Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=O)[CH2:8][CH2:7]1.[OH:25][C:26]([CH3:36])([CH3:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C.C(OCC)(=O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9](/[CH:13]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([OH:25])([CH3:36])[CH3:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Reactant: O=CC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]azepane-4-carbaldehyde (133.2 mg) in 2-propanol (1.89 mL) were added 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (142 mg) and piperidinium acetate (54.7 mg). The reaction mixture was stirred at 60° C. overnight, cooled to room temperature, and diluted with ethyl acetate. The mixed solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (86.3 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:32][CH2:33][CH3:34])[N:8]3[N:35]=[CH:36][N:37]=[C:7]23)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:1]=[C:2]1[CH2:3][CH:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:32][CH2:33][CH3:34])[N:8]3[N:35]=[CH:36][N:37]=[C:7]23)[CH2:5]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2C[C@@H](O)C2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CC(=O)C2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of 4-(cis-3-hydroxycyclobutyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.1 g), Dess-Martin reagent (0.13 g) and acetonitrile (5 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.077 g, 78%).
Reaction SMILES: [OH-:1].[Na+].[Cl-].[CH3:4][C:5]1([CH3:24])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14](=[O:22])C[N+]3C=CC=CC=3)[CH:12]=2)[NH:7][C:6]1=[O:23].Cl>O>[CH3:24][C:5]1([CH3:4])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:22])=[O:1])[CH:12]=2)[NH:7][C:6]1=[O:23]
Reactant: [OH-]
Reactant: CC1(C)C(=O)Nc2ccc(C(=O)C[n+]3ccccc3)cc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1(C)C(=O)Nc2ccc(C(=O)O)cc21
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
To a solution of sodium hydroxide (14 g) in water (480 ml) was added 1-[2-(2,3-dihydro-3,3-dimethyl-2-oxoindol-5-yl)-2-oxoethyl]pyridinium chloride (44.3 g) and the mixture was stirred for 1.5 hours at 80° to 85° C. After cooling, the reaction mixture was acidified with conc. hydrochloric acid. The residual crystal was collected by filtration, washed with water and dried to give 2,3-dihydro-3,3-dimethyl-2-oxoindole-5-carboxylic acid (21 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc(C(CN2CCNCC2)c2ccc(Cl)cc2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Clc1ccc(C(CN2CCNCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
1-[2,2-Bis-(4-chloro-phenyl)-ethyl]-piperazine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.63 [M+H]+ 326.00. 1H NMR (Me-d3-OD) δ 3.55-3.68 (8H, m), 3.74 (1H, t), 4.10-4.17 (2H, m), 7.39 (2H, d), 7.48 (2H, d), 7.54 (2H, d), 7.70 (2H, d), 8.57 (2H, br s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([F:17])[F:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
4-Bromo-2-chlorophenol (1.0 g, 4.8 mmol) was dissolved in DMF (35 mL) and water (5 mL) was added followed by sodium chloro(difluoro)acetate (2.0 g, 12 mmol) and cesium carbonate (3.1 g, 9.6 mmol). The mixture was stirred for 15 minutes at room temperature and then heated to 100° C. for 2 hours under nitrogen. The mixture was partitioned between water (50 mL) and TBME (50 mL). The organic phase was separated, washed brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to afford the title compound as colourless oil (0.83 g, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][N:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:20]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C([O-])([O-])=O.[Cs+].[Cs+].[ClH:52]>O1CCOCC1.CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:28].[ClH:52].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:20]=2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cnn(C2CCN(C)CC2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cnn(C2CCN(C)CC2)c1
Temperature: 80 °C
Yield: 42.5 %

Procedure:
To a suspension of 1-(6-bromo-4-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)quinolin-3-yl)ethanone (50 mg, 0.116 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) and Pd(dppf)Cl2 (11 mg, 0.015 mmol) in dioxane (4 mL) was added Cs2CO3 (1.0 M in H2O, 0.4 mL, 0.4 mmol). N2 gas was bubbled through the reaction mixture and the mixture was then heated at 80° C. for 2 h. The solution was allowed to cool to room temperature, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded a residue that was dissolved in methanol (4 mL) and HCl (1.25 M in methanol, 1.0 mL, 1.25 mmol) was added. The resultant solution was concentrated to give the desired product (18.6 mg, 27%) as a yellow solid. 1H NMR (500 MHz, MeOD) δ 9.26 (s, 1H), 8.25-8.18 (m, 1H), 8.18-8.07 (m, 2H), 8.00 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.36-7.32 (m, 2H), 4.70-4.61 (m, 1H), 3.68 (d, 2H), 3.53-3.45 (m, 1H), 3.41-3.22 (m, 1H), 2.94 (s, 3H), 2.80 (s, 3H), 2.53-2.33 (m, 4H). ESI MS m/z 510 [C26H25Cl2N5O2+H]+; HPLC 97.4% (AUC), tR=9.46 min.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:31][C:32]([O:34][CH:35](I)[CH3:36])=[O:33])[CH:28]([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:35]([O:34][C:32]([O:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:33])[CH3:36])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)COC(=O)OC(C)I
Agent: [Na+]
Product: CC(C)COC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 74.1 %

Procedure:
In the same manner as in Example 81, 334 mg of the title compound was prepared from 346 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 278 mg of 1-(isobutyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=[C:13]([CH3:15])[CH3:14])[CH:7]2[CH:6]=[CH:5]1.[H][H]>[Pd].C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=[C:13]([CH3:15])[CH3:14])[CH:7]2[CH2:6][CH2:5]1
Reactant: CC(C)=C1C2C=CC1c1c(Cl)cccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)=C1C2CCC1c1c(Cl)cccc12
Yield: 97.3 %

Procedure:
170 g of 5-Chloro-9-isopropylidene-1,4-dihydro-1,4-methano-naphthalene (0.785 mol), 0.5 g of Pd 10% (0.2 mmol) and 1 liter THF were charged in an hydrogenation reactor. 19 liter Hydrogen was feed at ambient temperature; the reaction was carried out at 0.05 MPa pressure. After complete conversion, the reaction mixture was filtered off over hyflo and product solution was evaporated to give 167 g product (Purity: 92%; Yield: 90%). The product was crystallized with MeOH, filtered off and dried. Purity: 97.54%
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=O)[CH:16]=2)[NH:11][N:10]=1.[NH2:20][C:21]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[C:22]=1[C:23]([NH2:25])=[O:24].OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[NH:25][C:23](=[O:24])[C:22]4[C:21](=[CH:29][C:28]([O:30][CH3:31])=[CH:27][C:26]=4[O:32][CH3:33])[N:20]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccc2[nH]nc(COC3CCCCO3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]nc(CO)c4c3)nc2c1
Temperature: 120 °C

Procedure:
To a solution of 3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carbaldehyde (0.32 g, 1.23 mmol) and 2-amino-4,6-dimethoxy-benzamide (0.24 g, 1.23 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (58.5 wt %, 0.27 g, 1.48 mmol) and p-toluenesulfonic acid monohydrate (0.05 g, 0.25 mmol); the reaction mixture was heated at 120° C. for 16 hours, then cooled to room temperature. Solvent was removed under reduced pressure. The residue was diluted with water (100 mL). The separated solid was filtered and washed with water and dried under vacuum. The residue was purified by the Simpliflash system (0-5% methanol in CH2Cl2 as eluent) to give the title compound as an off-white solid. Yield: 30 mg (7%). MP 264-266° C. 1H NMR (400 MHz, CD3OD): δ 8.60 (s, 1H), 8.10 (d, J=8.98 Hz, 1H), 7.65 (d, J=8.98 Hz, 1H), 6.85 (d, J=1.95 Hz, 1H), 6.55 (d, J=1.95 Hz, 1H), 5.05 (s, 2H), 3.96 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.CS[C:15](=[N:20][CH3:21])[S:16]([O-:19])(=[O:18])=[O:17]>C(#N)C.CO>[CH3:21][NH:20][C:15]([S:16]([OH:19])(=[O:18])=[O:17])=[N:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: NCCSCc1ncccc1Cl
Reactant: CN=C(SC)S(=O)(=O)[O-]
Solvent: CO
Solvent: CC#N
Product: CNC(=NCCSCc1ncccc1Cl)S(=O)(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 2-(3-chloropyrid-2-ylmethylthio)ethylamine (2.03 g) in dry acetonitrile (150 ml) was added dropwise, with stirring, to a solution of 1-methylthio-1-methyliminomethanesulphonate (1.69 g) in dry acetonitrile (150 ml) at 50°. The mixture was stirred at 60° for 30 minutes and then allowed to cool. The mixture was stripped to dryness, dissolved in methanol and absorbed onto silica gel. Chromatography on a column of silica gel produced a viscous oil which was collected by eluting the column with a chloroform/methanol mixture and evaporating off the solvent. The viscous oil analysed by micro-analysis and nuclear magnetic resonance spectroscopy to the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][CH:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)[OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH2:17][C:18]([CH3:20])([CH3:21])[O:19][C:15]=2[C:14]([O:22][CH3:23])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
Compound 45a (3.0 g) obtained in Step A of Example 45 was dissolved in methylene chloride (80 ml), and a powder of silica gel (15 g) and pyridinium chlorochromate (PCC) (2.1 g) were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was filtered and the obtained filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to give Compound 95 (1.3 g, 44.9%) as pale-yellow crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]N(C=O)C.CC(N(C)C)=O>C(#N)C>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Reactant: CN(C)C=O
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 105 °C

Procedure:
About 200 mg of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride was introduced in a gas chromatograph hypo vial and dissolved in 1 ml of acetonitrile. To the solution was added 0.2 ml of DMF DMA reagent. The vial was sealed with crimper and heated at 105° C. for 15 minutes in an oven. Seven vials were made. The contents of the vials were then put into a long-neck round bottom flask and evaporated to dryness by a flask evaporator. The solid mass was dissolved in a mixture of 30 ml of CHCl3 and 20 ml of water and shaken vigorously in a 60 ml separatory funnel. The aqueous layer was discarded and 20 ml of water was added and shaken. The CHCl3 layer was then taken and about 10 g of anhydrous Na2SO4 was added, the CHCl3 solution was decanted into a flask and evaporated to dryness. The solid material was dissolved in 2-pentanone (about 80 ml) at 70° C. The solution was concentrated and crystallized upon cooling. The crystals were collected and dried in a desiccator with P2O5 with vacuum for one hour.
Reaction SMILES: [H-].[Li+].[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=1)=[O:6].I[CH2:15][CH:16]([CH3:18])[CH3:17].Cl>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9](=[O:13])[CH:8]=1)=[O:6]
Reactant: CC(C)CI
Reactant: COC(=O)c1cc[nH]c(=O)c1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(CC(C)C)c(=O)c1
Reaction time: 0.17 h

Procedure:
LiH (78 mg) was suspended in DMF (5 ml), and a suspension of methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (500 mg) in DMF (5 ml) was added dropwise thereto at room temperature. The suspension was stirred as it was, and a solution of 1-iodo-2-methylpropane (506 μl) in DMF (5 ml) was added dropwise thereto over 10 min, followed by stirring at 50° C. for 15 hours. To the reaction solution was added 1M HCl at 0° C., followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over anhydrous MgSO4, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:EtOAc=90:10 to 50:50) to obtain methyl-1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (440 mg) as white powders.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]=[C:17]=[O:18].Cl.Cl.[CH2:23]([O:25][C:26]([C:28]1[C:29]([CH3:47])=[C:30]([C:34]([NH:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:35][C:36]=1[CH3:37])[C:31](O)=[O:32])=[O:27])[CH3:24]>C(OCC)C>[CH2:23]([O:25][C:26]([C:28]1[C:29]([CH3:47])=[C:30]2[C:34](=[CH:35][C:36]=1[CH3:37])[N:38]([CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:17](=[O:18])[N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([F:8])([F:19])[F:20])[C:31]2=[O:32])=[O:27])[CH3:24]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1c(C)cc(NCCN2CCCCC2)c(C(=O)O)c1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1c(C)cc2c(c1C)c(=O)n(-c1ccccc1C(F)(F)F)c(=O)n2CCN1CCCCC1
Yield: 72 %

Procedure:
Triethylamine (0.58 g) and o-(trifluoromethyl)phenyl isocyanate (0.53 g) were added to a solution of the benzoic acid described above (1.2 g) in diethyl ether (20 ml), and the mixture was refluxed for 4 hours. After evaporating the solvent, the residue was dissolved in ethanol (20 ml) containing 10% hydrogen chloride. The solution was refluxed for one hour and then concentrated. The concentrate was diluted with water and extracted with CHCl3, and the CHCl3 extracts were combined, washed successively with 10% aqueous Na2CO3 solution and brine, and dried over anhydrous Na2SO4. The solvent was evaporated, and the residue was recrystallized from diethyl ether-n-hexane to give 6-ethoxycarbonyl-5,7-dimethyl-1-(2-piperidinoethyl)-3-[2-(trifluoromethyl)phenyl]-2,4(1H,3H)-quinazolinedione (1.1 g, 72%) melting at 144°-145° C. MS: m/e, 517(M+), 498, 472, 433, 406. NMR: δ (ppm. CDCl3), 1.40 (3H, t), 1.50 (6H, b), 2.45 (3H, s), 2.52 (6H, t), 2.70 (3H, s), 4.30 (2H, t), 4.45 (2H, q), 7.10-7.80 (5H, m).
Reaction SMILES: ClCCCl.C[Al](C)C.[CH2:9]([SH:11])[CH3:10].[CH:12]([O:15][N:16]=[C:17]([C:27]([O:29]C)=O)[C:18]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[N:19][O:20][CH3:21])([CH3:14])[CH3:13]>C(OC(C)C)(C)C.O>[CH:12]([O:15][N:16]=[C:17]([C:18](=[N:19][O:20][CH3:21])[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:27](=[O:29])[S:11][CH2:9][CH3:10])([CH3:13])[CH3:14]
Reactant: CON=C(C(=NOC(C)C)C(=O)OC)n1cncn1
Reactant: CCS
Agent: C[Al](C)C
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: ClCCCl
Product: CCSC(=O)C(=NOC(C)C)C(=NOC)n1cncn1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To 8 ml of 1,2-dichloroethane was added 7.5 ml (7.5 mmol) of a trimethylaluminum (1 mol/l) hexane solution. Thereinto was drop-wise added 0.47 g (7.5 mmol) of ethanethiol at room temperature, followed by stirring for 30 minutes. To this mixed solution was added, at room temperature, a 1,2-dichloroethane solution containing 0.50 g (1.9 mmol) of the 1-(2-isopropoxyimino-2-methoxycarbonyl-1-methoxyiminoethyl)-1H-1,2,4-triazole produced in Example 12, followed by stirring for 1.5 hours. The reaction mixture was diluted with isopropyl ether. Thereto was added a small amount of water, followed by stirring. The resulting precipitate was removed by filtration. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/2) to obtain 0.56 g (yield: 98%) of a title compound as a yellow oily matter.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=3[CH2:24][CH2:25][O:26][CH3:27])(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1.Cl>CO.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)(=[O:13])=[O:14])=[C:16]([CH2:24][CH2:25][O:26][CH3:27])[CH:17]=1
Reactant: COCCc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COCCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
A mixture of N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-(2-methoxyethyl)-4-nitrobenzenesulfonamide (1 g, crude, 2.5 mmol) and Pd/C (0.2 g, 10%) in MeOH (50 mL) was stirred under 50 PSI H2 at room temperature for 2 hrs. The mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 um; liquid phase: [A-H2O+0.05% TFA; B-MeCN] B %: 5%-35%, 23 min), concentrated, acidified with HCl and freeze-dried to give the title compound (0.3 g, yield 32%) as HCl salt. 1H NMR: 400 MHz DMSO-d6 δ10.01 (s, 1H), 7.56-7.54 (m, 1H), 7.40-7.39 (m, 1H), 7.21-7.18 (m, 1H), 7.11-7.09 (m, 1H), 6.48-6.40 (m, 2H), 4.83 (s, 2H), 3.49-3.45 (m, 2H), 3.21 (s, 3H), 3.06-3.03 (m, 2H).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=O)[CH2:15]Br)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:18])=[C:8]([C:14]2[N:30]=[C:28]([CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)[O:29][CH:15]=2)[CH:9]=1
Reactant: COc1cccc(CC(N)=O)c1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)CBr
Product: COc1cccc(Cc2nc(-c3cc(Br)ccc3OCC(=O)O)co2)c1

Procedure:
Title compound was prepared from [4-bromo-2-(2-bromoacetyl)phenoxy]acetic acid ethyl ester and 2-(3-methoxyphenyl)acetamide according to GP5 and GP3: LC/MS (an 10p8) Rt 2.45 min, m/z 418 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:20])[CH2:14]2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].[ClH:29]>>[ClH:29].[NH:1]([C:5]1[S:6][C:7]([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([C:19]([NH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH2:14]2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CCOC(=O)CCNC(=O)C1CCCN(C(=O)c2sc(NC(=N)N)nc2C)C1
Agent: Cl
Product: Cc1nc(NC(=N)N)sc1C(=O)N1CCCC(C(=O)NCCC(=O)O)C1

Procedure:
103 mg of ethyl (RS)-3-[[1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-piperidine-3-carbonyl]-amino]-propionate are left to stand at RT in 2.1 ml of 25 percent hydrochloric acid for 6 hrs. The solution is evaporated and the residue is taken up in water and again evaporated. There are obtained 92 mg of (RS)-3-[[1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-piperidine-3-carbonyl]-amino]-propionic acid hydrochloride (1:2) as a white foam, MS: 383 (M+H)+.