Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([C:25]2[N:30]=[CH:29][C:28](Br)=[CH:27][N:26]=2)[CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[N:34]1.C(=O)([O-])O.[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[CH:15]=2)[C:25]2[N:30]=[CH:29][C:28]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[CH:27][N:26]=2)[CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CC(C)OC(=O)N1CC[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(Br)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)OC(=O)N1CC[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)C1
Temperature: 95 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
To a mixture of (S)-3-{(5-bromo-pyrimidin-2-yl)-[3-chloro-5-(trifluoromethyl)benzyl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (0.19 mmol, 100 mg), 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.23 mmol, 48 mg), tetrakis(triphenylphosphine)palladium(0) (0.02 mmol, 22 mg) and 2M aqueous sodium hydrogen carbonate (0.19 mL) in 1,2-dimethoxy-ethane (0.6 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: CH2Cl2/EtOAc). To the obtained mixture in CH2Cl2 (1 mL) is added saturated aqueous sodium carbonate (0.04 mL) and NaIO4 (82 mg). The mixture is stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (S)-3-{(3-Chloro-5-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-pyrrolidine-1-carboxylic acid isopropyl ester (67 mg, 67%); ESI-MS m/z: 523 [M+1]+, Retention time 2.16 min (condition A).
Reaction SMILES: C(=O)([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:21][CH:20]=2)[CH:9]=1)OC(C)(C)C.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[O:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([C:10]2[CH:9]=[C:8]([OH:7])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:11]=2)=[CH:20][CH:21]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3Oc3ccccc3)cc2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccc(-c3ccccc3Oc3ccccc3)cc2)nn1-c1ccccn1
Yield: 86 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 47 of Example C-21 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21](Cl)[CH:20]=[C:19]2[CH3:27]>O1CCOCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)[CH:20]=[C:19]2[CH3:27]
Reactant: CC1CCNCC1
Reactant: Cc1cc(Cl)nc2ccc(Br)cc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCC(C)CC2)nc2ccc(Br)cc12

Procedure:
0.24 mL (2.0 mmol) of 4-methylpiperidine and 0.28 mL (2.0 mmol) of triethylamine are added to a solution of 0.51 g (2.0 mmol) of 6-bromo-2-chloro-4-methylquinoline in 15 mL of 1,4-dioxane and the reaction mixture is refluxed overnight. After cooling, the precipitate is filtered off, the filtrate is evaporated down, the residue is combined with acetonitrile and MTBE, filtered to remove insoluble ingredients, and the filtrate is evaporated down again. Yield: 0.69 g (100% of theoretical); C16H19BrN2 (M=319.240); calc.: molpeak (M+H)+: 319/321 (Br); found: molpeak (M+H)+: 319/321 (Br); HPLC-MS: 4.7 min (method B).
Reaction SMILES: C([C:5]1[C:10]([NH2:11])=[C:9]([N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:13]2)[CH:8]=[CH:7][N:6]=1)(C)(C)C.[NH2:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1>>[NH2:26][C:27]1[C:28]([C:34]([NH:11][C:10]2[CH:5]=[N:6][CH:7]=[CH:8][C:9]=2[N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([O:18][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:13]2)=[O:35])=[N:29][C:30]([Br:33])=[CH:31][CH:32]=1
Reactant: CC(C)(C)c1nccc(N2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)c1N
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCCN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (S)-4-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)pyridin-3-amine was coupled to 3-amino-6-bromopicolinic acid yielding (S)-3-amino-6-bromo-N-(4-(3-(tert-butyldimethyl-silyloxy)piperidin-1-yl)pyridin-3-yl)picolinamide. LCMS (m/z): 506.2 (MH+); LC Rt=4.03 min.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=O)=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:22])=[CH:23][CH:24]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: NCCCCCn1ccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(COc1ccc(Cl)cc1)NCCCCCn1ccnc1
Reaction time: 2 h

Procedure:
1,1′-Carbonyldiimidazole (6.48 g) was added to a solution of 4-chlorophenoxyacetic acid (7.46 g) in THF (144 ml) at ambient temperature. The mixture was stirred for 2 hours and then 1-(5-aminopentyl)imidazole (6.1 g) was added. The mixture was stirred at ambient temperature for 18 hours and then worked up as described in Example 9a to give an oil which was purified by flash chromatography on silica using ethyl acetate/methanol/triethylamine, 18:2:1 as the mobile phase to give 2-(4-chlorophenoxy)-N-[5-(imidazol-1-yl)pentyl]acetamide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH2:20])=[O:18])[CH2:11][CH2:10]1.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]([NH:19][NH:20][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])=[O:18])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCC(=O)NN)CC1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(CCC(=O)NNC(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a suspension of 3-[4-(2-methoxyphenyl)piperazino]propanohydrazide D2 (1.00 g, 3.60 mmol) in anhydrous toluene (2 mL), phenyl isocyanate (0.45 g, 0.41 mL, 3.78 mmol) was added and the mixture was stirred at room temperature for 30 min and then heated at reflux for 1 h. The solution was allowed to cool slowly to room temperature and the resulting precipitate was filtered and washed with hexane to afford 1.2 g (83.9%) 2-{3-[4-(2-methoxyphenyl)piperazino]propanoyl}-N-phenyl-1-hydrazinecarboxamide D5 as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[C:21]([N:23]3[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[N:25]([CH2:31][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)[C:24]3=[O:42])[CH:20]=[CH:19][C:18]=2[O:43][CH3:44])[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:44][O:43][C:18]1[CH:19]=[CH:20][C:21]([N:23]2[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[N:25]([CH2:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=[CH:34][CH:33]=3)[C:24]2=[O:42])=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][NH:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCCNC1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCCNC1CCNC1

Procedure:
A solution of 40 mg 3-{2-[5-(4,4-dimethyl-2,5-dioxo-3-quinolin-4-ylmethyl-imidazolidin-1-yl)-2-methoxy-phenoxy]-ethylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester in 2 ml of a 8 N solution of hydrochloric acid in methanol was stirred for 1 hour at room temperature. After removal of the solvent under reduced pressure the residue was dissolved in a mixture of 2 ml water and 1 ml acetonitrile. Lyophilization of the resulting mixture yielded a white foam. The product was obtained as its hydrochloric salt.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:22]([Cl:23])=[C:21]3[C:17]([CH2:18][N:19]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:20]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:31]1([CH:37]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:38]CBr)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:23][C:22]1[CH:21]=[C:17]2[C:16](=[CH:15][C:14]=1[N:11]1[CH2:12][CH2:13][N:8]([CH2:6][CH2:38][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:9][CH2:10]1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[CH2:18]2
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2Cl)C(=O)N(C2CCCCC2)C3)CC1
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)c(Cl)cc2CN1C1CCCCC1

Procedure:
In the same manner as in Example 47, the title compound was prepared from 6-[4-(t-butoxycarbonyl)piperazin-1-yl]-5-chloro-2-cyclohexyl-2,3-dihydro-1H-isoindol-1-one obtained in Example 45 and 3,3-diphenylpropyl bromide.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:29])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:10]=2)[CH2:2]1.[CH:30]([CH:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[CH2:22]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][CH:13]=2)[C:9]([NH:8][CH2:7][C:6]([NH:5][CH:3]2[CH2:2][N:1]([CH:36]3[CH2:37][CH2:38][CH:33]([CH:30]([CH3:32])[CH3:31])[CH2:34][CH2:35]3)[CH2:4]2)=[O:29])=[N:10]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C1CCC(=O)CC1
Reactant: O=C(CNc1nn(Cc2ccccc2)c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3nn(Cc4ccccc4)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-benzyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [BrH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Br>[BrH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccccc1
Agent: Br
Product: NCC(=O)CCC(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 43 %

Procedure:
A stirred mixture of 5-amino-4-oxopentanoic acid hydrobromide (1.60 g, 7.5 mmol), benzyl alcohol (15 ml), and 48% hydrobromic acid (8 drops) was heated to 80° C. (bath temperature) for 2 days. The mixture was cooled to room temperature and excess benzyl alcohol was removed with a rotary evaporator at 0.12 mm Hg. The residue was titrated with diethyl ether (2×50 ml) and the residue was purified by flash chromatography on a 160×55 mm silica gel 60 column eluted sequentially with acetonitrile, 5% methanol in acetonitrile, and 10% methanol in acetonitrile. Fractions containing the product were combined and evaporated. The residue was titrated with diethyl ether (5×15 ml), filtered, and dried at 30° C. and 15 mm Hg to give 0.97 g (43%) tan powder, mp 62-67° C.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].S([O-])([O-])(=O)=O.[NH4+].[NH4+].Cl[Si](C)(C)C.[CH3:22][O:23][CH:24]1[CH2:28][CH2:27][CH:26](OC)[O:25]1.[Sn](Cl)(Cl)(Cl)Cl>C[Si](C)(C)N[Si](C)(C)C.ClC(Cl)C.C(OCC)(=O)C>[CH3:22][O:23][CH:24]1[O:25][CH:26]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH2:27][CH2:28]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC1CCC(n2cc(C)c(=O)[nH]c2=O)O1
Temperature: 145 °C

Procedure:
To a suspension of thymine (2.5 g, 20 mmol) in hexamethyldisilazane (30 mL) was added ammonium sulfate (50 mg) and chlorotrimethylsilane (0.5 mL) and the mixture was heated at 145° C. for 4 hr under nitrogen. The excess hexamethyldisilazane was removed at reduced pressure, and the residual oil was dissolved in xylene and evaporated in vacuo to give a colorless viscous oil. To this silylated thymine in dichloroethane (40 mL) was added 2,5-dimethoxytetrahydrofuran (7 mL). After cooling the solution to -30° C., tin tetrachloride (2.3 mL) was added dropwise via a syringe under nitrogen. The mixture was allowed to warm to -10° C. and was then poured into ice cold aqueous sodium bicarbonate (100 mL) and ethyl acetate (150 mL). The mixture was filtered and the organic phase was separated and dried (MgSO4). The solvent was removed under reduced pressure and the residual oil was chromatographed on silica gel using CH2Cl2 /5% MeOH as eluent to give the title compound as a cis/trans mixture in a ratio of 1:1 as shown by analytical HPLC and 1H-NMR: yield 3.4 g (75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([Br:39])=[C:35]([O:40][CH3:41])[CH:34]=2)[CH2:29][CH2:28]1)=[O:26].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Br:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:25](=[O:26])[CH2:24][N:4]3[C:3]([C:13]([F:14])([F:16])[F:15])=[C:2]([Cl:1])[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5]3)[CH2:28][CH2:29]2)=[CH:34][C:35]=1[O:40][CH3:41]
Reactant: FC(F)(F)c1n[nH]c(-c2ccccc2)c1Cl
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ccccc4)c(Cl)c3C(F)(F)F)CC2)ccc1Br

Procedure:
Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.42–7.52 (m, 4H), 7.36–7.38 (d, 1H), 6.42–6.46 (d, 1H), 6.34–6.38 (dd, 1H), 4.72 (s, 2H), 3.88 (s, 3H), 3.74–3.78 (m, 2H), 3.54–3.58 (m, 2H), 3.12–3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164, 156.2, 152, 132.6, 130.2, 130, 128.8, 110, 102.2, 56, 52, 50, 44.8, 42.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@H:9]1[C:18](OC(OCC)=O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][C@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)OC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [BH4-]
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: -40 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To the resulting reaction mixture containing (2S,4R)-1-t-butoxycarbonyl-2-ethoxycarbonyloxycarbonyl-4-methane sulfonyloxypyrrolidine obtained in Step D-3 cooling at -40° C., tetra-n-butylammonium bromide (11.8 g: 0.0365 mole) and a solution of sodium borohydride (52.5 g: 1.35 mole) in water (55 ml) are added. The mixture is allowed to warm to -10° C. and stirred for 1 hour. The aqueous layer is acidified with dilute hydrochloric acid to pH 3. The organic layer is taken, successively washed with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from a toluene-hexane mixture to give (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (101.3 g). Yield: 94%. Colorless crystals. mp. 95° to 96° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[ClH:21].O1CCOCC1>C(Cl)Cl>[ClH:21].[NH2:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl cis-4-(isopropylcarbamoyl)cyclohexylcarbamate (39.11 g, 138 mmol) in DCM (400 mL) was added 4 M HCl in dioxane (138 mL, 550 mmol), and 0.5 mL concentrated HCl. The reaction was stirred vigorously overnight at RT. A large amount of white precipitate had formed in the flask and it was collected by vacuum filtration, washed with DCM, and dried in vacuo, to generate cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride as a white powder (31.08 g, 102% yield).
Reaction SMILES: N1C=CC=CC=1OC(=S)OC1C=CC=CN=1.Cl[CH2:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[NH:30][CH2:29][CH:28]([N:32]([CH3:34])[CH3:33])[CH2:27]2)=[O:20]>CN(C=O)C>[CH3:33][N:32]([CH3:34])[CH:28]1[CH2:29][N:30]2[CH2:18][C:19](=[O:20])[NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:31]=32)[CH2:27]1
Reactant: CN(C)C1CNc2c(cccc2NC(=O)CCl)C1
Agent: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: CN(C)C=O
Product: CN(C)C1Cc2cccc3c2N(CC(=O)N3)C1

Procedure:
This compound was prepared using the procedure of Example 66, but substituting chloroacetic anhydride for di (2-pyridyl)thiocarbonate and cyclizing the initially formed N8 -(chloroacetyl)-1,2,3,4-tetrahydro-N3,N3 -dimethyl-3,8-quinolinediamine by heating at 150°0 C. in DMF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:15][CH2:16][CH3:17])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCC[C@H](CC(=O)OC)c1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a flask containing 27.1 (0.900 g, 2.99 mmol) and cesium carbonate (1.27 g, 3.88 mmol) in 8 mL of DMF was added benzyl bromide (0.43 mL, 3.59 mmol), and the resulting mixture was stirred overnight. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (0 to 20% EtOAc/Hexanes) to provide 27.2 (1.00 g, 86% yield).
Reaction SMILES: C(OC(=O)C)(C)(C)C.[C:9]([O:13][C:14](=[O:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=1)([CH3:12])([CH3:11])[CH3:10].NO.Cl.[N:29]1C=CC=CC=1>CO>[C:9]([O:13][C:14](=[O:25])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:29])[CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=O)c1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reaction time: 2 h

Procedure:
(3-Hydroxyimino-methyl)-phenoxy)-acetic acid tert-butyl ester. To a solution of (3-formyl-phenoxy)-acetic acid tert-butyl ester prepared of Preparation 20, Step A (2.05 g, 8.68 mmol) in MeOH (30 mL) was added NH2OH.HCl (0.66 g, 9.54 mmol) and pyridine (3.5 mL, 43.4 mmol) and the reaction was stirred for 2 hours. The MeOH was removed in vacuo and the residue was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous solution was washed with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound of Step B (1.99 g). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.23-7.28 (m, 2H), 7.12 (m, 1H), 6.93 (d, 1H), 4.51 (s, 2H), 1.46 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.NC(N)=[S:13].Br.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][SH:13])=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: OCCc1ccc(Cl)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: SCCc1ccc(Cl)cc1
Yield: 62.6 %

Procedure:
A mixture of 4-chlorophenethyl alcohol (50.0 g, 0.319 mole), thiourea (24.3 g, 0.319 mole) and 48% hydrobromic acid (161 g, 0.958 mole) was stirred under reflux for 9 hours. The mixture was cooled and a solution of sodium hydroxide (38.3 g, 0.958 mole) in water (380 ml) added, and the resulting mixture was stirred at reflux for 2 hours under a gentle stream of nitrogen. The mixture was cooled and the oily organic layer separated. The aqueous layer was acidified with hydrochloric acid and extracted with 3×50 ml portions of diethyl ether. The ethereal extracts were combined with the oily product and the combination washed with water followed by brine. The ethereal solution was dried (Na2SO4), concentrated and distilled to provide 34.5 g of the title compound, bp 72°-77° (0.03 mm).
Reaction SMILES: C(N[C@H:12]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1)=[O:21])[CH2:13]C1C=CC=CC=1)(OCC1C=CC=CC=1)=O.N1NC(=[O:43])C=CC=1.CC1C=NNC(=O)C1.C(N[C@H](C(NC1C=CC(C2C(C)CC(=O)NN=2)=CC=1)=O)CC(=O)N)(OCC1C=CC=CC=1)=O>>[OH:43][CH:12]([CH3:13])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]([CH3:36])[CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][CH:24]=1)=[O:21]
Reactant: O=c1cccn[nH]1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)cc1
Agent: CC1C=NNC(=O)C1
Agent: CC1CC(=O)NN=C1c1ccc(NC(=O)[C@H](CC(N)=O)NC(=O)OCc2ccccc2)cc1
Product: CC(O)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
A composition which comprises an effective blood pressure depressing, platelet aggregation inhibiting, or myocardial-contraction reinforcing amount of a compound selected from the group consisting of 6-[4-(N-carbobenzoxy-L-phenylalanylamino)-phenyl]-5-methyl -4,5-dihydro-3(2H)-pyridazinone, 6-[4-(L-phenylalanylamino)-phenyl-5-methyl-4,5-dihydro-3(2H)=pyridazinone, 6-]4-(N-carbobenzoxy-L-tryptophylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, and 6-[4-(N-carbobenzoxy-L-asparaginylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone; and a pharmaceutically acceptable carrier.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.S(=O)(=O)(O)O>O1CCOCC1>[NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([O:7][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCNCC1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1CCNCC1
Temperature: 0 °C
Yield: 20.2 %

Procedure:
To isonipecotic acid (41.5 g; 320 mmol) was added 1,4-dioxane (200 mL). Thus, an inhomogeneous solution was obtained. Thereto was added 41.5 mL of concentrated sulfuric acid over 30 minutes. Into this inhomogeneous solution was bubbled 100 g of isobutene over 5 hours. After completion of the bubbling, the mixture was cooled to 0° C. and 750 mL of 2-N aqueous NaOH solution was added thereto. The resultant mixture was ascertained to be basic. Thereafter, a reaction product was extracted with 500 mL of diethyl ether, and the extract was dried with sodium sulfate and then concentrated to obtain 5.98 g of t-butyl isonipecotate as the target compound.