Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:15][C:16]([O:18]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.Cl.[CH2:29]([NH:31][CH2:32][CH2:33][C:34]1[N:35]=[CH:36][NH:37][CH:38]=1)[CH3:30].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>CN(C=O)C>[CH2:29]([N:31]([CH2:32][CH2:33][C:34]1[N:35]=[CH:36][NH:37][CH:38]=1)[C:16](=[O:18])[NH:15][C@@H:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:30]
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCNCCc1c[nH]cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCN(CCc1c[nH]cn1)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 105.4 %

Procedure:
0.14 g (0.38 mmol) of methyl(S)-3-(4-methoxyphenyl)-2-(4-nitrophenoxycarbonyl-amino)propionate is diluted in 2 mL of DMF. The solution is heated to 80° C. and 0.16 g (0.76 mmol) of ethyl[2-(1H-imidazol-4-yl)ethyl]amine hydrochloride and 0.13 mL (1.3 mmol) of diisopropylethylamine are then added. After 5 minutes, the reaction medium is cooled to room temperature and stirred for 15 minutes. Toluene is added and the solvents are evaporated off. The crude product obtained is chromatographed on silica gel (eluent: 8/2 dichloromethane/methanol). 0.15 g of methyl(S)-2-{3-ethyl-3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)-propionate in the form of a colourless oil is obtained in a yield of 100%.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:9]([C:12]1[CH:13]=[C:14]([OH:20])[C:15]([O:18]C)=[CH:16][CH:17]=1)([O-:11])=[O:10].N1C=CN=[CH:22]1>CN(C=O)C>[C:4]([Si:1]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][C:14]=1[O:20][CH3:22])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
Add tert-butyl-dimethylsilylchloride (14 g, 90 mmol) to a solution of 4-nitroguaiacol (5 g, 30 mmol) in DMF (250 mL) and then add imidazole (6.13 g, 90 mmol). Stir the mixture at room temperature for 16 h. Quench the reaction mixture with water (150 mL). Extract with diethyl ether (3×200 mL). Wash the combined organic portions with water, brine, and dry over MgSO4. Filter and concentrate to a residue. Purify the residue by silica gel flash chromatography, eluting with 15% ethylacetate:hexanes to give the title compound (8.053 g, 95%) as a pale yellow oil. MS (ES+) 284.1 (M+1)+. 1H NMR (CDCl3): δ 7.79 (dd, J=7.8 Hz, 2.7 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 6.69 (d, J=7.8 Hz 1H), 3.85 (s, 3H), 0.96 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH2:19]=[O:20]>O1CCCC1.O>[OH:20][CH2:19][C:5]1([CH2:13][OH:16])[CH2:6][CH2:7][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]1=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCOc2ccccc21
Reactant: C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2OCCC1(CO)CO
Temperature: 40 °C
Reaction time: 48 h

Procedure:
To a solution of 3,4-dihydro-2H-benzo[b]oxepin-5-one (12.0 g; 74 mmol) in 215 ml of tetrahydrofuran were added, at room temperature, potassium carbonate (1.01 g) and formalin solution (44 ml; 36% solution in water). The reaction mixture was stirred at 40° C. for 2 days. The mixture was then diluted with 250 ml of water, and the phases were separated and extracted with ethyl acetate. The crude product was purified by column chromatography on silica gel (eluent: 1:1 hexane/ethyl acetate and ethyl acetate). This gave 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (colorless crystals; 13.1 g; 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=O)[CH3:16])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CCO>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=[N:19][OH:20])[CH3:16])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: NO
Reactant: COC(=O)C1(c2ccc(O)c(C(C)=O)c2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1(c2ccc(O)c(C(C)=NO)c2)CC1
Yield: 98.9 %

Procedure:
To a stirred solution of 1-(3-acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (14.6 g, 58.8 mmol) in EtOH (500 mL) were added hydroxylamine hydrochloride (9.00 g, 129 mmol) and sodium acetate (11.6 g, 141 mmol) at room temperature. The resulting mixture was heated at reflux overnight. After removal of EtOH under vacuum, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-[4-hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester (14.5 g, 98%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 11.09 (s, 1 H), 7.39 (d, J=2.0 Hz, 1 H), 7.23 (d, J=2.0 Hz, 1 H), 7.14 (s, 1 H), 6.91 (d, J=8.4 Hz, 1 H), 3.63 (s, 3 H), 2.36 (s, 3 H), 1.62-1.59 (m, 2 H), 1.18-1.15 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1.IC1C=C2C(=CC=1)C(=O)[NH:36]C(=O)C2=COC.NCC1C=CC(C2C=CC=CN=2)=C(O)C=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][N:36]=[CH:26][CH:25]=1)[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Agent: NCc1ccc(-c2ccccn2)c(O)c1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccncc2)c(O)c1
Yield: 40 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (50 mg, 0.15 mmol) and 5-Aminomethyl-2-pyridin-2-yl-phenol (40 mg, 0.20 mmol) in 40% yield: MS (ESI): 498.1 (M+1)+1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[CH3:27][C:23]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])=[CH:22][CH:21]=1)([CH3:26])[C:24]#[N:25]
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: Cc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2ncc([N+](=O)[O-])c(Nc3ccc(C(C)(C)C#N)cc3)c2c1
Reaction time: 2 h

Procedure:
4-Chloro-6-methyl-3-nitroquinoline (Compound of Preparation H, 660 mg, 2.97 mmol) and 2-(4-aminophenyl)-2-methylpropanenitrile (570 mg, 3.56 mmol) were dissolved in acetic acid (10 ml) and stirred for 2 hours. Water was added and the yellow precipitate was filtered off, washed with water, saturated aqueous NaHCO3 and water. The yellow solid was dried to obtain the title compound. Yield: 600 mg (58%); 1H NMR (DMSO-d6, 300 MHz): δ 9.952 (s, 1H,), 9.016 (s, 1H), 8.184 (s, 1H), 7.890-7.918 (d, 1H, J=8.4 Hz), 7.699-7.727 (d, 1H, J=8.4 Hz), 7.421-7.445 (d, 2H, J=7.2 Hz), 7.082-7.108 (d, 2H, J=7.8 Hz), 2.284 (s, 3H), 1.660 (s, 6H); MS: m/z 347 (M+).
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:22])([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:23]>O1CCCC1.O>[ClH:23].[NH2:14][C:15]([CH3:22])([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17]
Reactant: CC(C#N)(CC(F)F)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(N)(C#N)CC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.84 g (33.43 mmol; 92% purity) of rac-2-[(diphenylmethylene)amino]-4,4-difluoro-2-methylbutanonitrile from Example 70A were dissolved in 156 ml of tetrahydrofuran and 6 ml of water, 73.5 ml (36.77 mmol) of hydrogen chloride solution (0.5 N in diethyl ether) were added and the mixture was stirred at room temperature overnight. The reaction solution was admixed with 16.71 ml (33.43 mmol) of hydrogen chloride solution (2 N in diethyl ether) and concentrated by rotary evaporation. The isolated crude product was reacted further directly without further purification.
Reaction SMILES: O.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]=O.C([O:23][NH2:24])C1C=CC=CC=1.C(O)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[OH:23][N:24]([CH2:14][CH2:13][O:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)[C:35]([NH:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:36]
Reactant: O=CCOc1ccc2ccccc2c1
Reactant: O=C=Nc1ccccc1
Reactant: NOCc1ccccc1
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N(O)CCOc1ccc2ccccc2c1

Procedure:
A mixture of 2-naphthyloxyacetaldehyde hydrate (9.85 g), benzyloxyamine (5.94 g) and ethanol (100 ml) was stirred overnizght under nitrogen to precipitate 11.21 g of the protected oxime, m.pt. 68°-69.5° C. The oxime (10.1 g) in acetic acid (100 ml) was reduced with sodium cyanoborohydride, then the isolated O-benzyl hyroxylamine, without purification, was treated with phenyl isocyanate (1 equivalent) in toluene for 4 hours at 110° C. The product had m.pt. 75°-77° C. after chromatography over silica gel (elution with methylene chloride) and recrystallization from SVM. Hydrogenation of the last-mentioned O-benzylhydroxyurea over 5% palladium on charcoal in ethanol containing a few drops of acetic acid provided 1-Hydroxy-1-[2-(2-naphthyloxy)ethyl]-3-phenylurea, m.pt. 165°-167° C. (from ethanol).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:6][CH:5]([NH2:7])[CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:6][CH:5]([NH:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1CC(N)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1CC(NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a stirred solution of 3-methylcyclobutanamine hydrochloride (0.100 g, 0.8 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown solid (0.125 g, 93%). The material was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].Cl[Si](C)(C)C.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:26]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CCC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(NC(=O)c1ccccc1Cl)C(=O)O
Temperature: 25 °C
Yield: 81.4 %

Procedure:
This compound was prepared according to the procedures described in Int. J. Peptide Protein Res. 1989, 33, 353, and J. Chem. Soc., Chem. Commun. 1995, 2335. 2-Amino-butyric acid (3.87 g, 37.5 mmol) was suspended in 90 mL of dichloromethane, and treated with chloro-trimethyl-silane (9.6 mL, 75 mmol). The mixture was refluxed for 1 h and cooled in an ice bath. Diisopropylethylamine (11.3 mL, 65 mmol) and 2-chloro-benzoyl chloride (4.3 mL, 35.6 mmol) were added. The solution was stirred with cooling for 20 min and then warmed up to room temperature for 1.5 h. The mixture was concentrated and then distributed between ether and diluted NaHCO3 solution. The phases were separated. The aqueous layer was extracted with ether and the ether layer was back washed with water. The combined aqueous layers were acidified to pH 2 with 1N HCl and extracted with ethyl acetate three times. The combined ethyl acetate layers were dried over sodium sulfate, filtered and concentrated to give 2-(2-chloro-benzoylamino)-butyric acid as an off-white solid (7.0 g, 77% yield), which was used directly in the next step without further purification. LCMS calcd for C11H12ClNO3 (m/e) 241, obsd 242 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[C:10]=1[C:11](=[O:21])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)C1C=CC=CC=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>CC(C)=O.O>[OH:8][C:9]1[C:10]([C:11](=[O:21])[CH:12]=[CH:13][CH:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH2:19]2)=[C:22]([O:26][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(C=CC(=O)c2c(O)cccc2OCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(O)c1C(=O)C=CC1C=CC(C)=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2′-benzyloxy-6′-hydroxy-4-methylchalcone (0.69 g) in acetone (10 mL)-N,N-dimethylformamide (10 mL) were added potassium carbonate (0.41 g) and methyl bromoacetate (0.21 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (10 mL). To the solution was added 10% palladium-carbon powder (0.29 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. Dichloromethane was added to the mixture, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.58 g).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:21][CH:20]([CH3:22])[NH:19][CH:18]([CH3:23])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1.Cl([O-])(=O)(=O)=O.[Li+].[C:44]([O:48][CH2:49][CH3:50])(=[O:47])[CH:45]=[CH2:46]>>[ClH:36].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:17][CH:18]([CH3:23])[N:19]([CH2:46][CH2:45][C:44]([O:48][CH2:49][CH3:50])=[O:47])[CH:20]([CH3:22])[CH2:21]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=CC(=O)OCC
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CCOC(=O)CCN1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(C4CC4)c3c2OC)CC1C
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
150 mg of the compound from Example 39A are provided with 4 eq. of lithium perchlorate and ethyl acrylate in excess (approximately 400 μl) is added. The suspension is stirred at RT for 12 h and then purified directly via preparative HPLC (method 6). 79 mg (42% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[N:17]=1>CN(C=O)C.O>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:19][N:20]=3)[N:17]=2)=[N:5][CH:4]=[N:3]1
Reactant: Clc1ccc2nnc(-c3ccccc3)n2n1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1COc1ccc2nnc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-methyl-2 H-1,2,4-triazol-3-yl)methanol (0.9 g, 8.0 mmol) (prepared using the conditions described in EP-A-421210) in DMF (30 ml) was added sodium hydride (0.32 g of a 60% dispersion in oil, 1.6 mol eq.) and the reaction mixture was stirred at room temperature for 30 minutes. After this time the product from Example 88 Step a) (1.15 g, 5.0 mmol) was added as a solution in DMF (20 ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (200 ml) and the aqueous extracted with dichloromethane (4×150 ml). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using 4% MeOH in dichloromethane as eluent to give the required product, (1.5 g, mp=254° C.). 1H NMR (360 MHz, CDCl3) δ3.98 (3 H, s), 5.61 (2 H, s), 6.90 (1 H, d, J=9.8 Hz), 7.51-7.60 (3 H, m), 7.94(1 H, s), 8.12 (1 H, d, J=9.8 Hz), 8.39 (2 H, dd, J=9.6, 1.5 Hz); MS (ES+) m/e 308 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1)[CH3:2].F[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:15]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=2[CH:17]=[O:18])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: O=Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccc(F)cc2C=O)c1
Temperature: 120 °C
Yield: 22.3 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid ethyl ester (1.0 g, 5.2 mmol), 2,5-difluorobenzaldehyde (0.80 g, 5.2 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were combined in 1,4-dioxane (30 mL) and heated to 120° C. for 3 days. After work-up, the crude material was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the desired product (0.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([O:15]C(=O)C)[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:8]3=[O:28])=[CH:4][CH:3]=1.O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:8]3=[O:28])=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@H](O)CN12
Reaction time: 4 h
Yield: 47.4 %

Procedure:
To a solution of (5S,7S)-5-(4-bromobenzyl)-3-(3,5-dichloro-phenyl)-7-acetoxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.10 g) in THF (5 mL), MeOH (0.10 mL), and water (0.10 mL) was added 2N LIOH (0.11 mL). After 4 hours, the mixture was quenched with acetic acid (0.10 mL) and concentrated. Purification by chromatography (Silica gel: 4% methanol/CH2Cl2, Chromatotron) afforded the titled compound (0.0435 g). MS (m/z) 469 (MH+), mp 88.3° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:33])=[O:32])=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A 0° C. solution of Example 1E (0.1 g, 0.39 mmol) in dichloromethane (4 mL) was treated with pyridine (0.038 mL, 0.47 mmol) and benzenesulfonyl chloride (0.05 mL, 0.4 mmol), stirred at 0° C. for 1 hour, then stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated from dichloromethane/hexanes to provide 91 mg (59%) of the desired product. MS(ESI(+)) m/e 397 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H); 8.25 (s, 1H); 7.77 (m, 2H); 7.65-7.55 (m, 3H); 7.24 (m, 4H); 1.99 (s, 3H); Anal. Calcd. for C19H16N4O2S2.0.3C2H4O2: C, 57.37; H, 4.39; N, 13.25. Found: C, 57.22; H, 4.48; N, 13.32.
Reaction SMILES: C(O)(=O)C.C(O)=O.[C:8]([O:12][C:13]([N:15]1[CH:19]([CH2:20][O:21][C:22]2[C:26]3[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=3[O:24][N:23]=2)[CH2:18][O:17]C1(C)C)=[O:14])([CH3:11])([CH3:10])[CH3:9]>O>[C:8]([O:12][C:13]([NH:15][CH:19]([CH2:18][OH:17])[CH2:20][O:21][C:22]1[C:26]2[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=2[O:24][N:23]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C(COc2noc3ccc(Cl)cc23)COC1(C)C
Solvent: O=CO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a mixed solution of 19 ml of acetic acid and 19 ml of formic acid is added 3.84 g of 3-[(3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)methoxy]-5-chloro-1,2-benzoisoxazole at 20°-25° C., and they are subjected to reaction at the same temperature for one hour. Subsequently, the reaction mixture is poured into 190 ml of water and they are stirred at the same temperature for one hour. The crystals precipitated are collected by filtration, to obtain 2.78 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29].C(N(CC)CC)C>CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19](/[C:22](=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])/[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\NC(N)=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone (320 mg, 1 mmol) in methanol (30 mL) was added semicarbazide hydrochloride (334 mg, 3.0 mmol). Triethyl amine was added dropwise to the reaction mixture to adjust the pH to 5˜6. The reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration and dried over vacuum pump to afford 250 mg (yield: 66%) title compound as a white solid. 1H-NMR 400 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.85 (dd, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 7.98 (d, 1H), 7.94 (d, 1H), 7.77 (d, 1H), 7.66 (s, 1H), 7.47 (q, 1H), 6.73 (b, 2H), 4.56 (s, 2H), 2.23 (s, 3H). LCMS (method A): [MH]+=378, tR=4.64 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O(CC1C=CC=CC=1)[Na].[C:20]([O:26][CH2:27][C@H:28]([C:34]1[C:43]([CH3:44])=[CH:42][C:37]2[N:38]=[C:39](Cl)[S:40][C:36]=2[C:35]=1[Br:45])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>>[C:20]([O:26][CH2:27][C@H:28]([C:34]1[C:43]([CH3:44])=[CH:42][C:37]2[N:38]=[C:39]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[S:40][C:36]=2[C:35]=1[Br:45])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]OCc1ccccc1
Product: Cc1cc2nc(OCc3ccccc3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (415 mg, 10.38 mmol) was added to BnOH, stirred at rt for 0.5 h. The NaOBn solution was transferred to a flask charged with (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65I) (1.6 g, 3.46 mmol). The reaction mixture was heated at 60° C. for 45 min. The reaction mixture was washed by sat NaHCO3, extracted by EtOAc, the organic phase was washed by brine, dry over MgSO4, filtered, concentrated down, distilled most NaOH off. The residue was purified by silica gel column, eluting by 0-50% EtOAc in hexanes.