Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:7]1=[O:23])[NH2:5].[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:7]1=[O:23])[NH:5][C:38](=[O:39])[C@H:36]([CH3:37])[NH:35][C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)C(N)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 50 h

Procedure:
In 20 ml of dimethylformamide were dissolved 1 g of 2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl] glycine methyl ester and 1.5 g of N-hydroxysuccinimide ester of benzyloxycarbonyl-L-alanine, and the solution was stirred at room temperature for 50 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium hydrogen carbonate, and dried over sodium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to give benzyloxycarbonyl-L-alanyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl] glycine methyl ester as a white powder. This powder was dissolved in a mixture of 50 ml of methanol and 10 ml of acetic acid and stirred with 500 ml of palladium black in a stream of hydrogen at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dried in a desiccator overnight and dissolved in 50 ml of methanol. With adjusting pH to 9-10 with 1 N sodium hydroxide, the solution was stirred at room temperature for 3 hours. This reaction mixture was adjusted to pH 5 and concentrated under reduced pressure. The residue was dried in a desiccator overnight, dissolved in 10 ml of a 30% solution of hydrogen bromide in acetic acid, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and adjusted to pH 4 with saturated sodium hydrogen carbonate. It was chromatographed on a column (200 ml) of MCI gel CHP-20P, and water to 50% aqueous methanol-water gradient elution was carried out. The eluate was concentrated under reduced pressure and lyophilized to give L-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH2:13][O:14]C(C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][OH:14])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CCOC(C)=O
Product: CC(=O)c1cc(Br)ccc1OCCO

Procedure:
The product was prepared analogously to Example 1.1a starting from 1-(5-bromo-2-hydroxyphenyl)ethanone. Yield: 7.30 g (30% of theoretical); C10H11BrO3 (M=259.097); calc.: molpeak (M+H)+: 259/261 (Br); found: molpeak (M+H)+: 259/261 (Br); Rf value: 0.25 (silica gel, PE/EtOAc 1:1).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:26]=2[NH:25][CH:24]=[CH:23]3)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:17])[CH:23]=[CH:24]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3cc[nH]c23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 2-[(1H-indole-7-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (57) (220 mg, 0.63 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (58) as an off white solid (186 mg, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:39])[CH2:37][CH3:38]
Reactant: COc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)c1
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cccc(OC)c2)cc1
Yield: 90.3 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methoxyphenyl)benzamide (238.0 mg, 0.50 mmol) and propionyl chloride (0.077 ml, 0.60 mmol), the procedure of Inventive Example 94 was repeated to obtain 240.0 mg (90.4%) of the title compound in a yellow amorphous form.
Reaction SMILES: [Mg].C(Br)C.[CH3:5][C:6]1[CH2:7][CH:8]2[CH:12]([CH2:13][CH:14]=1)[C:11](=O)[O:10][C:9]2=[O:16].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C1COCC1>[CH3:5][C:6]1[CH2:7][CH:8]2[CH:12]([CH2:11][O:10][C:9]2=[O:16])[CH2:13][CH:14]=1
Reactant: CC1=CCC2C(=O)OC(=O)C2C1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCBr
Product: CC1=CCC2COC(=O)C2C1
Temperature: 25 °C

Procedure:
A 5-L round bottom reaction flask was charged with magnesium metal (Mg) (140 g) and THF (1 L) under nitrogen. Ethyl bromide (EtBr) (630 g) was fed into the reaction mixture dropwise while the temperature was maintained at 25° C. or below using a dry ice bath. After the feeding was completed, the reaction mixture was aged at room temperature for half an hour. Crude 5-methyl-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione (1.7 L, ˜56% of the mass of the resulting mixture obtained in EXAMPLE I) was then added dropwise while the temperature was maintained at 25° C. using a dry ice bath. The reaction mixture was consequently further aged at room temperature for another hour. The reaction mixture was poured into sulfuric acid (H2SO4) (10%) containing ice. Toluene was added. The organic and aqueous layers were shaken in a separatory funnel and separated. The aqueous layer was further washed with toluene. The organic layers were combined and washed with sodium carbonate (Na2CO3) solution until basic. The resulting solution was then distilled to afford 3,3-diethyl-5 or 6-methyl-3a,4,7,7a-tetrahydro-3H-isobenzofuran-1-one (457 g).
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=1[F:43].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=2[F:43])[CH2:26]1)#[N:29]
Reactant: COC(=O)c1ccc(Br)c(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)c(F)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 104.8 %

Procedure:
2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.11 g, 0.18 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.86 g, 1.8 mmol), methyl 4-bromo-3-fluorobenzoate (0.50 g, 2.1 mmol, Combi-Blocks: Cat. #CA-4107), and cesium carbonate (1.7 g, 5.4 mmol) in toluene (25.0 mL) under N2, followed by palladium acetate (0.040 g, 0.18 mmol). The reaction mixture was stirred at 120° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, filtered, and concentrated under reduced pressure to afford the desired crude product (1.06 g) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=562.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:14]([CH3:15])=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH3:16])[N:6]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([C:10]1[CH:9]=[C:8]([CH3:16])[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[S:3][CH:4]=2)=[C:14]([CH3:15])[CH:13]=1)#[N:12]
Reactant: Cc1cc(C#N)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-Aminothiazol-4-yl)-3,5-dimethylbenzonitrile (84 mg, 0.37 mmol) in DCM (2 mL) was added DMAP (84 mg, 0.74 mmol) followed by isonicotinoyl chloride hydrochloride (85 mg, 0.48 mmol). Then the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated, and the saturated aqueous sodium bicarbonate (30 mL) was added. The aqueous solution was extracted with DCM (3×10 mL). The combined organic layers were dried with anhydrous sodium sulfate. After removal of all the solvent, the residue was purified by silica gel chromatography (hexane/acetone=2:1) to give INH174 (55 mg, 44%) as a white solid; mp 248-250° C. 1H NMR (400 MHz, CD3OD) δ 8.88-8.86 (m, 2H), 7.76-7.74 (m, 2H), 7.38 (s, 2H), 6.91 (s, 1H), 2.16 (s, 6H). 13C NMR (125 MHz, DMSO-d6) δ 150.9, 141.0, 139.7, 139.2, 131.2, 122.2, 119.4, 113.3, 111.0, 20.4. MS (ESI) m/z 335.0 (M+H+). HRMS calculated for C18H14N4SONa (M+Na+), 357.0786. found, 357.0789.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClCCl.[CH3:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=1[C:29]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:39]([N:41]2[C:47]3[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=3[CH:45]([OH:53])[CH2:44][CH2:43][CH2:42]2)=[O:40])=[C:36]([CH3:38])[CH:37]=1)=[O:30].N1C=CC=CC=1>O>[Cl:52][C:50]1[CH:49]=[CH:48][C:47]2[N:41]([C:39](=[O:40])[C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:22])=[CH:37][C:36]=3[CH3:38])[CH2:42][CH2:43][CH2:44][CH:45]([O:53][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:46]=2[CH:51]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 74.4 %

Procedure:
Palmitoyl chloride (1.24 ml, 4.4 mmol) was added to a dichloromethane (20 ml) solution of tolvaptan (2.00 g, 4.4 mmol) and pyridine (0.40 ml, 5.0 mmol), and the mixture was stirred at room temperature over night. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The combined organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate) to thereby obtain 2.25 g (74%) of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}hexadecanoate as amorphous.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12](O)=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([NH2:20])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][S:17][C:3]1=2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)SCC3
Reaction time: 2 h

Procedure:
A mixture of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (3.0g., 0.012 mol) and 1,1'-carbonyldiimidazole (2.0 g., 0.012 mol) in tetrahydrofuran (180 ml) and dimethylformamide (3.5 ml) is refluxed under nitrogen for 5 hours. The solution is cooled in an ice-bath and anhydrous ammonia is bubbled through for 15 minutes. The mixture is stirred at ice-bath temperature for 2 hours and at room temperature for one hour. The reaction mixture is cooled and the precipitate is filtered off and washed with tetrahydrofuran. The precipitate is treated with hot 0.5 mol aqueous sodium bicarbonate solution, filtered, washed with water, washed with acetone and sucked dry to give the product (2.0 g.), mp 334° C. (dec).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:33])([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[C:14]([CH:31]=[CH2:32])=[CH:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[C:14]([CH2:31][CH3:32])=[CH:13]2)([CH3:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1cn(C2(C)CN(C(=O)OC(C)(C)C)C2)c2cc3c(cc12)OCC1=NNC(=O)[C@@H](C)N13
Agent: [Pd]
Solvent: CO
Product: CCc1cn(C2(C)CN(C(=O)OC(C)(C)C)C2)c2cc3c(cc12)OCC1=NNC(=O)[C@@H](C)N13
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
A mixture of 3-methyl-3-((R)-1-methyl-2-oxo-8-vinyl-1,2,3,5-tetrahydro-6-oxa-3,4,10,11 b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.177 mmol) and 10% Pd/C (0.002 g, 0.018 mmol) in methanol (2 mL) was stirred under an atmosphere of H2 at 20° C. for 2.5 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by prep-HPLC (Table 3, Method 32) to give 3-((R)-8-ethyl-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.04 g, 49%) as a gum. 1H NMR (400 MHz, methanol-d4): δ 7.18 (s, 1H), 7.00 (s, 1H), 6.81 (s, 1H), 4.98 (m, 1H), 4.61-4.47 (m, 4H), 4.27 (m, 2H), 2.70 (q, J=7.6 Hz, 2H), 1.77 (s, 3H), 1.50-1.47 (m, 12H), 1.32 (m, J=7.6 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.896 min.; MS m/z: 454 [M+H]+.
Reaction SMILES: C[O:2][C:3]([P:8]([CH3:11])(=[O:10])[O-:9])(OC)[CH2:4][CH3:5].[Na+:12].O>C(O)(=O)C>[CH3:11][P:8]([C:3](=[O:2])[CH2:4][CH3:5])(=[O:9])[O-:10].[Na+:12]
Reactant: CCC(OC)(OC)P(C)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)P(C)(=O)[O-]
Reaction time: 16 h

Procedure:
The product of Example 48 (13.6 g) was dissolved, with warming on the steam bath in acetic acid (100 ml) containing water (3 ml). The solution was left for 16 hrs and was then worked up as in Example 8(a).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([CH3:16])[C:5]=2[C:4](=[O:17])[NH:3]1.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:16][C:6]1[C:5]2[C:4](=[O:17])[N:3]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:2](=[O:1])[C:14]=2[C:13]2[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Cc1ccc2nc(C)c3c(c2c1)C(=O)NC3=O
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(C)c3c(c2c1)C(=O)N(CCN1CCOCC1)C3=O

Procedure:
A mixture of 5 g (0.022 mole) of 1,3-dioxo-4,8-dimethyl-2H-pyrrolo [3,4-c]quinoline (vii) (also known as 2,6-dimethyl quinoline 3,4-dicarboximide), 4.65 g (0.025 mole) of N-(2-chloroethyl) morpholine, 6.9 g (0.05 mole) K2CO3, and 50 ml of dry DMF was stirred and heated at 50° for 18 hours. The dark mixture was poured into H2O with stirring and the solids filtered; yield, 6 g after drying in vacuo.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]2[N:8]=[C:9](SC)[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:13][OH:14])[C@H:3]1[OH:15].Cl.[NH:17]1[CH2:20][CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CCO>[N:17]1([C:9]2[O:10][C@H:6]3[CH2:5][C@H:4]([CH2:13][OH:14])[C@@H:3]([OH:15])[C@@H:2]([F:1])[C@H:7]3[N:8]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: C1CNC1
Reactant: CSC1=N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: OC[C@H]1C[C@@H]2OC(N3CCC3)=N[C@@H]2[C@H](F)[C@@H]1O
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a solution of (3 aS,4S,5R,6R,7aS)-4-fluoro-6-(hydroxymethyl)-2-(methylthio)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (50 mg, 0.21 mmol) in EtOH (3 mL) was added azetidine hydrochloride (100 mg, 1.06 mmol). The mixture was heated at reflux for 17 h. After cooling, solid NaHCO3 (100 mg, 1.19 mmol) was added and stirred for 10 min. Solvent was evaporated and the residue was purified by silica gel column chromatography, eluted with 5%-10% 2 M NH3 MeOH solution in DCM to give the product (3aS,4S,5R,6R,7aS)-2-(azetidin-1-yl)-4-fluoro-6-(hydroxymethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-5-ol (31.4 mg, 60%) as a white solid. MS m/z 245.1 (M+1, 100%); 1H NMR (400 MHz, MeOD) δ 4.57-4.61 (m, 1H), 4.58 (ddd, J=52.8 Hz, 3.7 Hz, 1.6 Hz, 1H), 4.02 (t, J=7.6 Hz, 4H), 3.85 (ddd, J=26.1 Hz, 7.1 Hz, 3.8 Hz, 1H), 3.66-3.73 (m, 2H), 3.49 (ddd, J=30.2 Hz, 10.0 Hz, 1.5 Hz, 1H), 2.27-2.38 (m, 3H), 2.01-2.09 (m, 1H), 1.73-1.81 (m, 1H); 13C NMR (100 MHz, MeOD) δ 165.85, 93.17 (d, J=178.6 Hz), 80.71, 70.65 (d, J=19.1 Hz), 64.45 (d, J=17.3 Hz), 63.94, 51.87, 35.47 (d, J=5.8 Hz), 28.39, 17.77.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:15]=[N+:16]=[N-:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reaction time: 18 h

Procedure:
233.5 g 4-acetylaminobenzenesulfonic acid chloride (approximately 1 mol) are added in cold condition (at 2° to 3° C.) and while being stirred into a solution of 70 g sodium azide (approximately 1 mol) in 800 g water. Subsequently, stirring is continued for 18 hours at room temperature and then the temperature is held at 40° C. for one hour; finally, aspiration is applied and washing with excess water follows. A brown substance is obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[O:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:31]2[O:32][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)o1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2ccc(C)o2)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 5-methyl-2-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=74%).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:21])[CH2:6][C:7]([CH3:20])([O:9][O:10][C:11](=[O:19])[CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:8])=[O:3].[NH2:22][NH2:23].C(Cl)(Cl)=O>>[C:2]([O:4][CH:5]([CH3:21])[CH2:6][C:7]([CH3:20])([O:9][O:10][C:11](=[O:19])[CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:8])(=[O:3])[NH:22][NH2:23]
Reactant: NN
Reactant: CCCCC(CC)C(=O)OOC(C)(C)CC(C)OC(=O)Cl
Agent: O=C(Cl)Cl
Product: CCCCC(CC)C(=O)OOC(C)(C)CC(C)OC(=O)NN

Procedure:
1,3-Dimethyl-3-(2-ethylhexanoylperoxy)butyl carbazate was prepared by reacting 1,3-dimethyl-3-(2-ethylhexanoylperoxy)butyl chloroformate with 11 molar excess of 54% aqueous hydrazine. 1,3-Dimethyl-3-(2-ethylhexanoylperoxy)butyl chloroformate was initially prepared with a purity of 72% by reacting 3-hydroxy-1,1-dimethylbutyl peroxy-2-ethylhexanoate with excess phosgene followed by removal of excess phosgene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:9]([OH:11])=O)[N:3]=1.P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:35][CH:36]1[C:61](=[O:62])[N:38]2[C:39]([C:45]([O:47][CH:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])=[C:40]([CH:43]=[CH2:44])[CH2:41][S:42][C@H:37]12>C(OCC)(=O)C.C(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:12][O:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:9]([NH:35][CH:36]2[C:61](=[O:62])[N:38]3[C:39]([C:45]([O:47][CH:48]([C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)=[O:46])=[C:40]([CH:43]=[CH2:44])[CH2:41][S:42][C@H:37]23)=[O:11])[N:3]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nccc(N)n1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3nccc(N)n3)[C@H]2SC1
Yield: 17.7 %

Procedure:
To a suspension of 2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (1.3 g) in ethyl acetate (25 ml) was added phosphorus oxychloride (0.5 ml) under ice-cooling with stirring, followed by stirring at 0° to 5° C. for half an hour. After trimethylsilylacetamide (28 mg) was added thereto, the mixture was stirred at the same temperature for half an hour. To the mixture was added phosphorus oxychloride (0.5 ml) at 0° to 5° C., followed by stirring at the same temperature for 15 minutes. Thereto was added N,N-dimethylformamide (0.37 ml) at 0° to 5° C., followed by stirring under ice-cooling for half an hour to prepare the activated acid solution. This solution was added at a time to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (1.32 g) and trimethylsilylacetamide (3.5 g) in methylene chloride (30 ml) at -20° C., followed by stirring at -10° C. for 40 minutes. The reaction mixture was poured into ethyl acetate, and the separated organic layer was washed with 5% aqueous sodium bicarbonate and 5% aqueous sodium chloride, followed by drying over magnesium sulfate. After removal of the solvent, the residual oil was subjected to column chromatography on silica gel (100 ml) using a mixed solvent of diisopropyl ether and ethyl acetate as an eluent. The fractions containing a desired compound were collected and then evaporated to obtain benzhydryl 7-[2-(4-aminopyrimidin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.4 g), mp 155° to 158° C.