Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([F:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl.[N:13]([O-])=O.[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24]>O.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[C:22]([N:13]=[N:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([F:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)[CH:21]=[CH:20][C:19]=1[OH:24]
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: Oc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(F)c1ccc(N=Nc2ccc(O)c(Cl)c2)cc1
Reaction time: 0.08 h

Procedure:
Sulfanilyl fluoride (17.5 g, 0.1 mole) was dissolved in 75 ml warn saturated methanolic HCl, and the resulting solution was cooled in a methanol-ice bath. Sodium nitrite (7.0 g, 0.1 mole), dissolved in 25 ml water was then added dropwise, and the solution stirred 5 minutes more. The diazonium salt solution was then added dropwise to a cold (cooled in an ice bath) solution of o-chlorophenol (12.8 g, 0.099 mole) dissolved in 150 ml pyridine. The reaction mixture was stirred an additional 15 minutes and then poured over ice and hydrochloric acid. The resulting precipitate was filtered off, washed with water, and air dried. The yield was 20.0 g (64%), m.p. 133°-134° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:18])[C:12]2[O:13][C:14]([CH3:17])=[CH:15][N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[O:13][C:14]([CH3:17])=[CH:15][N:16]=2)=[CH:2]1
Reactant: Cc1cnc([C@H](N)Cc2c[nH]c3ccccc23)o1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cnc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (R)-2-(1H-indol-3-yl)-1-(5-methyloxazol-2-yl)ethylamine (240 mg, 1.0 mmol) and 4-dimethylamino-4-phenylcyclohexanone (218 mg, 1.0 mmol) in 1,2-dichloroethane (15 mL) was mixed with powdered sodium triacetoxyboron hydride (317 mg, 1.5 mmol) and acetic acid (120 mg, 2.0 mmol) and stirred for 18 h at room temperature. The mixture was then diluted with ethyl acetate (80 mL), washed with sodium hydrogencarbonate solution (20 mL) and dried with sodium sulphate. The solvent was removed in a vacuum and the residue purified by flash chromatography (15 g, 12×2.5 cm) with methanol/dichloromethane (1:4).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl[C:10]1[CH:11]=[C:12](C)[CH:13]=[CH:14][C:15]=1[S:16]([Cl:19])(=[O:18])=[O:17].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:39]([Cl:43])(Cl)(Cl)Cl>>[Cl:43][C:39]1[CH:10]=[C:15]([S:16]([Cl:19])(=[O:18])=[O:17])[CH:14]=[CH:13][C:12]=1[CH2:11][Br:1]
Reactant: Cc1ccc(S(=O)(=O)Cl)c(Cl)c1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=S(=O)(Cl)c1ccc(CBr)c(Cl)c1
Yield: 14 %

Procedure:
N-Bromosuccinimide (13.76 g, 76 mmol) was added to a stirred solution of 3-chloro-4-toluenesulphonyl chloride (12 g, 76 mmol) in CCl4 (120 ml) under argon. After one hour benzoyl peroxide (0.92 g, 3.8 mmol) was added and the reaction mixture refluxed overnight. The mixture was allowed to cool, the resulting white precipitate filtered off and the filtrate evaporated to a yellow oil. Purification of the residue by chromatography over silica gel (3% ethyl acetate in hexane) afforded 3-chloro-4-bromomethylphenylsulphonyl chloride (3.3 g, 14 %) as a colourless ol.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[OH-].[Na+].O1CCCC1>O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCCCC2)cc1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCNS(=O)(=O)c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
7.8 g of 4-piperidinylbenzenesulphonyl chloride are added to a solution comprising 3.51 g of 5-aminovaleric acid and 3.6 g of sodium hydroxide dissolved in 35 cm3 of water, followed by the addition of 35 cm3 of tetrahydrofuran in order to obtain a solution. The temperature rises to 35° C. The mixture is kept stirring for 4 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid, diluted with 100 cm3 of water and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 5.8 g of expected product are obtained. M.p. 115°-120° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 120°-122° C., is obtained.
Reaction SMILES: C(O[C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23]CO2)=[C:8]([NH2:27])[N:7]=1)CCC.F[C:29](F)(F)[C:30]([OH:32])=O.[CH2:35]([NH:39]C1N=C2C(N=C(OC)N2)=C(N)N=1)[CH2:36][CH2:37][CH3:38].BrCCCBr.O1CCC(CN)CC1>>[CH2:35]([NH:39][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25][CH3:26])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:20]2[CH2:24][CH2:23][O:32][CH2:30][CH2:29]2)=[C:8]([NH2:27])[N:7]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCO3)c2n1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: BrCCCBr
Agent: NCC1CCOCC1
Product: CCCCNc1nc(N)c2nc(OC)n(CCCNCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 15 from N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt, 1,3-dibromopropane, and (tetrahydro-2H-pyran-4-ylmethyl)amine.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:5])[NH2:4].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br>CN(C=O)C>[CH:8](=[N:7][NH:6][C:3]([NH:4][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15])=[NH:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH3:4]
Reactant: N=C(N)NN=Cc1ccccc1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CNC(=N)NN=Cc1ccccc1)OC
Product: N
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2.88 g (0.06 mol) of sodium hydride dispersion (approximately 50% in oil; Fluka, Buchs, Switzerland) are added in portions over a period of 10 minutes, with stirring and with the introduction of nitrogen, to a solution of 8.1 g (0.05 mol) of benzaldehyde guanylhydrazone in 80 ml of DMF. After 25 minutes stirring at room temperature, 7.1 ml (0.06 mol) of bromoacetaldehyde dimethylacetal (Aldrich, Buchs, Switzerland; 97%, Cat. no. 24,250-0) are added dropwise to the mixture, which has been cooled in an ice-bath. The reaction mixture is stirred for one hour at room temperature and for 20 hours at 55° C., and then concentration by evaporation is carried out in vacuo and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water and brine and is concentrated by evaporation, and the oily residue is purified by flash chromatography on silica gel having a particle size of 0.04-0.063 mm, using ethyl acetate and ethyl acetate/methanol (9:1). Concentration of the product-containing fractions by evaporation yields the title compound in the form of an oil, Rf value=0.80 (silica gel/methylene chloride:methanol:conc. ammonia (40:10:1)), 1H-NMR (DMSO): δ=8.07 (s, 1H); 7.67-7.73 (m, 2H); 7.23-7.40 (m, 3H); 5.93 (bs, 3H); 4.48 (t, 1H); 3.32 (s, 6H); 3.29 (d, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17](=[O:20])([O-])[O-].[Na+].[Na+].O.O.[CH:25](O)([CH3:27])[CH3:26]>CN(C)C=O.BrCCCBr>[Br:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:26][CH2:25][CH2:27][N:9]3[CH2:10][CH2:11][N:12]([C:17](=[O:20])[C:6]4[CH:15]=[CH:16][C:3]([Br:2])=[CH:4][CH:5]=4)[CH2:13][CH2:14]3)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(Br)cc1)N1CCNCC1
Reactant: CC(C)O
Agent: BrCCCBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1)N1CCN(CCCN2CCN(C(=O)c3ccc(Br)cc3)CC2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a suspension of 66.7 g (0.218 mmol) of the 1-(4-bromobenzoyl)piperazine hydrochloride prepared in Preparation Example 1 in dimethylformamide (223 mL) were added 11.3 mL (98% purity, 0.109 mmol) of 1,3-dibromopropane and 33.5 g (0.316 mmol) of sodium carbonate. The mixture was stirred for 6 hours at 80° C. Water (670 mL) was added to the reaction mixture with stirring at 80° C. and the mixture was stirred for 0.5 hour at the same temperature and for 1.5 hours at 20° C. The precipitates were collected by filtration and washed with water (3×45 mL) to obtain crude crystals. A suspension of the crude crystals in water-isopropanol (7:3, 570 mL) was stirred for 2 hours at 85° C., for 0.5 hour at room temperature, and for 1 hour at 0° C. Precipitated crystals were collected by filtration and washed with water-isopropanol (5:1, 2×110 mL), whereby 60.0 g of 1,3-bis[4-(4-bromobenzoyl)-1-piperazinyl]propane was obtained as colorless fine needles (yield 95%).mp: 170.0 to 173.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([OH:25])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][OH:30]>>[CH2:1]([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([N:27]([CH2:28][CH2:29][OH:30])[CH3:26])=[O:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCn1c(C)nc2cc(C(=O)O)cc(OCc3ccccc3)c21
Reactant: CNCCO
Product: COCCn1c(C)nc2cc(C(=O)N(C)CCO)cc(OCc3ccccc3)c21
Yield: 99 %

Procedure:
The title compound was prepared as a white amorphous in 99% yield from 7-(benzyloxy)-1-(2-methoxyethyl)-2-methyl-1H-benzimidazole-5-carboxylic acid (5.00 g, 14.7 mmol, Step 5 of Example 1) and 2-(methylamino)ethanol (1.21 g, 16.2 mmol) by the same manner in Step 13 of Example 1.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.[K+].[C:18]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:19]C([O-])=O.C(N(CC)CC)C.[Mg+2].[Cl-].[Cl-]>C(#N)C>[CH3:5][O:6][C:7]1[C:8]([CH3:16])=[C:9]([C:10](=[O:12])[CH2:19][C:18]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1cccc(C(=O)O)c1C
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1cccc(OC)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Thionyl chloride (118 mL) was added to 3-methoxy-2-methyl benzoic acid (98.8 g, 595 mmol) and heated to reflux. After 2 hr, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was azeotroped with toluene (2×300 mL) and the resultant solid set aside. A suspension of ethyl malonate potassium salt (208 g, 1.22 mol) in acetonitrile (1.50 L) cooled to 5° C., triethylamine (166 mL, 1.49 mol) were added followed by MgCl2 (142 g, 1.49 mol). The cooling bath was removed and the mixture stirred for 3.5 hr at ambient temperature. The mixture was re-cooled to 5° C. and a solution of the aforementioned acid chloride in acetonitrile (100 mL) was added over 10 min. The mixture was warmed to ambient temperature, stirred for 15 hr, concentrated in vacuo and azeotroped with toluene (2×mL). The residue was suspended in EtOAc (750 mL) and toluene (750 mL), cooled in an ice bath and 4 N HCl (750 mL) was added slowly. The cooling bath was removed and the biphasic mixture was stirred vigorously for 30 min. The layers were separated, and the organic layer was washed with sat NaHCO3 (2×1.0 L) and dried over MgSO4. The mixture was filtered, concentrated in vacuo, and purified by flash chromatography (5, 10% EtOAc/heptane) on SiO2 to afford 138 g of the title compound as a pale yellow liquid: 1H NMR (500 MHz, CDCl3) indicated a mixture of keto ester and enol in a 2.5 1 ratio. For keto ester: δ 1.23 (t, 3H, J=7.2 Hz), 2.34 (s, 3H), 3.85 (s, 3H), 3.89 (s, 2H), 4.17 (q, 2H, J=7.1 Hz), 6.97 (d, 1H, J=7.8 Hz), 7.14 (d, 1H, J=8.7 Hz), 7.22 (d, 1H, J=7.9 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[CH:1]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:13][CH2:14][CH3:15])[CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC(CO)CCCc1ccccc1
Reactant: [H][H]
Product: CCCC(CO)CCCC1CCCCC1
Reaction time: 6 h
Yield: 91.8 %

Procedure:
365 g of 5-Phenyl-2-n-propyl-pentanol of Synthesis Example 1.2 were combined with 10 g Ru on activated carbon (Ru content: 5 wt. %) and hydrogenated at a hydrogen pressure of 20 bar and at a temperature of 120° C. After 5-7 hours the reaction was finished. The catalyst was removed and the product distilled. 345 g (content: 98.2%) of 5-cyclohexyl-2-n-propyl-pentanol are obtained. Yield: 90.8% of theoretical.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:24])[CH2:21][NH:22][CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][CH2:34]Br)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:24])[CH2:21][N:22]([CH2:34][CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCNC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.2 %

Procedure:
500 mg (1.42 mmol) of sarcosine benzyl ester p-toluenesulfonate, 478 mg (2.13 mmol) of 2-(tert-butoxycarbonylamino)-ethyl bromide, and 0.25 mL (2.13 mmol) of diisopropyl-ethylamine were dissolved in methylene chloride (10 mL), and then stirred at room temperature for approximately three days. After completion of the reaction, the reaction solution was concentrated and the residue obtained was purified by silica gel column chromatography (ethyl acetate) to yield 175 mg (38%) of {[2-(tert-butoxycarbonylamino)-ethyl]-methyl-amino}-acetic acid benzyl ester as a colorless viscous oil.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH2:29]([O:31][C:32](=[O:42])[C@H:33]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH2:34])[CH3:30].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C.C(O)(=O)C1C=CC=CC=1>CN(C=O)C.C(P(=O)(OCC)OCC)#N>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][O:18][C:19]4[CH:27]=[CH:26][C:22]([C:23]([NH:34][C@H:33]([C:32]([O:31][CH2:29][CH3:30])=[O:42])[CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:24])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc3ccc(COc4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 64.7 %

Procedure:
To a stirred suspension of 4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoic acid (0.19 g, 0.53 mmol) and L-glutamic acid diethyl ester hydrochloride (0.14 g, 0.58 mmol) (Aldrich) in DMF (3 ml) were added diethyl cyanophosphonate (0.09 ml, 0.6 mmol) DMF (3 ml) were added diethyl cyanophosphonate (0.09 ml, 0.6 mmol) (Aldrich) and triethylamine (0.15 ml, 1.1 mmol). Additional DMF (7 ml) was added but homogeneous solution was not obtained. The reaction mixture was stirred 45 minutes at room temperature and TLC analysis indicated remaining benzoic acid. Diethyl cyanophosphonate (2 drops) was added, the mixture stirred 45 minutes, and was then concentrated in vacuo. The residue was purified by chromatography on silica gel (50 g) eluting with ethanol:methylene chloride (1:9). The solid was filtered from a small volume of ethanol and dried under reduced pressure to give diethyl N-(4-((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methoxy)benzoyl)-L-glutamate (0.187 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.16 (t, J=7 Hz, 3H, ester CH3), 1.18 (t, J=7 Hz, 3H, ester CH3), 1.90-2.18 (m, 2H, glu CH2), 2.43 (t, J=7 Hz, 2H, glu CH2), 2.44 (s, 3H, C3 --CH3), 4.05 (q, J=7 Hz, 2H, ester CH2), 4.10 (q, J=6 Hz, 2H, ester CH2), 4.36-4.46 (m, 1H, glu CH), 5.43 (s, 2H, CH2O), 7.17 (d, J=9 Hz, 2H, Ar), 7.65 (d, J=9 Hz, 1H, Ar), 7.74 (dd, J=8,2 Hz, 1H, Ar), 7.88 (d, J=9 Hz, 2H, Ar), 8.08 (d, J=8 Hz, 1H, Ar), 8.26 (d, J=9 Hz, 1H, Ar), 8.58 (d, J=7 Hz, 1H, glu NH), 9.94 (s, 1H, Ar), 12.59 (s, 1H, N2H). Anal. Calculated for C30H31N3O7.1/4H2O: C, 65.50; H, 5.77; N, 7.64. Found: C, 65.54; H, 5.77; N, 7.61.
Reaction SMILES: ClCCl.ClC(Cl)(Cl)[C:6]([N:8]=C=O)=[O:7].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1/[C:18](=[N:36]/[O:37][CH3:38])/[C:19]([NH:21][C@@H:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH2:29][OH:30])[CH2:27][S:28][C@H:23]12)=[O:20].C(C(CCCC)C([O-])=O)C.[Na+:49]>C1COCC1.C(O)CO>[CH3:38][O:37]/[N:36]=[C:18](\[C:19]([NH:21][C@@H:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([O-:33])=[O:32])=[C:26]([CH2:29][O:30][C:6]([NH2:8])=[O:7])[CH2:27][S:28][C@H:23]12)=[O:20])/[C:14]1[O:13][CH:17]=[CH:16][CH:15]=1.[Na+:49]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h

Procedure:
A mixture of THF (60 ml), dichloromethane (25 ml), and trichloroacetyl isocyanate (6.2 ml) was protected from moisture and cooled to -10°.To the stirred mixture was added (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (10 g) in one charge followed by THF (20 ml). The temperature was controlled in the range 0° to +5° and the mixture stirred for 10 minutes. Ethane-1,2-diol (15 ml) was added followedby a solution of sodium 2-ethylhexanoate (10 g) in THF (20 ml) to raise thepH to 7.3. The mixture was warmed to 25° and left undisturbed for 1 hour. The mixture was then stirred briefly and left undisturbed for a further hour. The crystalline material which had separated from the mixture was collected by filtration, washed with THF (2×50 ml), and dried in vacuo at 35° to yield sodium cefuroxime (10.76 g) THF solvate. The isolated product was shown by G.L.C. to contain 8.8% w/w of THF and 0.56% w/w of ethane-1,2-diol.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C.[Cl:39][CH2:40][C:41](Cl)=[O:42]>C(Cl)Cl>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:41](=[O:42])[CH2:40][Cl:39])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Temperature: 4 °C
Reaction time: 25 h
Yield: 95.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (1.1 g, 2.5 mmol; prepared as described in Example 31-starting materials) was dissolved in a mixture methylene chloride (20 ml) and diisopropylethylamine (1.0 ml) under a nitrogen atmosphere. The solution was cooled in an ice/water bath to 4° C. and chloroacetyl chloride (0.2 ml, 2.63 mmole) was added. The reaction mixture was stirred cold for two 25 hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (1.14 g, 94.9%); Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)(=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 8.5 g of 4-hydroxybenzophenone in 75 ml of dry pyridine 6.75 ml of isobutyric chloride was added at 0°~10° C. The reaction mixture was allowed to stand at 25° C. for 2 h, poured into ice water. The precipitate was collected by suction and recrystallized from ethanol; M.P.~69°-69.5° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13](C)[C:14]#[N:15])[C:8](=[O:17])[C:7](=[O:18])[NH:6]2.[N-]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].O.[CH3:28][N:29](C)C=O>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[N:23]=[N:22][CH:28]=[N:29]1)[C:8](=[O:17])[C:7](=[O:18])[NH:6]2
Reactant: CN(C)C=O
Reactant: CC(C#N)n1c(=O)c(=O)[nH]c2cc(C(F)(F)F)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(CCn2ncnn2)c1=O
Temperature: 120 °C
Yield: 37.8 %

Procedure:
345 mg (1.2 mmol) of 3-[(6-trifluoromethylquinoxaline-2,3-dion-1-yl)propionitrile is heated together with 407 mg (6.3 mmol) of sodium azide and 333 mg (6.3 mmol) of ammonium chloride in 13 ml of dimethylformamide for 3 hours to 120° C. bath temperature. After adding once more 203 mg (3.2 mmol) of sodium azide and 160 mg (3.1 mmol) of ammonium chloride, it is heated for 5 hours more to 120° C. bath temperature. After dilution with water and adjusting the pH to 2, it is extracted with ethyl acetate. During the shaking out with saturated common salt solution, the desired compound is precipitated from the organic phase. By concentration by evaporation of the organic phase and absorptive precipitation in ethyl acetate, another fraction is obtained. Altogether, 150 mg (37.8% of theory) of 2-[(6 trifluoromethylquinoxaline-2,3-dion-1-yl)ethyl]-tetrazole of melting point 279.8° C. is obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.O>[CH3:21][S:22]([O:1][CH:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1CSCCC1O
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CSCCC1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 4-hydroxytetrahydro-2H-thiopyran-3-carboxylate (3.00 g, 17.0 mmol) in DCM (170 mL) was stirred at 0° C. DIPEA (5.95 mL, 34.0 mmol) was added followed by the dropwise addition of methanesulfonyl chloride (1.95 g, 17.0 mmol). The resulting mixture was stirred at 0° C. for 30 minutes then warmed to ambient temperature and stirred for an additional 30 minutes. The mixture was carefully diluted with water and extracted with DCM (2×). The combined organic extracts were washed with 1N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.