Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11](=O)[C:12]([OH:14])=[O:13])([O-:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[N:25]=[C:26]([NH:29][NH2:30])[S:27][CH:28]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]>C(O)(=O)C.C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]2[N:25]=[C:26]([NH:29][N:30]=[C:11]([CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[C:12]([OH:14])=[O:13])[S:27][CH:28]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)C(Cc1ccccc1[N+](=O)[O-])=NNc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 133 %

Procedure:
3-(2-Nitro-phenyl)-2-oxo-propionic acid (1.0 mmol, 209 mg) in 5% acetic acid (2 mL) was added in to solution of 4-(3,4-dichloro-phenyl)-thiazol-2-yl-hydrazine (1.0 mmol, 259 mg) in ethanol (4 mL). The reaction mixture was stirred at 90° C. for 1 h and cooled to 0° C.; the orange solid was precipitated out, filtered and washed by water. Recrystallization from MeOH—H2O afford the final product as a yellow powder (600 mg, 66.7%). mp ; Z/E isomer was further separated by HPLC-MS, using gradient eluting solvents: 0.05% HOAc in acetonitrile 50%: 0.05% HOAc in water 50% to 0.05% HOAc in acetonitrile 75%: 0.05% HOAc in water 25% in 20 min. 1H NMR (400 MHz) δ 12.85 (br, 1H), 12.10 (br, 1H), 8.06 (d, J=8.4 Hz, 1H), 8.03(s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64 (d, J=6.0 Hz , 2H), 7.61(s, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 4.28 (s, 2H). 13C NMR (125.78 MHz) δ 166.097, 164.759, 149.785, 134.607, 134.281, 133.663, 132.596, 132.182, 131.543, 130.680, 129.559, 128.927, 127.854, 126.318, 125.795, 125.299, 108.552, 36.896. Z-isomer: 1H NMR (400 MHz) δ 12.35 (br, 1H), 12.10 (br, 1H), 8.06 (dd, J=8.4 Hz, 1H), 8.03(s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64 (d, J=6.0 Hz, 2H), 7.61(s, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 4.12 (s, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:34]1([C:40]([OH:42])=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[Br:43][C:44]1[CH:53]=[CH:52][C:47]2[N:48]=[C:49]([NH2:51])[S:50][C:46]=2[CH:45]=1>C(Cl)Cl>[Br:43][C:44]1[CH:53]=[CH:52][C:47]2[N:48]=[C:49]([NH:51][C:40]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)=[O:42])[S:50][C:46]=2[CH:45]=1
Reactant: O=C(O)C1CCCCC1
Reactant: Nc1nc2ccc(Br)cc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccc(Br)cc2s1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
A mixture of Hunig's base (286 μl, 1637 μmol), HATU (830 mg, 2182 μmol) and cyclohexanecarboxylic acid (147 mg, 1146 μmol) was dissolved in 2.0 mL CH2Cl2 and stirred at room temperature for 10 min. 6-bromobenzo[d]thiazol-2-amine (250 mg, 1091 μmol) was added, and stirring was continued overnight. The solids were filtered and washed with CH2Cl2. The filtrate was concentrated, dissolved in CH2Cl2 and purified by silica gel chromatography using 100% CH2Cl2 to provide N-(6-bromobenzo[d]thiazol-2-yl)cyclohexanecarboxamide (290 mg, 78% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C14H15BrN2OS: 339.3/341.3. found 339.0/341.0.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[CH2:1]([N:5]([C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CN[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(C(=O)c1ccccc1)[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Nα-isobutyl-Nε-benzyloxycarbonyl-L-lysine (213 mg, 0.50 mmol) in CH2Cl2 (5 mL) was added benzoyl chloride (140 mg, 1.00 mmol) and DIEA (130 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography. Elution with 70% EtOAc in hexane provided Nα-isobutyl-Nα-benzoyl-Nε-benzyloxycarbonyl-L-lysine that was further hydrogenolyzed using 10% Pd/C and then treated with 9-fluorenylmethyl chloroformate instead of N-(9-fluorenylmethoxycarbonyloxy) succinimide as outlined in step D of example 38 to provide the title compound (90% yield).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17](=[S:19])[NH2:18])=[CH:15][N:16]=2)[CH2:8][CH2:7]1.Cl[CH2:27][C:28](=O)[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CO.O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[S:19][CH:27]=[C:28]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[N:18]=3)=[CH:15][N:16]=2)[CH2:8][CH2:7]1
Reactant: NC(=S)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Reactant: COC(=O)CC(=O)CCl
Solvent: CO
Solvent: O
Product: COC(=O)Cc1csc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Temperature: 82.5 °C

Procedure:
A mixture of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carbothioamide (240 mg, 0.62 mmol) and methyl 4-chloroacetoacetate (73 μL, 0.62 mmol) in methanol (3 mL) was heated in a sealed tube at 80-85° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (eluting with 30-60% EtOAc/hexanes) to give the title compound as a pale yellow gum.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[NH:16][C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)=[N:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([NH:26][CH:27]([CH:31]([CH3:33])[CH3:32])[C:28](O)=[O:29])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:22][O:23][C:24](=[O:25])[NH:26][CH:27]([C:28]([N:18]1[CH2:19][CH2:20][CH2:21][CH:17]1[C:15]1[NH:16][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:13][N:14]=1)=[O:29])[CH:31]([CH3:33])[CH3:32]
Reactant: Brc1ccc(-c2cnc(C3CCCN3)[nH]2)c2ccccc12
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
5-(4-bromo-naphthalen-1-yl)-2-pyrrolidin-2-yl-1H-imidazole (0.925 g), 2-methoxycarbonylamino-3-methyl-butyric acid (0.441 g), and HATU (1.00 g) were dissolved in anhydrous DMF (15 mL), and N-methylmorpholine (0.497 mL) was added. The reaction mixture was stirred at ambient temperature for 30 minutes and evaporated under vacuum. The oil was dissolved in DCM, purified by chromatography (0-100% ethyl acetate:hexanes), and evaporated under vacuum, giving (1-{2-[5-(4-bromo-naphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.814 g, 72%) as an off-white solid.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[F:27].CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]2[O:15][CH2:14][CH:13]([CH2:12][CH2:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]3)[CH2:16][O:17]2)=[CH:21][C:20]=1[F:27]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: CCCC[C@H]1CC[C@H](CCC(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](CCC2COC(c3ccc(Br)c(F)c3)OC2)CC1
Yield: 80 %

Procedure:
A solution of 6.1 g (0.025 mol) of 2-[2'-(trans-4"-butylcyclohexyl)ethyl]propane-1,3-diol, 5.1 g (0.025 mol) of 4-bromo-3-fluorobenzaldehyde, and g of TsOH in 125 cm3 of dichloromethane was refluxed for 5 hours over a hot water bath with a Dean-Stark trap. The solution was washed with water and the dichloromethane was distilled off. The residue was recrystallized from a solvent mixture of acetone and methanol to yield 8.4 g (0.02 mol) of 2-(4'-bromo-3'-fluorophenyl)-5-[2'-(trans-4"-butylcyclohexyl)ethyl]-1,3-dioxane.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:17])[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:17])[CH2:15][CH2:14][CH:13]([N:18]4[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=5)=[O:24])[CH2:19]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[NH:3][CH:2]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ccc3nc[nH]c3c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ccc4nc[nH]c4c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(3H-benzoimidazol-5-yl)-4-hydroxy-cyclohexanone (as prepared in Example 20, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=O)=[CH:36][CH:35]=1.[NH2:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][CH2:51][CH2:52][N:53]2[CH2:57][CH2:56][C@H:55]([OH:58])[CH2:54]2)=[C:48]([C:61]2[N:62]([CH3:66])[N:63]=[CH:64][CH:65]=2)[CH:47]=1>C1COCC1>[OH:58][C@H:55]1[CH2:56][CH2:57][N:53]([CH2:52][CH2:51][O:50][C:49]2[CH:59]=[CH:60][C:46]([NH:45][C:38](=[O:40])[C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:43])=[CH:42][CH:41]=3)=[CH:47][C:48]=2[C:61]2[N:62]([CH3:66])[N:63]=[CH:64][CH:65]=2)[CH2:54]1
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CC[C@H](O)C1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(C(F)(F)F)cc2)ccc1OCCN1CC[C@H](O)C1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of HATU (183 mg, 0.482 mmol), triethylamine (100 μl, 0.741 mmol) and 4-trifluoromethyl benzoic acid (92 mg, 0.482 mmol) in THF (1.0 mL) was stirred at room temperature. After 15 min, (S)-1-{2-[4-Amino-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-pyrrolidin-3-ol (112 mg, 0.370 mmol) was added, and the mixture was stirred at 100° C. for 10 minutes in microwave. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 58 mg, 33% yield). 1H NMR (DMSO-d6, 400 MHz) δ 1.67-1.74 (m, 1H), 1.78-1.90 (m, 1H), 2.09-2.18 (m, 1H), 2.88-2.97 (m, 1H), 3.31-3.37 (m, 1H), 3.47-3.61 (m, 2H), 3.69 (s, 3H), 4.31-4.36 (m, 4H), 6.31 (s, 1H), 7.24-7.28 (m, 1H), 7.50 (s, 1H), 7.75 (s, 1H), 7.90 (d, J=8.84 Hz, 1H), 7.94 (d, J=8.34 Hz, 2H), 8.16 (d, J=8.34 Hz, 2H), 9.93-10.11 (m, 1H), 10.5 (s, 1H). Exact mass calculated for C24H25F3N4O3 474.2, found 475.3 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[NH2:7].OS(O)(=O)=O.[CH3:20][C:21](=[CH2:23])[CH3:22].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[I:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[OH:14])[CH2:5][C@@H:6]([C:8]([O:10][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:9])[NH2:7]
Reactant: C=C(C)C
Reactant: N[C@@H](Cc1ccc(O)c(I)c1)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)c(I)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 5.0 g of 3-iodo-L-tyrosine (Aldrich) and 2.5 mL of conc. H2SO4 in 85 mL of 1,4-dioxane was added to 30 mL of liquid isobutylene (condensed at −78° C.) in a 300 mL pressure bottle. The vessel was stoppered and the contents stirred at RT. After 3 days the bottle was cooled in an ice water bath, opened and the solution poured into a mixture of 10 g of NaHCO3 in 150 mL of water. The resulting mixture was subjected to rotary evaporation to remove isobutylene and dioxane. A white solid resulted which was collected by filtration and dried in vacuo. Analysis by tlc (SiO2, 95:5 CH2Cl2:MeOH) indicated major and minor components at Rf=0.52 and 0.60 respectively. The crude product was purified by flash chromatography on silica gel (95:5 CH2Cl2:MeOH) to afford 3.4 g (58%) of tert-butyl 3-iodo-L-tyrosinate as a white crystalline solid, m.p. 158-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:68][O:69][C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([NH2:76])[CH:71]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:76][C:72]2[CH:73]=[CH:74][CH:75]=[C:70]([O:69][CH3:68])[CH:71]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cccc(N)c1
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2cccc(OC)c2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
A mixture of 3-iodo-phthalic acid dimethyl ester (1.0 g, 3.1 mmol), cesium carbonate (1.4 g, 4.3 mmol), Pd2(dba) (0.13 g, 0.14 mmol) and rac-BINAP (0.058 g, 0.093 mmol) in toluene (6 mL) was stirred at room temperature for 5 minutes. m-Anisidine (0.38 g, 3.1 mmol) was then added, and the reaction mixture was refluxed for 48 hours. The reaction mixture was diluted with methylene chloride (20 mL) and filtered through celite. The filter was washed with additional methylene chloride (25 mL). The combined filtrates were evaporated, and the residue was purified by ISCO silica gel flash chromatography using a hexanes-ethyl acetate gradient, eluting the product at 7:3 hexanes-ethyl acetate. It was then purified by preparative HPLC using an acetonitrile-water gradient, eluting the product at 6:4 acetonitrile:water to give the title product, 0.46 g in 47% yield; 1H NMR (CDCl3) δ 3.79 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 6.59-6.75 (m, 3H), 7.09-7.46 (m, 4H), 8.00 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]2[O:41][C:40](=[O:42])[NH:39][C:38]=2[CH:43]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]4[O:41][C:40](=[O:42])[NH:39][C:38]=4[CH:43]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc2oc(=O)[nH]c2c1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc4oc(=O)[nH]c4c3)n2)c1

Procedure:
Intermediate 4 was coupled to 5-(2-Amino-ethyl)-3H-benzooxazol-2-one following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 497. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 11.6 (s, 1H) 8.5 (d, 1H) 8.1 (m, 2H) 7.9 (m, 2H) 7.6 (m, 1H) 7.4 (m, 1H) 7.0 (m, 3H) 4.4 (s, 2H) 3.7 (m, 2H) 3.2 (m, 2H) 3.0 (s, 3H) 2.9 (m, 2H) 2.7 (m, 2H) 1.7 (m, 2H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[CH2:29][N:30]2[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:43].[Na+]>CO.O>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=2[CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([NH2:43])[CH2:32][CH2:31]2)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: CC[C@H](NC(=O)c1c(CN2CCC(=O)CC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC[C@H](NC(=O)c1c(CN2CCC(N)CC2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
0.477 g (1 mmol) of 3-(4-oxo-piperidin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (compound of Description 18), 0.462 g (6 mmol) of ammonium acetate were dissolved in 10 ml of methanol and stirred at room temperature for 1 h. Then 0.08 g of sodium cyanoborohydride were added and the mixture was stirred one night at room temperature. The reaction mixture was poured in 50 ml of water and the formed precipitate was filtered off. The aqueous phase was extracted with methylene chloride. The collected solid was dissolved in methylene chloride, both organic phases merged, washed with water, dried over MgSO4, concentrated to dryness. The residue was purified by micro flash chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 90/10/1) to afford 47 mg of the title compound as a white solid (yield ca 10%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=O)=[CH:4][CH:3]=1.Cl.[NH3:15]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH2:15])=[O:12])=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: Cl
Product: NC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31 %

Procedure:
25% Aqueous ammonia (30 mL) was added to methyl 4-hydroxybenzenepropanoate (1.5 g, 8.3 mmol), and the mixture was stirred at room temperature for 15 hrs. Dil. hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.43 g, yield 31%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([C:22](OCC)=[O:23])=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:22]=[O:23])=[N:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(C)cc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2nc(C=O)cc2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of ethyl 1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrazole-3-carboxylate (700 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and a 1.5 mol/L solution (3.8 mL) of diisobutylaluminum hydride in toluene was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in acetonitrile (15 mL) were added tetra-n-propylammonium perruthenate (66 mg), N-methylmorpholine N-oxide (442 mg) and molecular sieves 4 A powder (1.0 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow solid (yield 224 mg, 36%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:9])=[C:5]([CH:7]=O)[N:6]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[NH:11][NH2:12]>>[CH2:15]([O:14][C:10](=[O:13])[NH:11][N:12]=[CH:7][C:5]1[N:6]=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:9])[CH3:16]
Reactant: Cc1nc(C=O)c(C)[nH]1
Reactant: CCOC(=O)NN
Product: CCOC(=O)NN=Cc1nc(C)[nH]c1C

Procedure:
A 6.2 gm. portion of 2,5-dimethyl-4-imidazolecarboxaldehyde and 6.24 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 207.5°-210° C. (resolidifies 248°-252° C.)
Reaction SMILES: [CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=O)[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO.[OH-].[K+].O>[CH2:1]([C:3]1([CH3:23])[CH:8]([CH3:9])[C:7](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[N:4]1[O:14][CH:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH3:2]
Reactant: CCC1(C)CC(=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Reactant: NNC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1(C)CC(=NNC(N)=O)C(C)C(C)(CC)N1OC(C)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.8 %

Procedure:
2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-4-oxopiperidine prepared according to DE 199 09 767 A1 is dissolved in methanol containing 10% by weight of KOH and stirred for 5 hours at room temperature. Methanol is evaporated, the residue is washed with water and dried in vacuo. To a solution of 6.4 g (0.02 mol) 2,6-diethyl-2,3,6-trimethyl-1-(1-pheyl-ethoxy)-piperidine-4-one in 20 ml methanol are added 3.3 g (0.03 mol) semicarbazide hydrochloride and 1.67 g (0.025 mol) KOH (85%). The mixture is stirred under reflux 5 h and then diluted with 200 ml water. The precipitate is extracted into 100 ml of dichloromethane, the organic layer is washed with water, dryied over MgSO4 and evaporated to give 7.8 g (98.8%) of the title compound as a slightly yellow resin.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([CH2:24][NH2:25])[OH:23]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:25][CH2:24][CH2:22][OH:23])=[O:8])#[N:2]
Reactant: NCCO
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)NCCO)cc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a stirring suspension of 3-cyano-4-isopropoxybenzoic acid (1.0 g, 4.8 mmol) in DCM (20 mL) was added oxalyl chloride (3.7 g, 29.2 mmol) followed by two drops DMF. The reaction mixture was stirred at 50° C. for 2 h. The mixture was concentrated and the residue re-dissolved in DCM (10 mL). Ethanolamine (0.6 g, 9.7 mmol) and TEA (1.45 g, 14.4 mmol) were added and the reaction mixture was stirred overnight at room temperature. The resulting solid was filtered, washed with water, and dried to afford 1.0 g (83%) of 3-cyano-N-(2-hydroxyethyl)-4-isopropoxybenzamide which was used in the next step without purification. LCMS-ESI (m/z) calculated for C13H16N2O3: 248.3; found 249.0 [M+H]+, tR=2.41 min. 1H NMR (400 MHz, CDCl3) δ 8.02-7.79 (m, 2H), 6.97-6.87 (m, 1H), 6.71 (s, 1H), 4.65 (dt, J=12.1, 6.1 Hz, 1H), 3.82-3.70 (m, 2H), 3.56 (dd, J=10.2, 5.5 Hz, 2H), 1.96 (d, J=10.0 Hz, 1H), 1.40-1.29 (m, 6H).