Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH:29]C(OC(C)(C)C)=O)[CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C.O1CCOCC1.[ClH:52]>>[ClH:52].[CH2:1]([O:8][C:9](=[O:40])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:39])[CH2:16][N:17]([C:27](=[O:38])[C@H:28]([CH3:37])[NH2:29])[CH:18]1[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)N(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-N-(2-indanyl) glycyl-L-proline benzylester (2.72 g, 4.95 m mole) was dissolved in 4N hydrogen chloride dioxane solution (50 ml) and the mixture was stirred for 1 hour at room temperature. The solvent was distilled under reduced pressure from the solution, and thereby a sticky residue was obtained. After addition of ethyl ether the solution was filtered and a crystalline residue was obtained on the filter paper, and immediately dried in a desiccator to obtain a white powder of L-alanyl-N-(2-indanyl) glycyl-L-proline benzylester hydrochloride (2.31 g, 4.76 m mole, yield: 96%). This product had a hygrospic nature, and gave a single spot with Rf =0.42 by silica gel thin layer chromatography (developing solvent, chloroform:methanol:triethylamine=40:2:1, Colour forming method: spraying of 0.1% ninhydrin and heating).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@H:6]([NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[N:28](CCC#N)[N:27]=[N:26][N:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@H:6]([NH:20][C:21](=[O:33])[CH2:22][CH2:23][C:24]1[NH:25][N:26]=[N:27][N:28]=1)[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnn[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-butyric acid ethyl ester (137 mg, 0.297 mmol) in DCM (8 mL) at room temperature is added DBU (1.507 mL, 10.00 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction is extracted with DCM. The combined organic layer is washed with saturated NH4Cl, brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced. The obtained residue is purified by flash chromatography (silica gel, 2% to 10% EtOH/DCM) to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid ethyl ester (37 mg). To the obtained ester in EtOH (2 mL) at room temperature is added aqueous 1M NaOH (1 mL, 1.0 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction is added 1 mL of aqueous 1M HCl to pH=4, and the mixture is purified by reverse phase HPLC [30% to 60% acetonitrile-H2O (0.1% TFA)] to give (R)-4-bipheyl-4-yl-3-(3-1H-tetrazol-5-yl-propionylamino)-butyric acid. HPLC retention time=1.24 minutes (condition C); MS (m+1)=380; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (dd, J=6.7, 2.1 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 2.69-2.82 (m, 2H), 3.02 (t, J=7.7 Hz, 2H), 4.17-4.29 (m, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.34 (tt, J=7.3, 1.3 Hz, 1H), 7.42-7.48 (m, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.64 (dd, J=8.2, 1.1 Hz, 2H), 8.00 (d, J=8.1 Hz, 1H), 12.21 (br. s., 1H), 15.92 (br. s., 1H). Chiral HPLC retention time=5.64 min. Column: Daicel CHIRALCEL OJ-H (4.6×100 mm); flow rate=1 ml/min.; eluent: EtOH (containing 0.1% TFA)/heptane=2/8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=O)=[N:28]1>CO.N1CCCCC1>[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ncccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0362 g, 0.100 mmol) in methanol (3 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0147 g, 0.100 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0352 g, 72%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)C1CCCN1
Yield: 76.7 %

Procedure:
A solution of 3-(3-pyridyl)-1-propyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.0 g; 8.9 mmol) in methylene chloride (40 mL) and trifluoroacetic acid (8 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 1.60 g (77%) of the free amine as a thick oil. 1H NMR (300 MHz, CDCl3) δ 1.71-2.09 (m, 6H); 2.63 (m, 2H); 2.86 (m, 1H); 2.94 (m, 1H) 3.71 (m, 1H); 4.11 (m, 2H); 7.18 (m, 1H); 7.45 (m, 1H); 8.41 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=3)[NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Li+].C(O)(=O)C>O1CCCC1>[OH:24][CH2:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCc1c[nH]c2ccc(C(=O)O)cc12)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NCCc1c[nH]c2ccc(CO)cc12)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 104.3 %

Procedure:
A solution of 3-[2-[[(phenylmethoxy)carbonyl]amino]ethyl]-1H-indole-5-carboxylic acid (9 g) and carbonyldiimidazole (5.2 g) in dry tetrahydrofuran (THF) (150 ml) was stirred vigorously under nitrogen at room temperature for 5 h. A solution of lithium borohydride (1.6 g) in dry THF (70 ml) was added over 70 min and the mixture then stirred for 18 h. Aqueous acetic acid (30%, 25 ml) was added slowly to the ice-cooled mixture and the solution was then partitioned between brine (25%, 300 ml) and ethyl acetate (250 ml). The organic layer was washed with sulphuric acid (0.4M, saturated with sodium chloride, 3×80 ml), brine (100 ml) and potassium carbonate solution (25%, 2×100 ml). The dried (MgSO4) solution was evaporated in vacuo, the residue taken up in dichloromethane (150 ml) and insoluble material was filtered off. The filtrate was evaporated in vacuo to leave the alcohol (9 g) as a colourless oil containing some (ca. 45 mole %) ethyl acetate. T.l.c. Si02 /Et2O, Rf 0.25.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][C:8](=[O:21])[C:9]([CH3:20])([CH3:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Br:24]Br>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH:7]([Br:24])[C:8](=[O:21])[C:9]([CH3:19])([CH3:20])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(COc1ccc(Cl)cc1)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(COc1ccc(Cl)cc1)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
36.6 g (0.1 mole) of 1,4-bis-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were dissolved in 250 ml of chloroform, and 16.6 g (0.1 mole) of bromine were added dropwise at 20° C. in a manner such that continuous decolorization occurred. After the addition, the mixture was subsequently stirred at room temperature for 30 minutes and was then concentrated by distilling off the solvent in vacuo. 43.2 g (quantitative conversion) of 1,4-bis-(4-chlorophenoxy)-1-bromo-3,3-dimethyl-butan-2-one were obtained as an oil, which was further reacted directly. ##STR43##
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:26])[CH:22]=2)[CH:17]1[CH2:27][C:28](OCC)=[O:29])[CH:13]([CH3:15])[CH3:14]>O>[CH2:12]([N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:26])[CH:22]=2)[CH:17]1[CH2:27][C:28]([NH:10][C:9]([NH2:11])=[NH:8])=[O:29])[CH:13]([CH3:15])[CH3:14]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2ccc(C)cc2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)C(=O)N(CC(C)C)C2CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 40 h
Yield: 70.2 %

Procedure:
N-[(2-Isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 1.75 g of potassium tert-butoxide, 1.78 g of guanidinium chloride and 0.9 g of ethyl (2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 40 hours and is then poured into 150 cm3 of water and extracted with 3 times 150 cm3 of ethyl acetate. The organic extracts are combined, washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is taken up in diethyl ether and then filtered, giving 0.66 g of N-[(2-isobutyl-5-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine in the form of a white solid melting at 266° C. (Analysis C16H22N4O2% calculated C, 63.56; H, 7.33; N, 18.53; O, 10.58%. found C, 63.57; H, 7.48; N, 18.50).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.[Br:15][CH2:16][C:17](Cl)=[O:18].C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Br:15][CH2:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (33.6 g, 173 mmol) in CH.2Cl2 (150 mL) was added dropwise to a mixture of bromoacetylchloride (54.5 g, 346 mmol) and K2CO3 (53.0 g, 381 mmol) in CH2Cl2 (150 mL). The resulting solution was stirred at 0° C. for 1 hour, then warmed up RT for 4 hours. Water (150 mL) was added and the mixture was extracted with CH2Cl2 (2×100 mL). The organic phase was dried over Na2SO4, the solvent was removed to yield the 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (54.2 g, 99%). 1HNMR (400 MHz, DMSO) δ ppm 2.47(s, 2H), 3.25 (m, 2 H), 3.87 (s, 3 H), 4.21 (m, 2 H), 7.34 (s, 1 H), 8.42 (s, 1 H).
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][C:6]1[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:3].C1C=C(Cl)C=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][S:2]([CH2:4][CH2:5][C:6]1[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:42])=[O:3]
Reactant: CC[C@H](NC(=O)c1c(CCS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(CCS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a stirring solution of 3-[2-(methylsulfinyl)ethyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (12) (60 mg, 0.13 mmol) in CH2Cl2 at 0° C. was added MCPBA (70-75%, 36 mg, 0.16 mol). The cooling bath was removed and reaction stirred for 2 h, then sodium thiosulfate (1.2 eq.) and H2O (1 mL) were added and suspension stirred until all solids had dissolved. Aqueous 1 N NaOH (1 mL) and CH2Cl2 (2 mL) were then added, the layers shaken together, separated, the organics dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-20% EtOAc/CH2Cl2) to give the desired product (40 mg, 65% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.12 (d, J=8.2 Hz, 1H), 7.78-7.65 (m, 2H), 7.56-7.26 (m, 11H), 6.31 (d, J=7.7 Hz, 1H), 5.23 (q, J=7.6 Hz, 1H), 3.36-2.88 (m, 4H), 2.45-2.34 (m, 3H), 2.16-1.88 (m, 2H), 1.04 (t, J=7.4 Hz, 3H); HRMS m/z 473.1878, calcd 473.1899.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][OH:32])[CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:33]2[CH2:39][CH:38]3[N:40]([C:41](OC(C)(C)C)=[O:42])[CH:35]([CH2:36][CH2:37]3)[CH2:34]2)[C:9]=1[Br:48].Cl.[O:60]1CCOC[CH2:61]1>O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][OH:32])[CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:33]2[CH2:34][CH:35]3[N:40]([C:41](=[O:42])[CH2:61][OH:60])[CH:38]([CH2:37][CH2:36]3)[CH2:39]2)[C:9]=1[Br:48]
Reactant: C1COCCO1
Reactant: COc1ccc(-c2ccc(-c3cnn4c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c(Br)c(C5CC6CCC(C5)N6C(=O)OC(C)(C)C)nc34)cn2)cc1CO
Agent: Cl
Solvent: O
Product: COc1ccc(-c2ccc(-c3cnn4c(N)c(Br)c(C5CC6CCC(C5)N6C(=O)CO)nc34)cn2)cc1CO
Reaction time: 0.67 h

Procedure:
Tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-(3-(hydroxymethyl)-4-methoxyphenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (219 mg) was treated with 4N HCl in dioxane (4 mL) and water (1 mL) and the resulting mixture was stirred for 40 minutes, concentrated and lyophilized to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([O:20][CH3:21])[CH:10]=1)=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>CO.C(OCC)(=O)C.[Pd].N1C=CC=CC=1>[CH3:28][S:29]([NH:25][C:24]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([O:20][CH3:21])[CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)ccc1NS(C)(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(NC(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)ccc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 100 %

Procedure:
A suspension of 3-methoxy-4-nitro-N-(4-methanesulfonylamino-3-methoxyphenyl)benzamide (2.03 g) in methanol (50 ml) and ethyl acetate (50 ml) was stirred under hydrogen with palladium on carbon (10%, 50 mg) for 18 hours. The solvents were removed in vacuo to give a brown gum. The residue was dissolved in pyridine (5 ml) and cooled to 0° C. when methanesulfonyl chloride (1 ml) was added, the mixture was kept at 0° C. for a further 2 hours then brought to R.T. for 1 h. The mixture was poured onto ice (50 g) and hydrochloric acid (3M, 50 g), the resultant brown solid filtered and washed with water to give 4-methanesulfonylamino-3-methoxy-N-(4-methanesulfonylamino-3-methoxyphenyl)benzamide (2.1 g, 100%) as a pale brown solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39])[CH3:36].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:35]([O:37][C:38]([N:40]1[CH2:41][CH2:42][N:43]([C:14](=[O:15])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:29]3[C:34]2=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:44][CH2:45]1)=[O:39])[CH3:36]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(N[C@@H](CCCCOCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reaction time: 3 h

Procedure:
To a solution of 500 mg (S)-6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid in 7 ml DMF were added at 0° C. 172 mg piperazine-1-carboxylic acid ethyl ester, 0.14 ml N-ethylmorpholine and 357 mg TOTU. After stirring for 3 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 663 mg.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH:6]1([CH:12]=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([NH:5][CH2:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)N
Reactant: O=Cc1ccccc1
Reactant: O=CC1CCCCC1
Product: CC(C)(C)NCC1CCCCC1
Product: CC(C)(C)NCc1ccccc1

Procedure:
In an analogous manner to that in example 1c, except using 4.0% by weight of hydrogenation catalyst, based on the total amount of amine, 1 mol of tert-butylamine was reacted with cyclohexanal (example 3a) or benzaldehyde (example 3b) to give the corresponding secondary amines (tert-butylcyclohexylmethylamine and benzyl-tert-butylamine respectively) which were then analyzed by gas chromatography. For these reactions, yields of 87.3 area % (example 3a) and 14.2 area % (example 3b) of the corresponding secondary amines were achieved.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[C:10]([C:31]#[N:32])=[N:11][C:12]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=3)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:5][CH:4]=1.[OH-:44].[Na+]>O1CCOCC1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:43][CH:42]=2)[C:9]2[C:10]([C:31]([NH2:32])=[O:44])=[N:11][C:12]([C:21]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([CH:28]([CH3:30])[CH3:29])[N:22]=3)=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)=[CH:39][CH:38]=1
Reactant: [OH-]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C(N)=O)cc1

Procedure:
A suspension of 3-[bis(4-methoxybenzyl)amino]-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (3.00 g) in a mixture of 2N aq. NaOH (30 ml) and dioxane (21 ml) was refluxed for 36 hours. After cooling, the mixture was extracted with EtOAc, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (20:80 v/v) to give a solid. The solid was crystallized from a mixture of n-hexane and acetone to give 3-[bis(4-methoxybenzyl)amino]-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxamide (2.56 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Benzaldehyde (0.25 g) was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.48 g) in methanol (45 ml), and the mixture was stirred for 1.5 hours at room temperature. Acetic acid (0.13 ml) was added thereto and then a solution of sodium cyanoborohydride (0.1 g) in methanol (0.7 ml) was added dropwise with stirring. After adding, the reaction mixture was warmed at 50° C. for 2 hours under stirring and evaporated in vacuo. An aqueous solution of sodium bicarbonate was added to the residue and the mixture was triturated to give 6-(4-benzylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.68 g).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]12([CH2:20][OH:21])[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:21][CH2:20][C:12]23[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCC12CCC(CC1)CC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC23CCC(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
Solid para-toluenesulfonyl chloride (0.449 g) was added to a solution of bicyclo-[2,2,2]oct-1-ylmethanol (300 mg) and triethylamine (0.45 ml) in anhydrous acetonitrile (6 ml) under nitrogen. The mixture was stirred at room temperature for 16 hours then heated at reflux for 18 hours, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ether:hexane (1:9) and further purified by preparative normal-phase HPLC on a Dynamax™ Silica column with hexane:ethyl acetate gradient elution to give the sub-title compound as an oil (0.180 g).