3:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[N:17]=[C:16]([N:33]4[CH2:34][CH2:35][CH2:36][C@H:32]4[CH3:31])[N:15]=3)[C@H:10]([CH3:28])[CH2:9]2)=[N:6][CH:7]=1
Reactant: C[C@@H]1CCCN1
Reactant: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(Cl)n2)[C@H](C)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(Br)cnc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1

Procedure:
Heat a mixture of 4-[4-(5-bromo-3-methyl-pyridin-2-yl)-2-(R)-methyl-piperazin-1-yl]-2-chloro-6-(4-fluoro-phenyl)-pyrimidine (7.7 g, 16.2 mmol), (R)-2-methylpyrrolidine hydrobromide [prepared essentially as described by Nijhuis et. al. (1989) J. Org. Chem. 54(1):209] (3.5 g, 21.1 mmol) and K2CO3 (5.1 g, 37.3 mmol) in DMA at 110° C. for 16 h. Partition the mixture between EtOAc and water, dry (Na2SO4) the organic layer and concentrate under reduced pressure. Purify with flash silica gel column eluting with 10% EtOAc/hexanes. Concentrate under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[CH2:8]2.[Br:22][C:23]([CH3:28])([CH3:27])[C:24](Br)=[O:25]>>[Br:22][C:23]([CH3:28])([CH3:27])[C:24]([N:11]([CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1NNC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(Br)C(=O)Br
Product: CC(C)(Br)C(=O)N(Nc1ccccc1[N+](=O)[O-])C1C2CC3CC(C2)CC1C3

Procedure:
1-(Adamantan-2-yl)-2-(2-nitrophenyl)hydrazine prepared in Processes 1 and 2 in Example 180 and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and 2-bromo-N-(adamantan-2-yl)-2-methyl-N′-(2-nitrophenyl)propane hydrazide was obtained as a yellow oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([O:15][Si](C)(C)C)[NH:13][C:12]1=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:21]([O:15][C@H:14]1[NH:13][C:12](=[O:20])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:22]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1O[Si](C)(C)C
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -35 °C
Reaction time: 21 h
Yield: 59 %

Procedure:
After 156 mg of (3R,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one was dissolved in 1.6 ml of ethyl acetate, the mixture was cooled to -35° C. and thereto 0.03 ml (concentration: 1.84% by volume) of acetic acid, 0.5 ml of acetic anhydride and then 30 mg (concentration: 1.36% by weight) of 4-dimethylaminopyridine were added. The mixture was stirred for 21 hours at -35° C. After completion of the reaction and the same treatment as in Example 16, it was analyzed by means of high performance liquid chromatography used in Example 16 to find 83 mg of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (yield: 59%).