Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[C:8]=2[CH3:13])[N:3]=1.Br[C:18]1[C:23]2[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]4[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[O:26][C:22]=4[CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH3:13])[N:3]=1
Reactant: Cc1c(B(O)O)ccc2nc(N)nc(N)c12
Reactant: CC1(C)Oc2cccc(Br)c2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)ccc2nc(N)nc(N)c12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A solution of 2.1 grams (0.010 mole) of (2,4-diamino-5-methylquinazolin-6-yl)boronic acid in 25 mL of N,N-dimethylformamide is stirred, and 2.1 grams (0.009 mole) of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone (prepared in Step C of this Example), 2.8 grams (0.020 mole) of potassium carbonate, and 0.31 gram (catalyst-3 mole %) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction mixture is then warmed to 90° C., where it is stirred for about 16 hours. After this time the reaction mixture is poured into water. The resultant precipitate is collected by filtration and dried, yielding 2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)quinazoline.
Reaction SMILES: C([NH:8][C:9](=[N:11]C(OC(C)(C)C)=O)[NH2:10])(OC(C)(C)C)=O.[ClH:19]>C(Cl)Cl.CCO>[ClH:19].[ClH:19].[NH2:10][C:9]([NH2:11])=[NH:8].[NH2:10][C:9]([NH2:11])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(N)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N=C(N)N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The N′,N″-di-BOCguanidine (0.45 g, 0.60 mmol) was dissolved in CH2Cl2 (10 mL), diluted with dry EtOH (15 mL) and the chilled solution was saturated with dry HCl. The reaction was then kept stirring at room temperature for 3 days (drying tube), when by the product started forming a precipitate over time. After evaporating the solvent to dryness, the residue was washed with ether multiple times and was dried under vacuum at 50-60° C. over night to give whitish yellow solid of the bis-guanidine dihydrochloride; mp >300° C. 1H NMR (DMSO-d6): δ 7.85 (dd, J=1.5, 8.4 Hz, 4H), 7.92 (d, J=1.2 Hz, 4H), 8.00 (dd, J=1.5, 8.4 Hz, 4H), 9.09 (br s, 4H), 11.25 (br s, 2H). 13C NMR (DMSO-d6): δ 155.98, 138.35, 137.32, 135.00, 127.79, 127.22, 124.79. MS (ESI) m/e (rel. int.): 344 (M+, 6), 173 (100). Anal. Calc. for C20H20N6-2.0HCl-1.0H2O-0.2C2H5OH: C %, 55.11; H %, 5.71; N %, 18.90. Found C %, 55.39; H %, 5.50; N %, 18.71.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>O1CCCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][CH:29]=[C:20]([NH:19][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)[CH:21]=1
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(NC(=O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
4-Methoxy-3-nitrobenzoic acid (5.0 g, 25 mmol) was added to thionyl chloride (20 mL) under an inert atmosphere and stirred and heated to reflux. After 2 hours the mixture was stripped to dryness by rotary evaporator, and 2 portions of benzene were successively mixed with then stripped from the residue to leave a solid. This residue was dissolved in tetrahydrofuran (20 mL) and added dropwise to a stirred solution of methyl 3-aminobenzoate (3.83 g, 25 mmol) and pyridine (2 mL) cooled in an icebath. The mixture was allowed to warm to room temperature following the addition, then the solvent was removed under reduced pressure. The residue was suspended in 1N HCl, stirred, filtered off, and washed successively with 1N HCl, 1N NaHCO3 (2×), and water (2×). The resulting solid was boiled briefly in methanol (500 mL) then allowed to cool. Filtration afforded the product (8.0 g); m.p. 233-235° C., in sufficient purity for the next step.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][OH:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[H][H].Br[CH2:20][C:21]([CH3:23])=[CH2:22].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]([CH2:12][O:13][CH2:22][C:21]([CH3:23])=[CH2:20])[C:14]([OH:16])=[O:15])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C=C(C)CBr
Reactant: [H][H]
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Wash a 60% dispersion of sodium hydride in mineral oil (4.4 g, 115 mmol) with hexanes. Add DMF (30 mL), and cool in an ice bath. Add dropwise a solution N-(tert-butoxycarbonyl)-L-serine (10.0 g, 49 mmol) in DMF (160 mL). Warm to room temperature and stir until hydrogen evolution ceases after one hour. Cool in an ice bath and add 3-bromo-2-methyl-propene (7.40 g, 55 mmol). Stir for 2 hours. Pour mixture onto 5% aqueous sodium bicarbonate (800 mL). Wash twice with ethyl acetate. Add ethyl acetate (200 mL), and acidify the aqueous layer in its presence to pH=3 with concentrated hydrochloric acid. Wash the organic layer with water, dry (Na2SO4), and concentrate to afford the title compound as a clear oil (12.7 g): 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.70 (s, 3H), 3.65 (m, 1H), 3.85 (m, 1H), 3.86-3.94 (m, 2H), 4.44 (m, 1H), 4.89 (s, 1H), 4.93 (s, 1H), 5.43 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Cu]I>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35]
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1-c1ccn2c(n1)nc1ccccc12
Temperature: 120 °C
Yield: 44.8 %

Procedure:
1,1′ Bis(diphenylphosphino)ferrocnee]dichloropalladium(II),w/DCM (0.033 g, 0.040 mmol) was added to a solution containing 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.2 g, 0.806 mmol), tert-butyl (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (0.386 g, 1.209 mmol), Copper(I) iodide (0.015 g, 0.081 mmol), and Potassium carbonate (0.806 ml, 1.612 mmol) in DMF. The solution was heated in the microwave for 15 minutes at 120° C. The reaction was cooled to room temperature. Diluted with water, extracted with ethyl acetate, combined organics, dried, filtered and concentrated. Purified by Combiflash column using 0% to 80% ethyl acetate in hexanes to afford tert-butyl (2-(benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)phenyl)carbamate (0.13 g, 0.361 mmol, 44.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH2:18])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)=[O:22].[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1.N1C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([CH2:17][NH:18][S:34]([CH:31]3[CH2:33][CH2:32]3)(=[O:36])=[O:35])[CH:14]=[CH:13][C:12]=2[Cl:19])=[CH:5][C:4]=1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=1)=[O:22]
Reactant: COc1ccc(NC(=O)c2cc(CN)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(NC(=O)c2cc(CNS(=O)(=O)C3CC3)ccc2Cl)cc1C(=O)Nc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A mixture of 52.5 mg N-[4-methoxy-3-(4-bromophenyl)aminocarbonyl-phenyl]-2-chloro-5-aminomethyl-benzamide (0.10 mmol), 16.8 mg cyclopropylsulphonic acid chloride (0.12 mmol), 1.0 mL pyridine and 4.0 mL acetonitrile was stirred overnight, concentrated, dissolved in 3 mL DMF and purified by prep. HPLC.
Reaction SMILES: [F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:37][C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>ClCCl>[F:1][C:2]1[C:30]([N:31]2[CH2:36][CH2:35][N:34]([C:40]([C:39]3[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=3[CH3:37])=[O:41])[CH2:33][CH2:32]2)=[CH:29][C:5]2[N:6]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[C:7]([CH2:9][O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: Cc1ccccc1C(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
80 mg of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.026 ml 2-Methyl-benzoyl chloride (0.2 mmol). After 5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 74 mg light yellow solid (73%). MS (ISP) 619.4 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.C([Li])CCC.Cl[C:18]([O:20][CH3:21])=[O:19]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:21][O:20][C:18](=[O:19])[C:2]#[C:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: COC(=O)Cl
Reactant: Fc1cccc(C=C(Br)Br)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C#Cc1cccc(F)c1
Yield: 110.3 %

Procedure:
To a stirred solution of 1-(2,2-dibromo-vinyl)-3-fluoro-benzene (23.8 g) in anhydrous THF (350 ml) cooled to −78° was added dropwise over 30 minutes, n-butyllithium (2.2 eq, 1.6M in hexanes). The mixture was stirred for a further 30 minutes at −78° before methyl chloroformate (11.6 g, 9.5 ml) was added and the resultant mixture allowed to warm to 0° for 1 hour before being diluted with 1:1 saturated aqueous sodium bicarbonate:ammonium chloride (100 ml) and extracted into ether (2×100 ml). The combined organic extract was washed with brine (25 ml), dried (Na2SO4) and evaporated to dryness to give the title compound as a brown oil (16.7 g, 100%). MH− 173
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[S:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]2[S:20][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:9]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: COc1ccc(NC(=S)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c1
Temperature: 90 °C
Yield: 28.8 %

Procedure:
N-(4-Methoxyphenyl)-4-nitrobenzothioamide (39, 6.0 g, 20.81 mmol) was drenched in ethanol (1 mL) and 30% NaOH aqueous solution (6.66 g, 166.48 mmol) was added. The resulting reaction mixture was diluted with water (60 mL) and K3Fe(CN)6 (18.0 g, 41.62 mmol) dissolved in water (50 mL) was slowly added at 90° C. After heating the reaction mixture for 1 hour at 90° C. and cooling to room temperature, the produced precipitate was filtered and washed with water. After dissolving the remaining precipitate in ethyl acetate and removing drying over sodium sulfate, column chromatography yielded the target compound 2-(4-nitrophenyl)-6-methoxybenzothiazole (41, 1.718 g, 30%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+]([C:14]1[CH:15]=C(S([O-])(=O)=O)C=C[CH:19]=1)([O-])=O.OCC(CO)O.S(=O)(=O)(O)O.[OH-].[NH4+].C>O.C(O)(=O)C>[N:1]1[C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=2[CH:15]=[CH:14][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Nc1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: OCC(O)CO
Solvent: O
Product: O=C(O)c1cccc2ncccc12
Temperature: 50 °C
Yield: 35.2 %

Procedure:
To a solution containing 15 g (0.1 mol) of m-aminobenzoic acid, 27 g (0.13 mol) of m-nitrobenzene sulfonate and 25 g (0.4 mol) of glycerol, was added 125 g of 70% sulfuric acid. The resultant reaction mixture was refluxed for about 2.5 hours, diluted with 125 mL of water, basified to pH 9 using ammonium hydroxide, stirred overnight with 5 g of charcoal, and then filtered. The filtrate was then boiled with 5 g charcoal, filtered, and then cooled to 50° C., acidified to pH 5 with glacial acetic acid (15 mL), and filtered to provide a brown solid. This solid was boiled in 300 mL of water containing 10 mL of acetic acid and hot filtered to provide crude material. This material was purified using recrystallization from boiling acetic acid to provide 6.1 g of a pale brown solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.C(OCC)(=O)C>[Si:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyl)oxy-1-cyclohexanol (12.5 g) and triethylamine (9.8 ml) in dichloromethane (200 ml) was added dropwise methylsulfonyl chloride (4.6 ml) at 5° C. under nitrogen atmosphere. A reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. Insoluble material was removed by filtration and mother liquor was concentrated under reduced pressure to give residue, which was dissolved in ethyl acetate (200 ml) and washed in turn with 1N-aqueous hydrochloric acid (50 ml×2), saturated sodium hydrogen carbonate in water (50 ml×2) and saturated sodium chloride in water (50 ml×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with 10% ethyl acetate in n-hexane to give 3-(tert-butyldimethylsilyl)oxy-1-(methylsulfonyloxy)-cyclohexane(cis and trans mixture, 16.0 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].CO[C:10](OC)([CH3:12])[CH3:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1>[CH3:11][C:10]1([CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1
Reactant: OCC(CO)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)CO1
Reaction time: 60 h
Yield: 43.7 %

Procedure:
2-(Hydroxymethyl)-1,3-propanediol (1.0 g, 9.4 mmol), 2,2-bis(methyloxy)propane (2.3 mL, 18.8 mmol) and p-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) were dissolved in THF and stirred for ˜60 h. To the solution was added triethyl amine (1.0 mL) and the solvent was evaporated. Purification was accomplished by column chromatography (CH2Cl2:MeOH) to afford the title compound (0.6 g, 44%) as a oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 4.52 (t, 1H), 3.80 (dd, 2H), 3.59 (dd, 2H), 3.36 (dd, 2H), 1.63-1.72 (m, 1H), 1.28 (d, 6H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN(C)[CH:21]=[O:22]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]cc(C=O)c2c1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To stirred dimethylformamide is added dropwise phosphorus oxychloride. The mixture is stirred for 10 min and a solution of 5-methoxyindole in dimethylformamide is added dropwise. The mixture is heated to 40° C. for 45 min, cooled to room temperature and then treated with a solution of sodium hydroxide in water. The mixture is heated to 50° C. for 10 min, cooled to room temperature, poured onto crushed ice and filtered. The filter cake is recrystallised (methanol) to give the product as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)[C:5]([OH:7])=O.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1)[C:5]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:7]
Reactant: CON=C(C(=O)O)c1nnc(C)s1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nnc(C)s1
Yield: 49.6 %

Procedure:
2-Methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (anti isomer) (0.99 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.62 g.) were reacted according to a similar manner to that of Example 1(b) to give 7-[2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.25 g.), mp 110° to 115° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CS(C)=O>[CH3:17][C:14]1[S:13][C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[C:15]=1[CH3:16]
Reactant: Cc1sc(Br)c(C(=O)Nc2ccccc2O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1sc2c(c1C)C(=O)Nc1ccccc1O2
Temperature: 165 °C
Reaction time: 0.33 h
Yield: 56.4 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-4,5-dimethyl-3-thiophenecarboxamide (3.3 g) in dimethyl sulfoxide (50 ml) was added potassium carbonate (2.8 g) and the mixture was stirred at 160-170° C. for 20 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into water-ethyl acetate. The insoluble matter was filtrated and the filtrate was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 2,3-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.4 g).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([OH:13])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>>[C:1]1([S:7]([CH2:10][C:11]([O-:13])=[O:12])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:20][C:19]([NH2:21])=[NH2+:18]
Reactant: N=C(N)N
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Agent: O=C(O)O
Product: NC(N)=[NH2+]
Product: O=C([O-])CS(=O)(=O)c1ccccc1

Procedure:
Guanidinium phenylsulfonylacetate (Compound C14-A5) was prepared in an analagous manner from 2.310 g (0.01154 mol) of phenylsulfonylacetic acid and 1.039 g (0.005769 mol) of guanidine carbonate to afford 2.052 g of product; mp 137°-139° C. (dec). NMR was in agreement with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([NH:17][CH:18]=O)[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25].[C:26](=[O:29])([O-])[O-].[K+].[K+].[CH2:32](I)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([NH:17][CH:18]([CH:26]=[O:29])[CH3:32])[CH:7]=[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn(NC=O)c2cc(-n3cccc3)c(F)cc2c1=O
Reactant: CCI
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(NC(C)C=O)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
A mixture of 1.5 g (0.005 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-1-formylamino-4-oxo-1,4-dihydroquinoline-3-carboxylate and 1.3 g (0.01 mol) of potassium carbonate in 10 ml of dimethylformamide is stirred for 3 hours at room temperature, 2.35 g (0.015 mol) of ethyl iodide are then added and the mixture is kept for 4 hours at room temperature. It is poured into a water/ice mixture, the precipitate obtained is filtered off, washed with water and extracted with chloroform, the extract is washed with water, the organic layer is dried, the solvent is evaporated off and the residue is recrystallized from an ethanol/water mixture (1:1) to give 0.7 g of a solid melting at 192°-194° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([OH:16])=O)[N:11]=[C:10]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([NH:25][C:26]([NH:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[O:27])[C:22]=4[C:23](=[O:24])[C:9]=23)=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][C:48]([CH2:50][CH2:51][C@H:52]([NH:60][C:61]([C:63]1[CH:68]=[CH:67][C:66]([N:69](C(OCC2C=CC=CC=2)=O)[CH3:70])=[CH:65][CH:64]=1)=[O:62])[C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[O:49].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][C:48]([CH2:50][CH2:51][C@H:52]([NH:60][C:61]([C:63]3[CH:64]=[CH:65][C:66]([NH:69][CH3:70])=[CH:67][CH:68]=3)=[O:62])[C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[O:49])=[O:16])[N:11]=[C:10]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([NH:25][C:26](=[O:27])[NH:28][N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[C:22]=4[C:23](=[O:24])[C:9]=23)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1nc2c(c1-c1ccc(O)cc1)C(=O)c1c(NC(=O)NN3CCOCC3)cccc1-2
Reactant: CN(C(=O)OCc1ccccc1)c1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCN)C(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCNC(=O)Cn2nc3c(c2-c2ccc(O)cc2)C(=O)c2c(NC(=O)NN4CCOCC4)cccc2-3)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 38 (0.52 g, 1.1 mmol) and compound 12 (0.55 g, 1.1 mmol) were dissolved in DMF and HBTU (0.8 g, 2.1 mmol) was added as a solid followed by DIEA (0.52 ml, 3 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc and the organic phase washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to an oil. This oil was purified by flash silica chromatography (1 to 2 to 3 to 4 to 5% MeOH/CH2Cl2) to give a yellow foam (0.45 g, 0.47 mmol, 43%, compound 39).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:17](O)[CH:18]=[CH2:19]>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH:18]=[CH2:17])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)cc1F
Yield: 69 %

Procedure:
In a manner analogous to Example 1(a), starting with 8.3 g 53 mmoles) of 2-fluoro-4-hydroxybenzoic acid treated for 2 hours at 100° C. with 60 ml of allyl alcohol and 1.5 ml of concentrated sulfuric acid, 7.2 g (69% yield) of the expected ester having a melting point of 80°-81° C. are obtained.