Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[C:52]([N:71]1[CH:75]=[C:74]([C:76]2[CH:77]=[C:78]([CH:80]=[CH:81][CH:82]=2)[NH2:79])[N:73]=[CH:72]1)([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)CC)C>CN(C=O)C.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:79][C:78]4[CH:80]=[CH:81][CH:82]=[C:76]([C:74]5[N:73]=[CH:72][N:71]([C:52]([C:65]6[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=6)([C:59]6[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=6)[C:53]6[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=6)[CH:75]=5)[CH:77]=4)=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2cc3n(c2c1)CCCNC3=O
Reaction time: 0.17 h

Procedure:
To a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 61 mg, 0.25 mmol) in DMF (1.5 mL) is added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (194 mg, 0.37 mmol). The reaction mixture is stirred for 10 min and 3-(1-trityl-1H-imidazol-4-yl)aniline (100 mg, 0.25 mmol) and triethylamine (0.07 mL, 0.50 mmol) are added. The reaction mixture is stirred at room temperature for 16 h. Water (35 mL) is added and the resulting solid is collected by filtration and rinsed with water to afford the title crude compound which is used in the next step without purification.
Reaction SMILES: C([O:9][CH2:10][C@@H:11]1[CH2:15][C@:14]([O:17]C(=O)C)([CH3:16])[CH:13]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][C:24]([NH2:32])=[N:25][C:26]=3[O:30][CH3:31])[O:12]1)(=O)C1C=CC=CC=1>N>[NH2:32][C:24]1[N:23]=[C:22]2[C:27]([N:28]=[CH:29][N:21]2[CH:13]2[C@:14]([CH3:16])([OH:17])[CH2:15][C@@H:11]([CH2:10][OH:9])[O:12]2)=[C:26]([O:30][CH3:31])[N:25]=1
Reactant: COc1nc(N)nc2c1ncn2C1O[C@H](COC(=O)c2ccccc2)C[C@@]1(C)OC(C)=O
Agent: N
Product: COc1nc(N)nc2c1ncn2C1O[C@H](CO)C[C@@]1(C)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.4 %

Procedure:
Methanolic ammonia (7N, 20 mL) was added to ((2S,4R)-4-acetoxy-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-methyl-tetrahydrofuran-2-yl)methyl benzoate (from step 11) (1.53 g) and stirred at room temperature for 24 h in a sealed tube. The volatiles were evaporated under vacuum and the resulting residue was loaded directly on to the column and eluted with CH2Cl2/MeOH (10:1) as a gradient mixture to give 0.802 g of compound (79% yield). mp: 140° C.-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(I)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Yield: 27.8 %

Procedure:
1-(tert-Butoxycarbonyl)-5-iodoindole (3.46 g, 10.1 mmol) was dissolved in toluene (45.0 mL), and the solution was added with 4-methylpiperazine (2.24 mL, 20.2 mmol), 2,2′-(diphenylphosphino)-1,1′-binaphthyl (1.26 g, 2.02 mmol), cesium carbonate (4.94 mg, 15.2 mmol) and palladium acetate (226 mg, 1.01 mmol), followed by stirring under reflux for 24 hours. The mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (chloroform/methanol=9/1) to obtain 1-(tert-butoxycarbonyl)-5-(4-methylpiperazino)indole (887 mg, 28%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O)(=O)C>C(O)C.[Fe]>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccccc1-n1cccc1
Yield: 92.2 %

Procedure:
To a solution of 2-(1-pyrrolyl)nitrobenzene (1.11 g) in ethanol (30 ml) were added iron powder (1.65 g) and acetic acid (3.54 g) and the mixture was refluxed for 1 hour. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was diluted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution and the mixture was filtered through a bed of celite again. The organic layer was separated and washed with water and brine. The solution was dried over sodium sulfate and the solvent was evaporated in vacuo to give 2-(1-pyrrolyl)phenylamine (860 mg).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19](Br)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:23])[N:6]([C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:31]4[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)OC(=O)N(C)[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ncccc1-c1cnc2ccc(N3CC[C@H](N(C)C(=O)OC(C)C)C3)nn12
Temperature: 150 °C
Yield: 87.4 %

Procedure:
A mixture of [(S)-1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid isopropyl ester (88 mg, 0.23 mmol), 2-methoxypyridine-3-boronic acid (46 mg, 0.3 mmol), K2CO3 (95 mg, 0.69 mmol) and dichlorobis(triphenylphosphine)palladium(II) (8.4 mg, 0.012 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (82.5 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.06 Hz, 6H) 2.13-2.32 (m, 2H) 2.89 (s, 3H) 3.43 (dd, J=10.48, 6.95 Hz, 1H) 3.48-3.56 (m, 1H) 3.69-3.76 (m, 2H) 4.09 (s, 3H) 4.99 (dt, J=12.38, 6.19 Hz, 2H) 6.62 (d, J=9.85 Hz, 1H) 7.04 (dd, J=7.45, 4.93 Hz, 1H) 7.79 (d, J=9.85 Hz, 1H) 8.13-8.19 (m, 2H) 8.86 (dd, J=7.71, 1.64 Hz, 1H). LRMS (ESI) m/z 411.2 [(M+H)]+, calc'd for C21H26N6O3: 410.48.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:33])[C:5]([C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:16])=[O:6].Br[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][O:13][C:11]1[CH:10]=[CH:9][C:8]([NH:14][C:15]([C:17]2[C:18]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])=[C:7]([C:5](=[O:6])[N:4]([CH3:33])[CH3:3])[CH:12]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CN(C)C(=O)c1cc(O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(OCC(=O)OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Sodium hydride (34 mg) was dissolved in THF (9 ml), and the solution was cooled to 0° C. and thereto were added 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-hydroxyphenyl)amide (300 mg) and tetrabutyl ammonium iodide (10 mg). After addition of benzyl bromoacetate (160 mg), the resulting mixture was stirred at 40° C. for 1 hour. The mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through a Celite, and the filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give {3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenoxy}acetic acid benzyl ester (226 mg).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[C:8]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:4][CH2:12][C:11]1[N:7]([CH3:6])[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9][N:10]=1
Reactant: Cc1nnc(-c2ccncc2)n1C
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(CCl)nnc1-c1ccncc1
Reaction time: 2 h
Yield: 22.8 %

Procedure:
Sulfuryl dichloride (0.58 ml, 8.34 mmol) in DCM (8 ml) was slowly added to a cooled (−10° C.) solution of 4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridine (454 mg, 2.61 mmol) in DCM (25 ml) and DMF (8 ml) and then the solution was stirred for 2 h. NaHCO3 (sat.) was added and the mixture was extracted with EA. The organic phase was dried and concentrated. Recrystallization from EA afforded 124 mg (23%) of the title compound. 1H NMR: 3.83 (s, 3 H) 4.84 (s, 2 H) 7.62 (d, 2 H) 8.82 (d, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH3:20])=[N:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16]1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH3:20])=[N:18][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:16]1
Reactant: Cc1nc(-c2ccccc2)nn1-c1ccccc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)nn1-c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of 1-(2-benzyloxyphenyl)-5-methyl-3-phenyl-1,2,4-triazole are dissolved in 20 ml of anhydrous dichloromethane and a solution of 0,5 ml of BBr3 in 10 ml of dichloromethane is added dropwise. After 3 hours stirring at ambient temperature the mixture is diluted with a further 100 ml of dichloromethane and washed twice with water. After the organic phase has been dried over Na2SO4 the solvent is distilled off. The crude product remaining is purified by chromatography on silica gel (toluene:ethyl acetate 80:20).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[O:20]1[C:24]2([CH2:29][CH2:28][C:27](B(O)O)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:17]3[S:18][C:11]4[C:12](=[N:13][CH:14]=[CH:15][C:10]=4[O:9][C:8]4[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=4[F:1])[CH:16]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1
Reactant: OB(O)C1=CCC2(CC1)OCCO2
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
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: [Na+]
Solvent: C1COCCO1
Product: Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 0.461 g, 1.19 mmol), 1,4-dioxaspiro[4.5]dec-7-en-8-ylboronic acid (0.659 g, 3.58 mmol), tetrakis(triphenylphosphine)palladium (0.276 g, 0.239 mmol), Na2CO3 (2.98 ml, 5.97 mmol) and dioxane (50 mL). The reaction mixture was stirred at 100° C. until the starting material had been consumed (overnight). Then the reaction was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (0.418 g, 87.9%). LRMS (APCI pos): >97% purity, 254 nm, m/e 399 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.40 (d, 1H), 7.34 (s, 1H), 7.01 (t, 1H), 6.42-6.56 (m, 3H), 6.28 (s, 1H), 4.04 (s, 4H), 3.82 (br s, 2H), 2.80 (m, 2H), 2.52 (m, 2H), 1.98 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.Cl.Cl[CH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3csc(C)n3)cc2=O)c1
Temperature: 60 °C
Yield: 16 %

Procedure:
To a solution of Intermediate 2 (530 mg, 1.93 mmol) in N,N-dimethylformamide (2 mL) was added 4-(chloromethyl)-2-methyl-1,3-thiazole HCl (354 mg, 1.93 mmol), potassium carbonate (666 mg, 4.82 mmol) and 18-crown-6 (50 mg). The slurry was heated at 60° C. for three hours. The reaction was returned to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a colorless oil. (120 mg, 16% yield). MS (M+H): 386
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:34]([O:37][CH:38](Br)[CH3:39])(=[O:36])[CH3:35]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:38]([O:37][C:34](=[O:36])[CH3:35])[CH3:39])=[O:27])=[C:15]([CH2:18][O:19][C:20]([N:22]4[CH2:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(COC(=O)N4CCC4)CS[C@H]23)cs1
Reactant: CC(=O)OC(C)Br
Agent: [Na+]
Product: CC(=O)OC(C)OC(=O)C1=C(COC(=O)N2CCC2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound obtained in Example 8 and 1-bromoethyl acetate were reacted, whereby the title compound was obtained.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:26]1([C:32]2[N:33]=[CH:34][NH:35][C:36]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:33]3[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[C:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:35]=[CH:34]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCCc1oc(-n2cnc(-c3ccccc3)c2-c2ccccc2)nc1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 39.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 4,5-diphenylimidazole (270 mg), anhydrous potassium carbonate (220 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 12 hours. The reaction mixture was poured into water, the resulting solid precipitate was filtered and air-dried. Recrystallization of this solid from acetone-isopropyl ether gave 4-(4-chlorophenyl)-2-(4,5-diphenyl-1-imidazolyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole as pale yellow prisms (220 mg, 46%). Melting point 118-119° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][O:9][CH:10]=2)=[N:15][CH:16]=1)([CH3:25])[CH3:24]
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 95 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24 mmol) was converted using isopropylamine instead of 4-aminotetrahydropyran to the title compound (76 mg, 95%) which was obtained as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:12][CH2:13][CH:14]=[CH2:15])([CH2:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:32][C:33](=[O:39])[C@@H:34]1[CH2:38][CH2:37][CH2:36][NH:35]1)([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[CH2:13]([O:12][P:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH2:7][CH2:8][C:9]([N:35]1[CH2:36][CH2:37][CH2:38][C@H:34]1[C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:39])=[O:11])=[O:6])[CH:14]=[CH2:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C=CCOP(=O)(CCC(=O)O)OCC=C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: C=CCOP(=O)(CCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)OCC=C
Reaction time: 1 h

Procedure:
3-[bis(2-propenyloxy)phosphinyl]propionic acid (3.4 g., 0.014 mol.) is dissolved in 75 ml. of acetonitrile and stirred in an ice bath under a drying tube. 1,1'-Carbonyldiimidazole (2.26 g., 0.014 mole) in 25 ml. of acetonitrile is added and the mixture is stirred for 1 hour. L-Proline t-butyl ester (2.38 g., 0.014 mole) is added, the ice bath is removed, and the mixture is stirred overnight. The solution is evaporated in vacuo, the residue dissolved in ethyl acetate and washed with 5% potassium bisulfate, saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and evaporated to a viscous liquid, 1-[3-[bis(2-propenyloxy)phosphinyl)]-1-oxopropyl]-L-proline, tert-butyl ester, yield 4.2 g., 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:10]1[CH2:11][CH2:12][C:7]2[NH:6][C:5]3[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH2:9]1)=[O:34]
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1NC(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 2-Methoxyphenyl isocyanate (0.03 mL, 0.24 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 31 (32 mg, 33% yield) as a yellow solid. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: [N:1]12[C:7](=[O:8])[CH2:6][CH:5]1[CH2:4][C:3](=[O:9])[CH:2]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:20][C:21](OC(C)=O)=[O:22]>N1C=CC=CC=1>[C:21]([O:9][C:3]1[CH2:4][CH:5]2[N:1]([C:7](=[O:8])[CH2:6]2)[C:2]=1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:22])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
A solution of benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (20 mg) in anhydrous pyridine (200 μl) and Ac2O (100 μl) is kept at 0° C. for 8 hrs. The mixture is evaporated in vacuo and the residue dissolved in EtOAc. This solution is washed with pH 2 phosphate buffer, 5% NaHCO3, and brine, dried with MgSO4, filtered, and evaporated i.v. to provide benzyl 3-acetoxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate. By substituting Ac2O with ##STR50## in Method B, various 3-acyloxy derivatives are obtained.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[C:15]([C:18](=[O:31])[CH:19]([NH:27][CH:28]([CH3:30])[CH3:29])C(OCCCC)=O)[CH:14]=[CH:13][C:12]=2[OH:32])=[O:8])[CH2:3][CH2:4][CH3:5]>CO.O1CCCC1>[ClH:1].[CH2:2]([O:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[C:15]([CH:18]([OH:31])[CH2:19][NH:27][CH:28]([CH3:30])[CH2:29][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8])[CH:14]=[CH:13][C:12]=2[OH:32])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC(=O)c1cc2c(C(=O)C(NC(C)C)C(=O)OCCCC)ccc(O)c2[nH]1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOC(=O)CC(C)NCC(O)c1ccc(O)c2[nH]c(C(=O)OCCCC)cc12
Yield: 97 %

Procedure:
Under the conditions of Example 14(E), 380 mg of 4-(2-n-butoxycarbonyl-1-methylethylaminoacetyl)-7-hydroxyindole-2-carboxylic acid n-butyl ester hydrochloride in 10 ml of methanol and 5 ml of tetrahydrofuran is hydrogenated and worked up, yielding 185 mg of 4-[1-hydroxy-2-(2-n-butoxycarbonyl-1-methylethylamino)ethyl]-7-hydroxyindole-2-carboxylic acid n-butyl ester hydrochloride, decomposition point 75°-84° C.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([OH:7])[C:5]([C:8](=[N:29][O:30][CH3:31])[C:9]([NH:11][C@@H:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19]OC(=O)C)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:4][S:3]1.O.O.[Na].[CH3:35][N:36]1[C:40]([SH:41])=[N:39][N:38]=[N:37]1.C([O-])(O)=O.[Na+]>O.Cl.C(O)=O.CO.C(Cl)(Cl)Cl>[NH:1]=[C:2]1[N:6]([OH:7])[C:5]([C:8](=[N:29][O:30][CH3:31])[C:9]([NH:11][C@@H:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19][S:41][C:40]4[N:36]([CH3:35])[N:37]=[N:38][N:39]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:4][S:3]1
Reactant: Cn1nnnc1S
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(=N)n1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(=N)n1O
Temperature: 67 °C
Yield: 77.5 %

Procedure:
To a mixture of 7β-[2-(2-imino-3-hydroxy-4-thiazolinyl)-2-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (prepared as described in example 1) (120 mg), and 1-methyl-5 mercapto-1,2,3,4-tetrazole sodium salt di-hydrate, (30 mg), in distilled water (7.5 ml), NaHCO3 was added in small portions with stirring, until a clear solution was obtained and a pH value of 6.5-7 was reached. This solution was heated for 6.5 hours in an oil bath at 67° C.; the progress of the reaction can be monitored by TLC (three-days-old CHCl3 160/MeOH 70/HCOOH 30 or freshly prepared CHCl3 160/MeOH 10/HCOOH 30 phases; the product has a slightly lower Rf value than the starting material). After cooling at 5° C., a few drops of 8% HCl were carefully added under stirring, causing the separation of a precipitate (at about pH 3). This was collected, washed with acetone (in order to remove excess 1-methyl-5-mercapto-1,2,3,4-tetrazole) and dried, thus giving 70 mg of the title compound, which was identical to that prepared in example 2.