Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.NN>C(O)C>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][CH2:12][NH2:13])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(CCCN)CC1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
To a solution of N-[3-(4-isopropyl-1-piperazinyl)propyl]phthalimide (43.1 g) in ethanol (350 ml) was added 100% hydrazine hydrate (11.2 g). The resulting mixture was refluxed with stirring for 3 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with ethanol. The filtrate and washing were combined and concentrated under reduced pressure. The residual oil was subjected to column chromatography (aluminum oxide), eluting with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were collected and then evaporated under reduced pressure. The residual oil was distilled under reduced pressure to give 3-(4-isopropyl-1-piperazinyl)propylamine (15.0 g), (bp 45 mmHg/150° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[N:7]([C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:41][C:40]=1[NH2:51])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:16])[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:53](Cl)(=[O:56])[CH:54]=[CH2:55].O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:52])[N:7]([C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:46][CH2:47][O:48][CH2:49][CH2:50]2)=[CH:41][C:40]=1[NH:51][C:53](=[O:56])[CH:54]=[CH2:55])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:27]([Cl:37])=[C:28]([O:35][CH3:36])[CH:29]=[C:30]([O:33][CH3:34])[C:31]=2[Cl:32])[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:24])[CH3:25])=[O:16])[N:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(N4CCOCC4)cc3N)ncn2)c1Cl
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(N2CCOCC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(COCC[Si](C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1

Procedure:
To a solution of (2-amino-4-morpholin-4-yl-phenyl)-{6-[3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-ureido]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (80 g, 0.103 mmol) in DCM (5 mL) was added a solution of TEA (10 mg/mL, 1.2 mL, 0.12 mmol) and a solution of acryloyl chloride (10 mg/mL, 1 mL, 0.11 mmol) dropwise at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. Water (5 mL) was added to quench the reaction, and the reaction mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give crude product, which was used for the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[N:5][O:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH3:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[C:27]([CH3:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:4]1[C:3]([CH2:2][O:26][C:24]2[CH:23]=[CH:22][C:21]([C:27](=[O:28])[CH3:29])=[C:20]([CH3:19])[CH:25]=2)=[C:7]([CH:8]([CH3:10])[CH3:9])[O:6][N:5]=1
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)cc1C

Procedure:
A mixture of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropylisoxazole (104 mg, 340 μmol), 2-methyl-4hydroxyacetophenone (50 mg, 330 μmol), potassium carbonate (45 mg, 320 μmol), sodium iodide (9.9 mg, 66 μmol) in acetone (2.2 mL) was refluxed for 5 h. The reaction was filtered over a plug of silica gel, rinsed with ethyl acetate and condensed to a residue. Yield=138 mg (100%) of 1-(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(N(CC)CC)C>[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:6]([C:5]2[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:8])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc(N)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Chloronicotinic acid (3.15 g), 4-isopropylaniline (2.73 mL) and triethylamine (5.6 mL) were dissolved in DMF (150 mL). 1-Hydroxybenzotriazole monohydrate (hereinafter to be abbreviated as HOBt.H2O) (3.22 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter to be abbreviated as WSCI.HCl) (4.03 g) were added under ice-cooling. The mixture was stirred at room temperature for one day and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and ether was added to the residue. The precipitated solid was collected by filtration to give N-(4-isopropylphenyl)-6-chloropyridine-3-carboxamide (4.72 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH:26]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:42][Si](C(C)C)(C(C)C)C(C)C)=[CH:37][CH:36]=1)[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]>O1CCCC1.O>[OH:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([CH:26]([O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[C:30]#[N:31])=[CH:36][CH:37]=1
Reactant: CC(C)[Si](OCc1ccc(C(OC2CCCCO2)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(C(OC2CCCCO2)c2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Add a 1M solution in tetrahydrofuran of tetrabutylammonium fluoride (37 mL, 37 mmol) to a solution of 3-[(tetrahydro-pyran-2-yloxy)-(4-triisopropylsilanyloxymethyl-phenyl)-methyl]-benzonitrile (14.6 g, 30.4 mmol) in tetrahydrofuran (50 mL) and tetrahydrofuran stir at room temperature for 2 hours. Concentrate the reaction, dilute with water (200 mL), and extract with ethyl acetate (2×100 mL). Combine the extracts, dry over magnesium sulfate, filter, and concentrate. Purify the residue via silica chromatography eluting with 9:1 hexanes:ethyl acetate to 1:1 hexanes ethyl acetate to afford the title compound (8.0 g, 82%), as a colorless thick oil. LCMS (m/z) 323 M+1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:21])=[C:19](Cl)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:21])=[C:19]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:23])[CH2:10][C:11]3=[O:22])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(c(Cl)c(F)cc3c1=O)C(=O)CC2C
Reactant: C1CNCCN1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2c3c(c(N4CCNCC4)c(F)cc3c1=O)C(=O)CC2C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
6.75 g (0.02 mole) of 8-chloro-9-fluoro-5-methyl-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in 120 ml of chloroform, 6.89 g (0.08 mole) of piperazine was added thereto, and this mixture was stirred at 20°-25° C. for 6 hours. The resulting reaction solution was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography [using a chloroform-methanol mixture (with a volume ratio of 10.1) as the developing solvent]. The fraction containing the desired product was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from benzene to obtain 4.79 g (61.8% yield) of 9-fluoro-5-methyl-8-(1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester in the form of yellow crystals.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:9]1[N:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH3:17])[N:10]=1.C(OCCCC)CCC>>[CH:1]1([NH:7][C:9]2[N:14]=[C:13]([F:15])[CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(F)nc(F)n1
Reactant: NC1CCCCC1
Solvent: CCCCOCCCC
Product: COc1cc(F)nc(NC2CCCCC2)n1
Reaction time: 1 h

Procedure:
10.1 g (0.102 mol) of cyclohexylamine were added at 0°-to 2° C. to a mixture of 7.3 g (0.05 mol) of 2,4-difluoro-6-methoxypyrimidine in 50 ml of methyl t.-butyl ether within 15 minutes. After 1 hour at 0° C. and 3 hours at 25° C., the resulting precipitate was filtered off, and the filtrate was washed with water, dried over magnesium sulfate and concentrated. 8.3 g (73.8% of theory) of the title compound were isolated as an oil (nD23 =1.5211) after chromatography of the residue obtained in this way.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:11][C@@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)=[N+]=[N-].[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(OCC)(=O)C>[C:13]([NH:1][CH2:4][C@@H:5]1[O:11][C@@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[CH2:6]1)(=[O:15])[CH3:14]
Reactant: [N-]=[N+]=NC[C@@H]1CN2C(=O)C[C@@H]2O1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN2C(=O)C[C@@H]2O1
Yield: 89 %

Procedure:
(3S,5S)-3-azidomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (710 mg, 4.23 mmole) was hydrogenated in the presence of acetic anhydride (431 mg, 4.23 mmole) in ethyl acetate (20 ml) at 50 psi for 1 hr. After removal of solvent, the residue was purified by silica gel column chromatography using ethyl acetate-acetone (5:1) as eluent and the title compound was obtained as solid.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][N:3]=1.[CH3:12]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[N:4]([CH3:12])[N:3]=1
Reactant: Ic1n[nH]c2c1CCCCC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2c1CCCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of 3-iodo-1,4,5,6,7,8-hexahydrocycloheptapyrazole (600 mg, 2.29 mmol) in THF (8 ml) at 0° C. was added KOt-Bu (360 mg, 3.2 mmol). The reaction mixture was stirred at 0° C. for 30 min then iodomethane (0.20 ml, 3.2 mmol) was added. Stirring was continued at 0° C. for 30 min then at room temperature for 2 h. The reaction was quenched with water and extracted with EtOAc (2×). The organics were dried over MgSO4 and concentrated. The residue was absorbed on SiO2 and chromatographed with 10% to 20% EtOAc/hexanes to afford 387 mg (61%) of 3-iodo-1-methyl-1,4,5,6,7,8-hexahydrocycloheptapyrazole as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.77 (s, 3H), 2.65-2.76 (m, 2H), 2.43-2.54 (m, 2H), 1.77-1.88 (m, 2H), 1.59-1.76 (m, 4H). Also isolated 200 mg (32%) of the less polar 3-iodo-2-methyl-2,4,5,6,7,8-hexahydrocycloheptapyrazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 3.84 (s, 3H), 2.70-2.79 (m, 2H), 2.42-2.51 (m, 2H), 1.77-1.88 (m, 2H), 1.57-1.73 (m, 4H).
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([C@@H:9]([NH2:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:3]([OH:5])=O.[NH2:18][C@H:19]([C:21]([NH:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25])=[O:22])[CH3:20].[OH-].[Na+]>>[NH2:17][C@H:9]([C:7]([NH:6][C@H:2]([C:3]([NH:18][C@H:19]([C:21]([NH:23][C@H:24]([C:26]([OH:28])=[O:27])[CH3:25])=[O:22])[CH3:20])=[O:5])[CH3:1])=[O:8])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Reactant: C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
0.2 ml of aqueous solution containing 2 mM Mal-Phe-Ala OEtCl, 50 mM H-Ala-Ala-OH, 25 mM NaOH and 0.15 mg/ml papain are deep-frozen. Subsequently the reaction mixture is kept at -25° C. until the Mal-Phe-Ala-OEtCl is consumed. Following thawing, the yield is determined analytically by RP-HPLC and amounts to 79% of theory.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(=O)([O-])[O-].[K+].[K+].[SH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: CCOC(=O)CS
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
trans-N-Cyanomethyl-2-(4-fluorobenzenesulfonylmethyl)cyclohexanecarboxamide (3.384 g, 10 mmol) and potassium carbonate (2.34 g, 17 mmol) were weighed into a 100 mL round bottom flask fitted with a stir bar and a cap. Ethyl 2-mercaptoacetate (1.86 mL) was added, followed by the addition of dimethylformamide (30 mL). The reaction vessel was flushed with nitrogen and then sealed with a cap. After stirring the reaction mixture at 100° C. for 2 h, the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was diluted with ethyl acetate (300 mL), filtered, and washed with brine. The organic layer was dried over magnesium sulfate, filtered and evaporated on a rotavap. The residue was chromatographed on 500 cm3 of silica gel in a 5×25 cm column with 50:50 dichloromethane:ethyl acetate eluent to give the title compound as a white solid. 1H NMR (DMSO-d6): =8.59 (1H, t), 7.69 (2H,dd), 7.49 (2H,dd), 4.44-4.04 (6H, m), 3.37 (1H, q), 2.95 (1H, dd), 2.2-1.8(3H, m), 1.62 (3H, m), 1.30 (1H, m), 1.16 (6H, m) MS [ESI, (M−H)−] m/z=437.2 amu
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13](C)[C:14](=O)OCC1C=CC=CC=1.CCOCC.[BrH:30]>C(O)(=O)C>[BrH:30].[BrH:30].[CH3:14][NH:13][CH2:12][CH2:11][CH2:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: CN(CCCc1nc2ccccc2s1)C(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CNCCCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.1 %

Procedure:
1.7 g (4.99 mmol) of benzyl [3-(2-benzthiazolyl)propyl]methylcarbamate are dissolved at 0° in 40% hydrogen bromide in acetic acid and stirred at room temperature for 20 hours. Thereupon, 60 ml of ether are added and, after 1.5 hours, the precipitate formed is filtered off. After washing the crystalline precipitate with ether and drying there are obtained 1.71 g (93.1%) of 2-[3-(methylamino)propyl]benzthiazole dihydrobromide, m.p. 196°-197°.
Reaction SMILES: C(N1[C@@H](C)CN([C@H]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)C2C=CC=C(O)C=2)[C@H](C)C1)C=C.O.FC(F)(F)C(O)=O>CO.[Pd]>[CH2:28]([N:25]([CH2:26][CH3:27])[C:23](=[O:24])[C:22]1[CH:30]=[CH:31][CH:19]=[CH:20][CH:21]=1)[CH3:29]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@@H]1C
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccccc1

Procedure:
(±)-4-((αR*)-α-((2R*,5S*)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl) -N-N-diethylbenzamide (Example 14) (21.75 g, 0.0499 mol) was dissolved in 330 mL methanol:90 mL water. Trifluoroacetic acid (3.9 mL, 0.0499 mol) was added, followed by 14.5 g of 5% palladium on carbon. The solution was heated at reflux for three days and filtered through Celite. The solvent was removed, and the residue was purified by chromatography on silica gel with ethanol (0-20%) in dichloromethane containing 1% tdethylamine. The solvent was removed, and the residue was redissolved in dichloromethane and washed with water at pH 8. The organic layer was dried over sodium sulfate and concentrated to dryness. The resulting solid was triturated overnight in ethyl acetate. Filtration gave 9.09 g (46%) of (±)-4-((αR*)-α-((2R*, 5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N diethylbenzamide as a tan solid. Calc. for C24H33N3O2 0.5 H2O: C, 71.26; H, 8.47; N, 10.39. Found: C, 71.12; H, 8.47; N, 10.49. NMR (300 MHz, CDCl3): δ0.9 (d, J=6 Hz, 3H),1.2 (d and brtr, 9H); 1.5 (t, J=10 Hz, 1H); 2.2 (br m, 1H); 2.5 (m, 1H); 2.6 (d, J=9 Hz, 1H); 2.8 (m, 2H); 3.1-3.5 (br m, 5.3 (s, 1H); 6.6 (d, J=8 Hz, 1H) 6.7 (d, J=8 Hz, 1H); 6.8 (s, 1H); 7.1 (t, J=8 Hz, 1H); 7.2 and 7.3 (AB q, J=8 Hz, 4H), 9.0 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([CH:13]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]([NH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:15])#[N:12].O>C(O)C.O.C(O)C>[OH:3][NH:2][N:12]=[CH:11][CH:13]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:14]([NH:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27][CH3:28])=[O:15]
Reactant: NO
Reactant: COc1cc(OC)c(NC(=O)C(C#N)c2ccccc2)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(OC)c(NC(=O)C(C=NNO)c2ccccc2)c(OC)c1

Procedure:
Hydroxylamine hydrochloride (11.95 g, 0.17 mol) was added to a solution of triethylamine (23.9 mL, 0.17 mol) in 50% ethanol/water (40 mL), and the mixture was stirred with ice, cooling until the NH2OH.HCl dissolved (0.5 hour). The mixture was then diluted with ethanol (300 mL) and α-cyano-N-(2,4,6-trimethoxyphenyl)-benzene acetamide (44.9 g, 0.138 mol) added in one portion and the mixture refluxed for 8 hours, allowed to cool, and poured into water (2 L) to yield a 2-phase oil/water mixture. The aqueous phase was concentrated in vacuo and the precipitate collected. The oil phase was triturated with chloroform to yield a white solid which was combined with the previous lot to yield 33.6 g, 68%, %(found): C, 60.35; H, 6.11; N, 11.60.
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[C:37]([O:39][CH3:40])[C:36]([NH2:41])=[C:35]([O:42][CH3:43])[CH:34]=5)=[CH:29][N:28]=4)[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[CH:8][C:7]=1[O:44][CH3:45].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>N1C=CC=CC=1>[CH3:46][S:47]([NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[C:37]([O:39][CH3:40])[C:36]([NH:41][S:47]([CH3:46])(=[O:49])=[O:48])=[C:35]([O:42][CH3:43])[CH:34]=5)=[CH:29][N:28]=4)[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[CH:8][C:7]=1[O:44][CH3:45])(=[O:49])=[O:48]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(N)c(OC)c5)cn4)CC3)nc2)cc(OC)c1N
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(NS(C)(=O)=O)c(OC)c5)cn4)CC3)nc2)cc(OC)c1NS(C)(=O)=O
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a solution of 1,4-bis[5-(4-amino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine tetrahydrochloride (40.0 mg, 0.0570 mmol), which was synthesized in Example 34, in pyridine (1.0 mL) was added methanesulfonyl chloride (30.0 mg, 0.260 mmol). The reaction mixture was stirred for 15 minutes, and concentrated under reduced pressure. A solution of the residue in methanol-chloroform (1:10) was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform-hexane to yield the title compound as a pale brown crystalline powder (melting point: 235.0-239.0° C.) (28.0 mg, yield: 68%).
Reaction SMILES: CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC.[CH2:26]([N:28]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32](=[O:38])[N:31]([CH3:39])[C:30]2[CH:40]=[C:41]([O:44][CH2:45][CH2:46][CH2:47][NH:48][S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:42]=[CH:43][C:29]1=2)[CH3:27].O[CH2:62][CH2:63][N:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][C:68]([CH3:74])=[CH:69][CH:70]=2)[C:65]1=[O:75]>ClCCl.O.C1COCC1>[CH2:26]([N:28]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32](=[O:38])[N:31]([CH3:39])[C:30]2[CH:40]=[C:41]([O:44][CH2:45][CH2:46][CH2:47][N:48]([CH2:62][CH2:63][N:64]3[CH:73]=[CH:72][C:71]4[C:66](=[CH:67][C:68]([CH3:74])=[CH:69][CH:70]=4)[C:65]3=[O:75])[S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:42]=[CH:43][C:29]1=2)[CH3:27]
Reactant: Cc1ccc2ccn(CCO)c(=O)c2c1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCn3ccc4ccc(C)cc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
N,N,N′,N′-Tetra methyl azodicarboxamide (TMAD) (118 mg) and tri-n-butyl phosphine (0.17 ml) were added to a THF solution (5 ml) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitrobenzenesulfonamide (231 mg) and 2-(2-hydroxyethyl)-7-methyl-2H-isoquinolin-1-one (93 mg), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→10:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 205 mg (yield: 65%) of N-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-N-(2-(7-methyl-1-oxo-1H-isoquinolin-2-yl)ethyl)-2-nitrobenzenesulfonamide as a white amorphous solid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][C:12]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([F:14])[F:13])=[N+]=[N-].[ClH:23].CCOCC>CCO.[OH-].[Pd+2].[OH-]>[ClH:23].[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][C:12]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([F:14])[F:13]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN=[N+]=[N-]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Reaction time: 8 h

Procedure:
To a solution of diethyl 3-(2-(2-azidoethoxy)ethoxy)-1,1-difluoropropylphosphonate (1 eq) in EtOH (2 M) solution was added palladium hydroxide (0.05 eq) and 2 M HCl in ether (1.1 eq). The reaction mixture was stirred under hydrogen (1 atm) overnight. The palladium was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was used for the next reaction without further purification.
Reaction SMILES: CC(O[C:11]([C:13]1C=[CH:17][CH:16]=[C:15](S(O)(=O)=O)[C:14]=1[C:23]([OH:25])=[O:24])=[O:12])COC(C(C)=C)=O.C(OCCO)(=O)C(C)=C.C(C1(S(O)(=O)=O)CC(=O)OC1=O)C=C>>[CH2:15]([CH:14]1[CH2:13][C:11](=[O:12])[O:25][C:23]1=[O:24])[CH:16]=[CH2:17]
Reactant: C=C(C)C(=O)OCC(C)OC(=O)c1cccc(S(=O)(=O)O)c1C(=O)O
Agent: C=C(C)C(=O)OCCO
Agent: C=CCC1(S(=O)(=O)O)CC(=O)OC1=O
Product: C=CCC1CC(=O)OC1=O

Procedure:
By procedure (7) (a) above, β-hydroxyethyl methacrylate is esterified with an equimolar amount of allyl-sulfo-succinic anhydride obtained by the sulfonation of allyl-succinic acid anhydride obtained from propene and maleic anhydride by a procedure analogous to that of (8) (b) hereinabove.