Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)[CH2:4][CH2:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)[CH2:4][CH2:3]1
Reactant: O=c1nc(N2CCC(O)CC2)sc2ncccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCN(c2nc(=O)c3cccnc3s2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
120 mg of 2-(4-hydroxypiperidino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one (compound of Example 108), 250 mg of crushed molecular sieve (3A) and 7.2 ml of methylene chloride were mixed. To the mixture was then added 196 mg of pyridinium chlorochromate (PCC). The mixture was then stirred at room temperature for 1.5 hours. The reaction mixture was immediately filtered through 10 g of a silica gel layer, and then eluted with a 50:1:0.1 mixture of chloroform, methanol and aqueous ammonia. The resulting filtrate and elute were concentrated, subjected to separation through silica gel column chromatography (eluant: 50:1:0.1 mixture of chloroform, methanol and aqueous ammonia), and then washed with hot acetonitrile to obtain 72 mg of 2-(4-oxo-1-piperidinyl)-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1>>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Reactant: OB(O)c1cncnc1
Product: CCOC(=O)C1=Cc2ccc(-c3cncnc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using (1E,4E)-ethyl 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate and pyrimidin-5-ylboronic acid. MS APCI (+) m/z 309 (M+1) detected; 1H-NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 9.02 (s, 2H), 7.84 (s, 1H), 7.54 (d, 1H), 7.47 (d, 1H), 7.30 (dd, 1H), 4.34 (q, 2H), 2.99 (s, 2H), 1.40 (t, 3H).
Reaction SMILES: [NH2:1][C:2]12[CH2:6][C:4]([C:7]([OH:9])=O)([CH2:5]1)[CH2:3]2.C[Li].[Cl-].[NH4+].[C:14](OCC)(=O)C>C1COCC1>[NH2:1][C:2]12[CH2:3][C:4]([C:7](=[O:9])[CH3:14])([CH2:5]1)[CH2:6]2
Reactant: CCOC(C)=O
Reactant: NC12CC(C(=O)O)(C1)C2
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C12CC(N)(C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid (1 mmol) in anhydrous THF (2 mL) at 0° C. under nitrogen is added a methyllithium (1.4 M in diethyl ether, 4 mmol) in a dropwise manner. After addition, the reaction mixture is slowly allowed to warm to room temperature, stirred overnight, and treated with aqueous saturated ammonium chloride solution (4 mL). Ethyl acetate (2 mL) is added and organic layer are separated. The aqueous layer is extracted with ethyl acetate (3×1 mL). The combined organic layers are dried (Mg2SO4) and concentrated. The residue is purified by a flash chromatography on silica gel (EtOAc/hexnaes) to give 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone.
Reaction SMILES: O[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>O>[Cl:18][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2nc(O)ccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C(O)c1c[nH]c2nc(Cl)ccc2c1=O

Procedure:
1,4-Dihydro-7-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylic acid (10 g) and phosphoryl chloride (20 ml) were stirred and heated at 100° for 2.5 hours. The mixture was cooled and poured into iced water (800 ml). The solid was filtered off and crystallized from dimethylformamide, m.p. 271°-273° (87%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:29]=[CH:28][C:15]3/[C:16](=[CH:25]/[C:26]#[N:27])/[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19][CH2:20][C:14]=3[CH:13]=2)[C:9]2[CH:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:32]=[C:33]([CH3:34])[C:8]=2[N:7]=1)(O)=[O:2].[CH2:41]([N:43]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[CH3:41][NH:43][C:1]([CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:29]=[CH:28][C:15]3/[C:16](=[CH:25]/[C:26]#[N:27])/[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19][CH2:20][C:14]=3[CH:13]=2)[C:9]2[CH:30]=[C:31]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:32]=[C:33]([CH3:34])[C:8]=2[N:7]=1)=[O:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(-c2ccccc2)cc2c1nc(CCC(=O)O)n2Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Agent: CN
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)CCc1nc2c(C)cc(-c3ccccc3)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
[step 1] (E)-{2-[2-(2-Carboxyethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (100 mg, 0.19 mmol) obtained in Example 62, step 1 was dissolved in DMF (1 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (527 mg, 2.75 mmol), 1-hydroxybenzotriazole (421 mg, 2.75 mmol) and methylamine (2 mol/L THF solution; 0.38 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium hydrogen carbonate solution and water were added to the mixture, and the precipitated solid was collected by filtration to give (E)-{2-[2-(methylcarbamoylethyl)-4-methyl-6-phenylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (102 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[N+:13]([O-])=O.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[N:5]=[CH:4][C:3]=1[NH2:13]
Reactant: O=[N+]([O-])c1cnn(C2CCOCC2)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cnn(C2CCOCC2)c1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 5-chloro-4-nitro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (0.4 g, 2 mmol) in ethanol (10 mL) was added ammonium chloride (0.3 g, 5 mmol) and iron (0.3 g). The reaction was stirred at 90° C. for 30 minutes before filtered through celite and concentrated. The residue was triturated in EtOAc and filtered. The filtrated was concentrated to give the title compound (0.34 g, quant.)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]3[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=3)[C:24]=2[CH3:39])=[C:19]([CH3:40])[CH:18]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][C:34]([CH:35]=[O:36])=[CH:37][CH:38]=3)[C:24]=2[CH3:39])=[C:19]([CH3:40])[CH:18]=1)(=[O:5])=[O:4]
Reactant: Cc1cc(O)ccc1-c1cccc(COc2ccc(C=O)cc2)c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1cccc(COc2ccc(C=O)cc2)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trifluoromethanesulfonic anhydride was dropwise added under ice-cooling to a mixture of 4-[(4′-hydroxy-2,2′-dimethylbiphenyl-3-yl)methoxy]benzaldehyde, pyridine and dichloromethane; followed by stirring at 0° C. for 1 hour to obtain 3′-[(4-formylphenoxy)methyl]-2,2′-dimethylbiphenyl-4-yl trifluoromethanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:21])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Solvent: c1ccncc1
Product: S=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1

Procedure:
A stirred solution of 6.53 g. of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one (prepared as in J. Pharm. Sci. 53, 264) in 400 ml. of dry pyridine is heated in an oil bath, under nitrogen, with 5.05 g. of phosphorus pentasulfide at between about 110° to 120° C. for about 1 hour, cooled and concentrated under vacuum. Pyridine remaining in the residue is removed by the successive addition of xylene and toluene with vacuum concentration after each addition of solvent. The dark brown solid residue is triturated with a mixture of aqueous sodium carbonate solution and chloroform and the resulting finely divided tan solid is collected by filtration, washed with water, dissolved in a mixture of chloroform and ethanol, decolorized with activated carbon and crystallized to yield 3.39 g. of product melting at 249° C. (with decomposition) and 0.559 g. melting at 243° C. (with decomposition). The analytical sample is crystallized from ethanol to give pure 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione, with a melting point of 245° to 246° C. (with decomposition) and ultraviolet (ethanol) end absorption, μmax 219 mu (ε=24,100).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2].[NH4+:20].[OH-].O.[Cl-].[NH4+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[NH:7][C:8]1[C:13]([C:14](=[O:15])[NH2:20])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Yield: 99 %

Procedure:
The 2-(3-nitroanilino)-3-chloroformylpyridine was dissolved in tetrahydrofuran (2000 ml) and 70 ml of 30% solution of NH4OH was added dropwise with stirring to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours. Water was added to the mixture to dissolve the solid ammonium chloride that was formed. The tetrahydrofuran was removed, and the resulting aqueous slurry was filtered and washed yielding a yellow solid. The solid was washed with water and air dried yielding 64.8 g (250 mmole, 99% yield) of 2-(3-nitroanilino)-3-carbamoylpyridine (mp 240°-241° C.).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1O.C1([C@H:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[N:19]2)C=CC=CC=1>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:18][NH:19]1
Reactant: C1=N[C@@H](c2ccccc2)Cc2ccccc21
Agent: Oc1ccc2ccccc2c1
Product: c1ccc2c(c1)CCNC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 213.3 %

Procedure:
2-Naphthol (2.09 g, 14.5 mmol) was placed in a flask under nitrogen and (R)-3,4-dihydro-3-phenylisoquinoline 3.0 g (14.5 mmol) was added. The resulting mixture was stirred overnight at 80° C., whereupon no liquid remained. The resulting mixture was recrystallized from Et2O and collected to yield product 4 (4.12 g, 81% yield) as a solid. 1H NMR (CDCl3, 400 MHz, ppm): δ 11.85 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.84 (dd, J=8.4 Hz, J=31.2 Hz, 2H), 7.56-7.12 (m, 10H), 6.97-6.93 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.03 (s, 1H), 4.36 (dd, J=3.6 Hz, J=11.2 Hz, 1H), 3.38 (m, 1H), 3.16 (d, J=14.4 Hz, 1H), 2.80 (s, 1H); 13C NMR (CDCl3, 100 MHz, ppm): δ 155.74, 142.57, 135.61, 133.98, 133.37, 129.88, 128.89, 128.57, 128.37, 128.09, 127.01, 126.88, 126.84, 126.48, 122.67, 121.39, 120.12, 118.11, 59.31, 56.68, 38.38; HRMS calcd. for C25H22NO+1 (M+1): 352.1701. found: 275.1696.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].S(Cl)(Cl)(=O)=O>N1C=CC=CC=1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CCS(=O)(=O)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added ethanesulfonyl chloride (25 mg, 0.19 mmol) and the reaction mixture was stirred at room temperature for about 3 hours. Additional sulfonyl chloride (25 mg, 0.19 mmol) was added and the reaction mixture was stirred for about 48 hours. The reaction mixture was concentrated under reduced pressure and the residue dissolved in dichloromethane (10 mL) and washed with 1 N aqueous hydrochloric acid (10 mL). The organic portion was separated, dried under reduced pressure, and treated with hydrochloric acid (4 N in dioxane, 5 mL) and stirred at room temperature for about 12 hours. The reaction mixture was concentrated under reduced pressure and the crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 8.61 (s, 1H), 8.24 (s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.29-7.48 (m, 5H), 5.64 (s, 2H), 3.29 (d, J=9.2 Hz, 2H), 1.31 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 383 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])C)[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.F[C:33]1[CH:38]=CC(C2C=NC(N3CCN(S(CC4(C(O)=O)CCCCC4)(=O)=O)CC3)=NC=2)=C[CH:34]=1>>[OH:28][NH:27][C:25]([C:24]1([CH2:23][S:20]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:10]=[CH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:13][N:12]=3)[CH2:15][CH2:16]2)(=[O:21])=[O:22])[CH2:38][CH2:33][CH2:34][CH2:31][CH2:29]1)=[O:26]
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ncc(-c4ccc(F)cc4)cn3)CC2)CCCCC1
Yield: 18 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 1-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}cyclohexanecarboxylic acid (0.241 g), to yield the title compound as a white solid (0.045 g, 18%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[N:37][CH:36]=[C:35]([CH3:39])[N:34]=2)[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Product: Cc1cncc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(C)cc3NC(=O)OC(C)(C)C)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (257 mg, 1.0 mmol) and 3-[3-(6-methyl-pyrazin-2-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K16) (312 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (470 mg, 95%).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.O>N1CCOCC1>[CH2:35]([O:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][O:26][C:24]([N:21]2[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]2)=[O:25])=[CH:33][CH:32]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(OCc1ccc(OCc2ccccc2)cc1)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: O
Solvent: C1COCCN1
Product: O=C(OCc1ccc(OCc2ccccc2)cc1)N1CCNCC1

Procedure:
A solution of 274 mg (0.5 mmol) piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester 9H-fluoren-9-ylmethyl ester in 13 ml morpholine was stirred at rt for 1 h. Then 23 ml of chilled water was added, the suspension filtered and the filtrate extracted with TBME. The organic layer was washed with water, brine, dried over Na2SO4 and evaporated: 54 mg piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester as light yellow, waxy solid. MIR: 3300 cm−1, 1688 cm−1. 1H-NMR (CDCl3): 1.77 br, 1H; 2.75–2.90 m, 4H and 3.40–3.50 m, 4H; 5.06 s and 5.07 s, 4H; 6.96 d, J=8.8 Hz, 2H and 7.28–7.44 m, 7H. MS (ISP): 327.3 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH2:35][C:36]1([NH2:39])[CH2:38][CH2:37]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:39][C:36]2([CH2:35][C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:25]=3)[CH2:38][CH2:37]2)=[CH:11][CH:10]=1
Reactant: NC1(Cc2ccc3ccccc3c2)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccc5ccccc5c4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 197 mg (1 mmol) 1-naphthalen-2-ylmethyl-cyclopropylamine. Yield: 20 mg (5%, trifluoroacetate); mass spectroscopy: [M+H]+=405.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1)[NH2:2].[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18].Cl>CCO>[NH2:18][C:17]1[N:1]([C:3]2[CH:11]=[C:10]3[C:6]([CH2:7][CH2:8][C:9]3=[O:12])=[CH:5][CH:4]=2)[N:2]=[C:15]([C:14]([CH3:21])([CH3:20])[CH3:13])[CH:16]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc2c(c1)C(=O)CC2
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)CC3)n1
Yield: 28.6 %

Procedure:
To a solution of the 6-hydrazinoindan-1-one (2.1 g, 14.3 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (2.15 g, 1.2 eq) in EtOH (50 mL) was added conc. HCl (5 mL). The resulting mixture was heated at reflux overnight. After removal of the solvent, the residue was washed with ether to afford 6-(5-amino-3-t-butylpyrazol-1-yl)indan-1-one (1.1 g, 38.5% yield), which was put to the next reaction without further purification. MS (ESI) m/z: 270 (M+H+).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH:6]=[O:7])([O-:3])=[O:2].[CH2:8](O)[CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([O-:3])=[O:2]
Reactant: O=CCC[N+](=O)[O-]
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])CCC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask fitted with a Dean-Stark trap and reflux condenser, a solution of 3-nitro-propionaldehyde (138 g, 1.34 mol) in toluene (1 L) was treated with ethylene glycol (83 g, 1.34 mol) and p-toluenesulfonic acid monohydrate (5.0 g, 26 mmol). The mixture was heated at reflux, open to air, for 4 h, and then cooled to rt. A black residue was removed by paper filtration. The filtrate was washed with satd. aq. NaHCO3 (250 mL) and brine (3×100 mL). Charcoal and MgSO4 were added, and the resulting suspension was stirred for 1 h. Filtration and concentration of the filtrate gave the title compound, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): 5.03 (t, J=3.6, 1H), 4.50 (t, J=6.8, 2H), 4.05-3.90 (m, 2H), 3.90-3.80 (m, 2H), 2.44 (td, J=6.8, 3.6, 2H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:11][C:9]([OH:10])=[C:8]([OH:12])[C@@H:7]([OH:13])[CH2:6]1)=[N+:2]=[N-:3].CN(C)C=O.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.CO>[N:1]([CH2:4][C@H:5]1[O:11][C:9]([OH:10])=[C:8]([OH:12])[C@@H:7]([O:13][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: BrCc1ccccc1
Reactant: [N-]=[N+]=NC[C@@H]1C[C@H](O)C(O)=C(O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: [N-]=[N+]=NC[C@@H]1C[C@H](OCc2ccccc2)C(O)=C(O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 7.5 gm. of the azide in 150 ml. of dry dimethylformamide and add 2.5 gm. of sodium hydride. Stir the mixture at 25°C. for 1 hour, then add 10 gm. of benzylbromide and stir the mixture at 25°C. for 6 hours. Add a 20% solution of methanol in ether and filter off the solids and wash with chloroform. Combine the filtrates and pour into water and extract with chloroform and dry over MgSO4. Evaporate the chloroform extract and chromatograph the resultant residue on a silica gel column (110 × 2.5 cm) using 5 % acetone in hexane as the eluant to obtain 6-azido-3-O-benzyl-4,6-dideoxy-D-threo-hex-1-enopyranose.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:5]=1.[H][H]>[Pd].C1COCC1>[CH3:1][O:2][C:3](=[O:48])[C:4]1[CH:5]=[C:6]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(O)cc2)cc(C(=O)OC)c1
Yield: 51.2 %

Procedure:
A mixture of 0.40 g of 3-(octadecyloxy)-5-[3-[4-(phenylmethoxy) phenoxy]propoxy]benzoic acid methyl ester and 0.1 g of 10% palladium on carbon in 25 ml of THF was stirred in a hydrogen atmosphere for 4 hours. The usual workup followed by purification by chromatography on 12 g of silica gel (230-400 mesh) using 20% ethyl acetate-hexane to give 0.177 g (51% yield, mp 85°-88°) of 3-[3-(4-hydroxyphenoxy)propoxy]-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH:11]([NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:10]
Reactant: COc1ccc(N)cn1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(NC(C)C)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-amino-2-methoxypyridine (747 mg, 6.02 mmol) in CH2Cl2 (50 mL) was added acetone (500 μL) and sodium triacetoxyborohydride (1.95 g, 9.20 mmol). The reaction was stirred at room temperature for 20 hours and was diluted with aqueous NaHCO3. The aqueous solution was washed with CH2Cl2 (3×) and the combined organic solutions were washed with brine (1×), dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (5% EtOAc in hexanes to 50% EtOAc in hexanes) to provide 810 mg of isopropyl-(6-methoxy-pyridin-3-yl)-amine. 1H NMR (CDCl3) δ 7.55 (s, 1H), 6.96 (dd, 1H), 6.61 (d, 1H), 3.86 (s, 3H), 3.52 (m, 1H), 1.19 (d, 6H).