Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:16](=[O:22])[CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C)(=O)=O.[OH-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1([C:16](=[O:22])[C:17](=[N+:34]=[N-:35])[C:18](=[O:21])[CH2:19][CH3:20])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1
Reactant: CCC(=O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)C(=[N+]=[N-])C(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-methoxy-4-(1,3-dioxopent-1-yl)piperidine-1-carboxylate (0.227 g, 0.724 mmol) from Step C in dichloromethane (10 mL) was added triethylamine (0.101 mL, 0.724 mmol). Next, a solution of mesyl azide (0.087 g, 0.724 mmol) in dichloromethane (1 mL) was added. The reaction mixture was stirred for 3.5 h at room temperature. Additional mesyl azide (0.026 g, 0.217 mmol) was added. After 2 h, the reaction mixture was diluted with dichloromethane, poured into 1N sodium hydroxide solution, and extracted three times with dichloromethane. The organic layers were combined, washed with saturated sodium chloride, dried over sodium sulfite, filtered, and concentrated. The residue was purified by flash chromatography eluting with 5% ethyl acetate/dichloromethane to afford the title compound (0.174 g). MS/EI (acetonitrile/water): m/z 362 (M+Na) retention time=3.37 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:19])[C:12]([N+:16]([O-])=O)=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([NH2:16])=[C:11]([CH3:19])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1cc(OCc2ccccc2)cc(C)c1N
Yield: 90.5 %

Procedure:
Zinc dust is added to a solution of 5-benzyloxy-2-nitro-m-xylene (22.9g) in 250 ml of glacial acetic acid. The reaction mixture is stirred until the solution is colorless. The reaction mixture is cooled, filtered through Celite to remove excess zinc and the filtrate diluted with H2O and cooled with ice. NH3 is added to make the solution slightly alkaline followed by small amount of sodium hydrosulfite. The product is filtered, dissolved in methylene chloride, dried and concentrated to give 18.3 grams of a tan solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:33][CH2:34][CH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38].[C:42]([OH:45])(=[S:44])[CH3:43]>C1COCC1>[C:42]([S:44][CH2:33][CH2:34][CH:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38])(=[O:45])[CH3:43]
Reactant: CC(O)=S
Reactant: OCCC(CCO)CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCC(CCO)CCO
Temperature: 0 °C
Reaction time: 0.92 h
Yield: 37.7 %

Procedure:
To a solution of triphenylphosphine (1.77 g, 6.8 mmol) in anhydrous THF (15 mL) was added diethyl azodicarboxylate (2.2 M in toluene, 2.4 mL, 5.4 mmol) dropwise at 0° C. After stirred at 0° C. for 55 minutes, a solution of 3-(2-hydroxyethyl)pentane-1,5-diol (740 mg, 5 mmol) and thioacetic acid (335 μL, 4.5 mmol) in dry THF (7 mL) was added dropwise. After 1 hour the ice/water bath was removed and the reaction was stirred at room temperature for 16 hours. The solvents were removed by rotary evaporation in vacuo. The residue was purified by flash chromatography (CHCl3/MeOH, 20:1, 15:1, 10:1, 4:1) to give 3-(2-acetylthioethyl)pentane-1,5-diol as white solid (350 mg) and recovered starting material triol (406 mg). 1H NMR (400 Hz, CDCl3): δ 3.65-3.63 (m, 4H), 3.45 (bs, 2H), 2.84-2.80 (m, 2H), 2.28 (s, 3H), 1.73-1.67 (m, 1H), 1.55-1.49 (m, 6H). MS (ESI): m/z 229.0 (M+Na)+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([Cl:17])[CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1

Procedure:
5-Bromo-2-furoic acid (1 g, 4.8 mmol) was coupled to 3,5-dichloro-phenylboronic acid (833 g, 4.4 mmol) acid using Method F to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:22]([O-])=O)[CH:7]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:22][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Yield: 92 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate (8.53 g, 24.8 mmol) and Pd/C (10%, 0.85 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an oil (7.15 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 6.15 (s, 1H), 5.60 (br, 2H), 4.30 (q, 2H), 4.13 (t. 2H), 4.08 (t, 2H), 3.78 (t, 2H), 3.73 (t. 2H), 3.45 (s, 6H), 1.36 (t, 3H); LC-MS (ESI) m/z 314 (M+H)+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25].O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:26]1([CH:24]([C:23]2[C:3]3[C:4](=[O:22])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:35][N:34]=2)[CH3:25])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C(=O)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O)c1ccccc1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1cccc(C(F)(F)F)c1)c1ncccc21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-phenylpropionyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (119 mg, 0.27 mmol) produced in Synthesis Example 38 in DMF (1 mL) was added hydrazine monohydrate (purity of 80%, 43 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution, and an oily substance was collected. To the oily substance was added isopropyl ether, and the mixture was heated. Then the resulting matter was allowed to stand to a room temperature for crystallization. The resulting crystal was separated by filtration and dried to give 3-(1-phenylethyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (69 mg, yield 59%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1([CH:20]([CH3:24])[C:21](O)=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(Cl)Cl>[F:7][C:8]1([CH:20]([CH3:24])[C:21]([Cl:4])=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)C1(F)CC=CC=C1c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)C1(F)CC=CC=C1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.8 g, 30 mmol) was combined with methylene chloride (30 mL). The resulting mixture was cooled to 0° C. and dimethylformamide (10 drops) was added. After 5 minutes of stirring a solution of 2-fluoro-α-methyl-biphenylacetic acid (3.0 g, 12 mmol) in methylene chloride (30 mL) was added dropwise over a 30 minute period. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated to give the product in a quantitative yield as a yellow solid. 1H NMR (CDCl3) δ: 1.58 (d, 3H), 4.20 (q, 1H), 7.11 (t, 2H), 7.33-7.47 (m, 4H), 7.54 (d, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:30]>O1CCCC1.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)[CH2:15][O:16][CH3:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
A mixture of 4-[2-Hydroxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.53 mmol) in tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 70 mg, 1.75 mmol) followed by iodomethane (230 mg, 1.62 mmole). The mixture was stirred at 0° C. for three hours. The reaction was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate. Filtration, concentration gave a crude oil which was loaded onto a column of silica gel. Elution with 50% ethyl acetate/hexanes gave 4-[2-Methoxy-1-(3-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (190 mg, 92% yield) as a colorless oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][N:22]=4)[CH:18]=3)[N:13]([CH3:34])[C:12](=[O:35])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH2:36](Cl)[Cl:37].[K]>COCCOC.O.CC(O)C>[Cl:37][CH2:36][C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:34])[C:12](=[O:35])[CH:11]=[C:10]2[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=1)([C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:21]1[N:25]([CH3:26])[CH:24]=[N:23][N:22]=1
Reactant: ClCCl
Reactant: Cn1cnnc1C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: N#N
Agent: [K]
Solvent: O
Solvent: CC(C)O
Solvent: COCCOC
Product: Cn1cnnc1C(CCl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 1 h
Yield: 51 %

Procedure:
N2 was bubbled at room temperature to a solution of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone (0.00105 mol), obtained in Example B7, in DME (8.5 ml) for 30 minutes. DCM (2 ml) was added. Then 2-methyl, 2-propanol, potassium salt (0.0021 mol) was added portionwise. The mixture was stirred for 1 hour, poured out into water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue (0.55 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100 to 95/5; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.35 g, 64%) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.28 g (51%) of 6-[2-chloro-1-(4-chlorophenyl)-1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, mp. 260° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Temperature: 5 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of 30 g (105.58 mmol) of [5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl]-methanol in 210 mL of dichloromethane is added 41.96 g (158 mmol) of triphenylphosphine. The resulting mixture is cooled in an ice bath (about 0-10° C.) and added in portions to carbon tetrabromide (53 g, 158.37 mmol). The reaction is stirred at room temperature for 2 h. The solvent is evaporated to obtain an orange oil which is purified on silica gel column chromatography using Hexanes to hex/EtOAc 8:2 as eluent, to obtain 33 g of the title compound as a white solid (90%). MS (m/e): 346 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Product: O=C(C=Cc1cccc(Cl)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 3-chlorobenzaldehyde and acetophenone, 3-(3-chlorophenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[OH:11][NH:12][C:13](=[NH:23])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:23]=[CH:1][O:11][N:12]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: CCOC(OCC)OCC
Reactant: N=C(NO)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ncon2)cc1
Temperature: 0 °C
Yield: 51.5 %

Procedure:
Triethyl orthoformate (2.93 g, 19.8 mmol) was added to a stirred solution of N-hydroxy-4-nitro-benzamidine (1.2 g, 6.6 mmol) in THF (15 mL). The mixture was cooled to 0° C. and boron triflouride dimethyl ether (900 mg, 7.9 mmol) was added drop wise. The mixture was maintained at room temperature for three hours. The volatiles were evaporated and the residue was washed with ether and dried to afford 650 mg (55%) of 3-(4-nitro-phenyl)-[1,2,4]oxadiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:8][C:6]1[CH:7]=[C:2]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH:3]=[C:4]([F:22])[C:5]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: OB(O)c1ccncc1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1c(F)cc(-c2ccncc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2,6-difluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and pyridine-4-boronic acid. MS (FIA) 372 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([OH:8])=O.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][C:6]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:8]
Reactant: C1COCCN1
Reactant: COC(=O)[C@@H](CC(=O)O)CC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CC(=O)N1CCOCC1)CC1CCCCC1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 96.7 %

Procedure:
(R)-2-(Cyclohexylmethyl) succinic acid 1-methyl ester (1.00 g, 4.38 mmol) was dissolved in 10 mL of DMF and cooled to 0° C. with an ice-water bath. EDC (1.12 g, 5.69 mmol) then 1-hydroxybenzotriazole (0.77 g, 5.69 mmol) were added and stirring continued, under argon, for 25 min. Morpholine (0.76 mL, 8.76 mmol) was added and stirring was continued overnight (16 h). The solution was diluted with 200 mL of EtOAc and washed with a 1.0 M solution of HCl (3×100 mL), a saturated solution of NaHCO3 (3×100 mL), water (100 mL), then with brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated by rotary evaporation to give (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid 1-methyl ester (1.26 g, 99%) as a white solid. The product was used in the following step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:18](OC)=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[N:16]([CH:18]=[O:19])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2NCCNC2=O)cc1OC
Reactant: COC=O
Product: COc1ccc(C2C(=O)NCCN2C=O)cc1OC

Procedure:
23.6 g (0.1 mol) of 3-(3,4-dimethoxyphenyl)-piperazin-2-one, prepared in accordance with Example 1, are heated at 110° C. with 150 ml of methyl formate for 3 hours in an autoclave. The residue remaining after the mixture has been concentrated in vacuo is triturated with ether, filtered off with suction and dried.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](=[O:10])[NH:2]1.C(N(CC)CC)C.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(#N)C>[N:18]1([C:24]([N:2]2[C:3](=[O:10])[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[S:1]2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=c1[nH]sc2ncccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N1CCOCC1)n1sc2ncccc2c1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a suspension of isothiazolo[5,4-b]pyridin-3-one (5.0 g, 32.86 mmol) in acetonitrile (180 ml) was added dropwise triethylamine (14 ml, 99 mmol) and afterwards 4-morpholinecarbonyl chloride (3.8 ml, 32.9 mmol) at room temperature. The reaction mixture was stirred for 3 h at 60° C. The solvent was removed under reduced pressure. To the crude oil was added water (50 ml) and ethyl acetate (50 ml), the phases separated and the aqueous phase extracted with ethyl acetate. The organic layers were combined, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by high performance liquid chromatography (RP silica gel, acetonitrile/water/trifluoroacetic acid) and lyophilization of the product fractions provided 5.0 g (57%) of the title compound as a white powder.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1COCC1>[CH3:12][O:11][C:1](=[O:10])[CH:2]([O:3][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1)=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(OC(=O)Nc1ccc(Cl)cc1)c1ccccc1
Yield: 93.9 %

Procedure:
To a solution of methyl mandelate (0.83 g) and triethylamine (0.51 g) in THF (40 ml) was added 4-chlorophenyl isocyanate (0.77 g). The reaction mixture was mixed at 60° C. for 3 hours, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with silica gel column (ethyl acetate/hexane=1/6 to 1/3) to obtain the title compound as a pale brown crystal (1.5 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[C:4]2=[O:8])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirred suspension of 4-methyl-3-nitro-2-pyridone (2.0 g, 13 mmol) in DMF (60 mL) was added NaH (60% suspension in oil, 0.52 g). After 1 hour, 4-methoxybenzyl chloride (1.8 mL) was added, and the mixture was stirred at rt overnight. Ethyl acetate was added, and the organic phase was washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane) gave 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (2.0 g, 7.3 mmol, 56%).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[OH:14]N1C2C=CC=CC=2N=N1.[CH:24]1([N:30]=[C:31]=[N:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:31]([NH:30][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)([NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:14]
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
[3S-[3α(Z),4β]]-3-[[(2-Amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-4-methyl-2-oxo-1-azetidinesulfonic acid (2.18 g), 0.93 g of tributylamine, 0.1 g of N-hydroxybenzotriazole and 0.05 g of 4-dimethylaminopyridine were dissolved in 20 ml of dimethylformamide and a solution of 1.06 g of dicyclohexylcarbodiimide in 5 ml of dimethylformamide was added. After stirring for 15 minutes at room temperature, a solution of 0.94 g Girard Reagent P in 20 ml of dimethylformamide was added. After 3 hours of stirring, formed dicyclohexylurea was filtered off and the dimethylformamide of the filtrate was distilled off. Addition of 50 ml of tetrahydrofuran to the residue yielded 1.8 g of crude product, which was purified by column chromatography on HP-20 using water as an eluent, yielding 0.63 g of product, melting point 235° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12]Br>CCCCCC>[Br:12][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: CCCCCC
Product: O=[N+]([O-])c1cc(CBr)ccc1F
Temperature: 50 °C

Procedure:
To a stirred melt of 1-fluoro-4-methyl-2-nitro-benzene (10 g) at 150° C. under a sunlamp was slowly added 3.65 ml of bromine over a 5 hr period. Cooled the brown mixture to 50° C. and poured into 125 ml of hexane. Cooled in an ice bath, filtered, and obtained 10.1 g of 4-bromomethyl-1-fluoro-2-nitro-benzene as white crystals. ##STR146##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][CH2:10][N:9]2[C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc(C2CCN2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
To a mixture of 2-(4-bromophenyl)azetidine (200 mg, 0.808 mmol) and triethylamine (98 mg, 0.97 mmol) in anhydrous dichloromethane (6 mL) was added acetic anhydride (200 mg, 0.97 mmol). The mixture was stirred at rt for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (100 mg, 49% yield) as a yellow oil that was taken on without further purification.