Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.Cl.Cl.Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]2)[CH2:30][CH2:29]1>>[OH:42][CH:39]1[CH2:38][CH2:37][N:36]([CH2:35][CH2:34][N:31]2[CH2:30][CH2:29][CH:28]([NH:27][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:33][CH2:32]2)[CH2:41][CH2:40]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example 50) and amine 21.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.OS(O)(=O)=O.[C:14]([O:19][CH3:20])(=[O:18])C(C)=O.OO>C(Cl)Cl.C([O-])(O)=O.[Na+].O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].C(Cl)Cl.O>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]([O:19][CH3:20])=[O:18])[CH:4]=1
Reactant: COC(=O)C(C)=O
Reactant: Brc1ccncc1
Agent: [Fe+2]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)ccn1
Reaction time: 0.25 h

Procedure:
A solution of 4-bromopyridine hydrochloride (595 mg, 3.06 mmol) in DCM (20 mL) is washed with aqueous NaHCO3 (2×20 mL), dried (MgSO4) and filtered. The filtrate is made up to 45 mL by the addition of more DCM, then water (3 mL) is added, followed by iron(II) sulphate heptahydrate (8.51 g, 30.6 mmol) and conc. H2SO4 (0.95 mL, 9.18 mmol). In a separate flask, methyl pyruvate (4.15 mL, 46 mmol) is treated with hydrogen peroxide (3.5 mL, 30.6 mmol, 30% solution in water) at −10° C., then this solution is added to the DCM/water mixture at −10° C. with vigorous stirring. After 15 minutes, the reaction is diluted with iced water (100 mL) and extracted into DCM (4×20 mL). The combined DCM phases are dried (MgSO4) and removed in vacuo. The title compound is obtained after sequential column chromatography (gradient elution—10-40% EtOAc in heptane with 0.5% triethylamine, then repeating with 0-20% EtOAc in heptane with 0.5% triethylamine).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.[H-].[Na+].[C:21](=[O:29])([O:25][CH:26](Cl)[CH3:27])[O:22][CH2:23][CH3:24]>CN(C=O)C>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([O:17][CH:23]([O:22][C:21]([O:25][CH2:26][CH3:27])=[O:29])[CH3:24])=[O:16])[C:3]([OH:18])=[CH:2][CH:1]=1
Reactant: CCOC(=O)OC(C)Cl
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diflunisal (5.0 g) in 40 ml DMF was added 0.8 g of sodium hydride (oil suspension containing 60% of NaH). The resultant mixture was stirred for 1.5 hours at room temperature before 3.0 ml of ethyl 1-chloroethyl carbonate was added dropwise. The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The concentrate was partitioned between ether/ethyl acetate and acidified water. The organic layer was separated and the aqueous layer was extracted again with ether. The organic layers were combined, washed well with water, dried over anhydrous sodium sulfate and concentrated to 6.6 g of crude product. After further purification by chromatography (eluted through 120 g of silica gel with hexane, and then 5% ethyl acetate in hexane), the product was crystallized from hexane to afford 3.71 g of 1-(ethoxycarbonyloxy)ethyl 5-(2,4-difluorophenyl)salicylate.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:17])[C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([O:13][CH:14]([CH3:16])[CH3:15])[CH:7]=1>CO>[OH:12][C:10]1[CH:9]=[C:8]([O:13][CH:14]([CH3:16])[CH3:15])[CH:7]=[C:6]([CH:11]=1)[C:5]([OH:17])=[O:4]
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1cc(O)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
After adding 10 ml of 4N aqueous sodium hydroxide solution to a solution of the 3.0 g (14.3 mmol) of 5-hydroxy-3-isopropoxybenzoic acid methyl ester obtained in Production Example 59 in methanol (50 ml), the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous ammonium chloride was added, extraction was performed with chloroform, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=50:1) to obtain 2.44 g of 5-hydroxy-3-isopropoxybenzoic acid (yield: 87%) as a white solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[OH-].[K+:14]>O>[C:1]([O-:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O-:6])=[O:5].[K+:14].[K+:14]
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccccc1C(=O)[O-]
Reaction time: 2 h

Procedure:
In a 2-liter beaker equipped with a stirrer were placed 100 g of phthalic acid, 141 g of a 48% aqueous solution of caustic potash and 1230 g of water. A reaction was carried out for 2 hours at 30° C. with stirring to obtain an aqueous solution of potassium phthalate having a pH value of 10.3 and containing 10.1% by weight of a solid matter.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[C:14]([Cl:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:33][OH:34].C(N(CC)CC)C>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]=[C:7]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:33][OH:34])=[NH:20])=[C:14]([Cl:21])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC#N)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC(=N)NO)c(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
2.2 g {4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-acetonitrile were dissolved in a mixture of 6 ml tetrahydrofuran and 12 ml methanol. 3.3 g hydroxylamine hydrochloride were added followed by the addition of 6.6 ml triethylamine. The reaction mixture was stirred at 60° C. for two hours. The solvents were removed in vacuo and the resulting residue poured into water and extracted five times with portions of 30 ml ethylacetate. The combined organic extracts were dried over MgSO4 and the solvent was evaporated in vacuo to provide 2.3 g 2-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-N-hydroxy-acetamidine as crude material.
Reaction SMILES: CN(C)C=O.[NH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:35]([F:38])([F:37])[F:36])[O:24][N:23]=[C:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([CH3:34])[CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(OCC)(=O)C>CN(C)C(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([C:35]([F:37])([F:36])[F:38])[O:24][N:23]=[C:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:6][N:7]4[CH:11]=[CH:10][CH:9]=[N:8]4)=[O:30])=[C:27]([CH3:34])[CH:26]=3)[CH2:21]2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nn1cccn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nn1cccn1

Procedure:
In 4 mL of N,N-dimethylacetamide, 0.23 g of 50% N,N-dimethylformamide solution of 1-aminopyrazole was added, and 0.30 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 2 hours. After the completion of the reaction, 20 mL of ethyl acetate was added in the reaction mixture, washed with water (20 mL×1), and then the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 0.22 g of the aimed product as yellow resinous substance.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10][CH2:9]2.[Al+3].[Cl-].[Cl-].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+](C1C=CC=CC=1)([O-])=O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:1]#[N:2])=[CH:11][CH2:10][CH2:9]2
Reactant: [C-]#N
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Al+3]
Agent: [Br-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2c(c1)CCC=C2C#N
Reaction time: 2 h

Procedure:
A mixture of 1.3 g of dry AlCl 3, 0.64 g of dry NaCN, and 87 mg of tetrabutylammonium bromide (TBAB) in 8.7 ml of dry nitrobenzene (NB) was stirred for two hours under a nitrogen atmosphere. Then 1.53 g of 6-methoxytetralone (6-MT) were added to provide a reaction mixture containing the 6-MT, NaCN, and AlCl3 in a mol ratio of 1/1.5/1.1 and containing 5.6% of TBAB, based on the weight of 6-MT. The reaction mixture was stirred at 90° C. for 10 hours to form 6-methoxy-1-cyano-3,4-dihydronaphthalene (6-MCDN). After workup the VPC ratio of 6-MT/6-MCDN was determined to be 8/92. The process resulted in an 85% isolated yield of 6-MCDN.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C=O.[C:31](O)(=O)C.[Na]>C1COCC1>[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:31])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)C
Reactant: CC(=O)O
Agent: C=O
Agent: [Na]
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Compound 314 (0.38 g), 30% aqueous paraformaldehyde (0.8 mL) and acetic acid (60 μL) in THF was added sodium triacetoxyboronhydride (0.42 g). After stirring at room temperature for two hours, the THF was removed by evaporation under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography with 10% to 60% MeOH in DCM. The combined pure fractions were evaporated to give a white solid, which was triturated in EtOAc/DCM (2:1) and filtered. The filtrate was evaporated to dryness under reduced pressure. The resulting residue was extracted between water and DCM. The organic phase was dried over anhydrous Na2SO4 and evaporated to give Compound 317 (0.31 g). 1H-NMR (400 MHz, CDCl3) δ: 1.27 (s, 9H), 1.90 (br, 2H), 2.47 (s, 3H), 2.79 (d, J=4.8 Hz, 3H), 3.04 (br, 2H), 4.16 (br, 2H), 4.29 (d, J=9.5 Hz, 1H), 4.32 (br, 2H), 5.95 (br, 1H), 7.20-7.23 (dd, J=2.0, 9.6 Hz, 1H), 7.47-7.53 (m, 5H), 7.82 (d, J=9.5 Hz, 1H). LCMS (+ESI) m/z 398.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[CH:3]=[C:2]1[C:13]([OH:15])=O.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:13]([C:2]2[NH:1][C:12]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[C:7]2[C:11]=3[CH:10]=[CH:9][NH:8]2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2ccc3[nH]ccc3c2[nH]1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(c1cc2ccc3[nH]ccc3c2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 1,6-dihydro-1,6-diaza-as-indacene-2-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 186-188° C. (diethyl ether).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CN(CCN(C)C)C>O1CCCC1.[Cu]>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cu]
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCC(F)(F)C(=O)OCC
Reaction time: 8 h

Procedure:
Commercially available ethyl bromodifluoroacetate (16 mL, 120 mmol) and ethyl acrylate (11 mL, 100 mmol) were dissolved in tetrahydrofuran (100 mL), and copper powder (15.2 g, 240 mmol) and TMEDA (16.7 mL, 110 mmol) were sequentially added thereto at room temperature. After stirring for about 8 hours, the reaction was terminated by the addition of a saturated aqueous solution of 1.0 N hydrochloric acid and was extracted two times with toluene. The reaction solution was distilled under reduced pressure and the concentrated title compound was directly used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Yield: 91.9 %

Procedure:
A solution of ethyl 1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazole-4-carboxylate (Intermediate 10) (1.5 g, 5 mmol) and a 1N NaOH solution (7.5 mL, 1.5 eq) in ethanol (50 mL) was stirred at reflux for 48 hours. The solvent was evaporated and the residue was acidified with a 1N HCl solution (15 mL). The precipitate formed was filtered, washed with water and dried to give the title compound as a white solid (1.25 g, 92%). LC/MS: m/z 272 (M+H)+. Rt: 2.05 min.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][C:17]=3[CH3:25])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:22]1([C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[C:17]([CH3:25])[CH:18]=2)[CH2:24][CH2:23]1
Reactant: Cc1cc(C2CC2)ccc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)ccc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 77.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(4-cyclopropyl-2-methylphenyl)piperazin-1-yl]methanone (260 mg) described in Preparation Example 140 and oxazolidin-2-one (66 mg), the title compound (205 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]([F:38])[C:30]2[O:34][C:33](SC)=[N:32][C:31]=2[CH:37]=1>C([O-])(=O)C.C([O-])(=O)C.[Hg+2]>[Br:26][C:27]1[CH:28]=[C:29]([F:38])[C:30]2[O:34][C:33]([NH:15][C@H:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:24][CH:23]=3)=[N:32][C:31]=2[CH:37]=1
Reactant: CSc1nc2cc(Br)cc(F)c2o1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3cc(Br)cc(F)c3o2)C(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
The mixture constituted by aminoester 4-2 (865 mg; 2.46 mmoles), 5-bromo-7-fluoro-2-(methylthio)-benzoxazole (804 mg; 3.07 mmoles) and mercury diacetate (437 mg) is agitated for 3 hours, under nitrogen and at 100° C. After cooling down, the medium is chromatographed eluting with a CH2Cl2/ethyl acetate mixture 95/5, 564 mg of expected product is obtained, which is repurified by recrystallizing from isopropyl oxide. 528 mg of purified product is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:10].[NH4+].N[C@H:13]([C:18]([O-])=[O:19])[CH2:14][C:15]([O-])=[O:16].[Na+:21].[Na+]>>[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5].[Na+:21].[Na+:21].[C:18]1(=[O:19])[NH:10][C:15](=[O:16])[CH2:14][CH2:13]1
Reactant: [NH4+]
Agent: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Product: O=C1CCC(=O)N1

Procedure:
The reactions and procedures of this Example were repeated, except that the monomer ratios of ammonium aspartate and sodium aspartate were adjusted (in part A) to produce a 1:2 copolymer of sodium aspartate and succinimide. A solution of this copolymer was titrated to pH 4.0 and ring-closed as above. The resulting terpolymer of sodium aspartate, asparagine, and succinimide had a residue ratio of 0.53:1:0.97 (asp:asn:suc). This terpolymer also was water-soluble.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]C(=O)OC(C)(C)C)=[CH:14][C:13]=2[F:26])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]>Cl.O1CCOCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=2)=[C:13]([F:26])[CH:14]=1
Reactant: CC(=O)Nc1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2F)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Reaction time: 0.42 h
Yield: 88 %

Procedure:
A solution of tert-butyl 4-(2-acetamidopyridin-4-yloxy)-3-fluorophenylcarbamate (110 mg, 0.30 mmol) in 4 M HCl/1,4-dioxane (1.5 mL) was stirred at 0° C. for 20 min then at room temperature for 25 min. The mixture was diluted with EtOAc (25 mL) and saturated aq. NaHCO3 solution (20 mL), and stirred vigorously for 5 min. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (69 mg, 87%) as a yellow solid. 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 8.13 (d, 1H, J=5.6 Hz), 7.60 (m, 1H), 6.95 (dd, 1H, J=8.6, 9.2 Hz), 6.60 (dd, 1H, J=2.5, 5.6 Hz), 6.48 (dd, 1H, J=2.5, 13.2 Hz), 6.40 (dd, 1H, J=2.0, 8.6 Hz), 5.44 (s, 2H), 2.02 (s, 3H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16](Cl)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][N:32]=[C:31]([C@@H:34]([NH2:36])[CH3:35])[CH:30]=2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(OCC)(=O)C.[Cl-].[Na+]>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH:36][C@H:34]([C:31]2[CH:30]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[O:33][N:32]=2)[CH3:35])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1cc(-c2ccc(Cl)cc2)on1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Cl)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cc(-c2ccc(Cl)cc2)on1
Temperature: 25 °C

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (70 mg, 0.209 mmol), (S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethanamine (60 mg, 0.23 mmol, 1.1 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.091 mL, 0.52 mmol, 2.5 equiv) in DMSO (1.0 mL) was heated at 85-110° C. for 3-5 h. The reaction was cooled to room temperature and diluted with ethyl acetate (30 mL) and dilute aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to give crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(6-chloro-2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one, which was used without further purification. MS m/z 520.2 (M+H)+; Rt-1.31 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[NH:18][CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:18]([CH2:20][C:21](=[O:22])[N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=[CH:16][N:8]2[C:9](=[O:15])[C:10]=1[O:11][C:12](=[O:14])[CH3:13])=[O:4]
Reactant: O=C(CCl)N1CCCCC1
Reactant: COC(=O)c1nc2[nH]ccn2c(=O)c1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OC(C)=O
Temperature: 25 °C
Yield: 66.8 %

Procedure:
To a solution of compound 6-acetoxy-5-oxo-1,5-dihydro-imidazo[1,2-a]pyrimidine-7-carboxylic acid methyl ester (PCT/AU2007/001980) (2.0 g, 7.96 mmol) in anhydrous acetonitrile (20 ml) was added compound 2-chloro-1-piperidin-1-yl-ethanone (2.0 g, 12.42 mmol), K2CO3 (1.7 g, 12.32 mmol), KI (133 mg, 0.8 mmol) successively. The mixture was heated at refluxed for 3 hours. After cooling to the room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give titled compound (2.0 g, yield 66.7%).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([N:19]2[CH2:40][CH2:39][C:22]3([NH:26]/[C:25](=[N:27]/[C:28]([C:30]4[C:35]([NH2:36])=[N:34][C:33]([NH2:37])=[C:32]([Cl:38])[N:31]=4)=[O:29])/[NH:24][CH2:23]3)[CH2:21][CH2:20]2)=[O:18])[CH:12]=1)=[O:9])C.[Li+].[OH-]>C1COCC1>[NH2:36][C:35]1[C:30]([C:28](/[N:27]=[C:25]2/[NH:26][C:22]3([CH2:39][CH2:40][N:19]([C:17]([C:13]4[CH:12]=[C:11]([NH:10][C:8](=[O:9])[NH:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])[CH:16]=[CH:15][CH:14]=4)=[O:18])[CH2:20][CH2:21]3)[CH2:23][NH:24]/2)=[O:29])=[N:31][C:32]([Cl:38])=[C:33]([NH2:37])[N:34]=1
Reactant: CCOC(=O)CCNC(=O)Nc1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(NC(=O)NCCC(=O)O)c4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[3-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-phenyl)-ureido]-propionic acid ethyl ester (step 1) (2.17 g, 3.70 mmol) in THF (20 ml) was treated with LiOH (0.167 g, 4.07 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and water and the aqueous portion was acidified to neutral pH and concentrated in vacuo. The residue was suspended in water (100 ml), and the resulting suspension was filtered, washed with cold water (100 ml) and dried to afford the title product; LC-MS Rt 0.73 mins; 559.3 [M+H]+, Method 2minLC_v003.