Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1)[CH3:2].C([Li])(C)(C)C.[CH3:15][C:16]1([CH3:48])[CH:25]=[C:24](OS(C(F)(F)F)(=O)=O)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]3[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([F:47])[CH:37]=3)[CH:22]=2)[S:17]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:35][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([F:47])[CH:37]=4)[CH:22]=3)[S:17][C:16]([CH3:15])([CH3:48])[CH:25]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)S3)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1F
Temperature: 25 °C

Procedure:
A solution of 4-ethylbromobenzene (185.0 mg, 1.00 mmol) in 2.0 mL of THF was cooled to -78° C. and tert-butyllithium (128.5 mg, 2.0 mmol, 1.2 mL of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (204.5 mg, 1.5 mmol) in 4.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethylsulfonyloxy-(2H)-thiochromen-6-ylethynyl)-2-fluorobenzoate (Compound 234, 200.0 mg, 0.39 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 1 hour, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 158.0 mg (86%), was isolated by column chromatography (5% EtOAc/hexanes) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ: 7.88 (1H, d, J=7.8 Hz), 7.39-7.20 (9H,m), 5.86 (1H, s), 4.40 (2H, q, J=7.1 Hz), 2.72 (2H, q, J=7.6 Hz), 1.49 (6H, s), 1.40 (3H, t, J=7.1 Hz), 1.30 (3H, t, J=7.6 Hz).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]([N:5]([CH2:14][C:15]([N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CN)c1
Product: COc1cccc(N(CC(=O)N(C)c2ccccc2)C(=O)CNC(=O)Nc2cccc(C)c2)c1
Yield: 53.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with 2-[2-amino-N-(3-methoxyphenyl)acetamido]-N-methyl-N-phenylacetamide (1.6 g) and 3-methylphenyl isocyanate (0.67 g), and after recrystallisation in acetonitrile, 2-{N-(3-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}-N-methyl-N-phenylacetamide (1.2 g), m.p. 179° C., is obtained.
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][C:8]2[O:12][C:11]([C:13]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:25]([O:28][CH3:29])=[N:26][CH:27]=4)[CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][N:17]4S(C3C=CC=CC=3)(=O)=O)=[N:10][N:9]=2)[CH2:5][CH2:4][N:3]2[CH2:44][CH2:45][CH2:46][C@@H:2]12.[OH-].[Na+]>O1CCOCC1>[CH2:1]1[N:6]([CH2:7][C:8]2[O:12][C:11]([C:13]3[CH:21]=[C:20]([C:22]4[CH:23]=[C:24]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[C:25]([O:28][CH3:29])=[N:26][CH:27]=4)[CH:19]=[C:18]4[C:14]=3[CH:15]=[N:16][NH:17]4)=[N:10][N:9]=2)[CH2:5][CH2:4][N:3]2[CH2:44][CH2:45][CH2:46][C@@H:2]12
Reactant: COc1ncc(-c2cc(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
N-[5-[4-{5-[(8aS)-Hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylmethyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (95 mg, 0.143 mmol) was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 0.143 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was dried down under a stream of nitrogen and the residue partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml). The organic layer was separated, dried by passing through a hydrophobic frit and the solvent removed in vacuo to give an orange oil. This was triturated with cyclohexane to give the title compound as an orange solid (26 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][N:13](C(OCC3C=CC=CC=3)=O)[N:12]2[C:26](=[O:44])[C@@H:27]([CH2:32][N:33]([CH:42]=[O:43])[O:34]CC2C=CC=CC=2)[CH2:28][CH2:29][CH2:30][CH3:31])=[O:10])=[N:6][CH:7]=1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][NH:13][N:12]2[C:26](=[O:44])[C@@H:27]([CH2:32][N:33]([CH:42]=[O:43])[OH:34])[CH2:28][CH2:29][CH2:30][CH3:31])=[O:10])=[N:6][CH:7]=1
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccc(F)cn2)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCC[C@H](CN(O)C=O)C(=O)N1NCC[C@H]1C(=O)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
To a solution of phenylmethyl (3S)-3-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl]-1-pyrazolidinecarboxylate (230 mg, 0.38 mmol) in methanol (30 mL) was added Pd(OH)2/C (230 mg). The mixture was degassed and then stirred under an H2 atmosphere for 3 h at rt. The catalyst was filtered off. The filtrate was concentrated and the residue was purified by pre-HPLC to provide the title compound (67 mg, 48%). LCMS: (M+H)+: 382.2.
Reaction SMILES: [CH3:1][O:2][C:3]([O:12][CH3:13])([O:10][CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14](O)(=O)[C:15]1C=CC=CC=1>>[CH3:13][O:12][C:3]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[O:10][CH:11]2[CH:1]([CH2:14][CH2:15]2)[O:2]1
Reactant: O=C(O)c1ccccc1
Reactant: COC(OC)(OC)c1ccccc1
Product: COC1(c2ccccc2)OC2CCC2O1
Yield: 4737.1 %

Procedure:
21.5 g (0.25 mol) of cyclobutane-cis-1,2-diol, 47.8 g (0.26 mol) of orthobenzoic acid trimethyl ester and 0.5 g of benzoic acid are heated to 100° to 150° C. in the course of 3 hours. The methanol which forms is distilled off continuously. The residue is subjected to fractional distillation and gives 40.0 g (78%) of 3-methoxy-3-phenyl-2,4-dioxa-bicyclo[3,2,0]heptane (stereoisomer mixture) of boiling point0.7 92°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:13])[C:5]2[CH:6]=[CH:7][C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22]>CN(C=O)C>[F:1][C:2]1[CH:3]=[N+:4]([O-:13])[C:5]2[CH:6]=[CH:7][C:8](=[O:12])[N:9]([CH2:22][CH:21]=[CH2:20])[C:10]=2[CH:11]=1
Reactant: C=CCI
Reactant: O=c1ccc2c(cc(F)c[n+]2[O-])[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 7-fluoro-1,5-naphthyridin-2(1H)-one 5-oxide (0.995 g, 5.524 mmol) and potassium carbonate were stirred in anhydrous DMF (20 mL) under argon, and allyl iodide (1.5 mL, ca. 3 eq.) was added. The mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue was partitioned between DCM (100 mL) and water (50 mL). The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give the crude product as a brown gum. This was purified by column chromatography on silica gel eluted with 0-10% methanol in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give 7-fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one 5-oxide (0.341 g) as a tan amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:35])[CH:3]=1.Cl.[NH2:37][OH:38].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][S:29]([CH3:32])(=[O:30])=[O:31])=[O:25])=[CH:33][CH:34]=2)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:35])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N-(2-(methylsulfonyl)ethyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=530.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[C:12](=[N:21][OH:22])[C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CC(C)=O)cc1OC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(=NO)C(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of 1-(3,4-dimethoxyphenyl)butane-1,3-dione (41) were initially introduced into 25 ml of acetic acid, and. 1.71 g of sodium nitrite, dissolved in 5 ml of water, were then added dropwise at 15° C. The reaction solution was stirred at RT for 1 h and then remained standing for 2 h. 50 g of ice were added to the solution and the whole was then stored at 0° C. for 12 h, in connection with which the product precipitated out. The product was subsequently filtered off with suction and dried at 50° C. in a drying oven. The following was obtained: 42 C12H13NO5 (251.24); MS (ESI) 252 (M+H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH:28]([O:31][C:32](=[O:49])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[C:34]=1[CH3:48])([CH3:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH:28]([O:31][C:32]([C:33]1[C:34]([CH3:48])=[C:35]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])=[NH:9])[S:11][C:12]=3[S:25][CH3:26])(=[O:17])=[O:16])[CH:19]=2)[CH:36]=[CH:37][CH:38]=1)=[O:49])([CH3:30])[CH3:29]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1C(=O)OC(C)C
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: CCO
Solvent: Cc1ccccc1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2cccc(C(=O)OC(C)C)c2C)c1
Yield: 49.3 %

Procedure:
The procedure used in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid isopropyl ester ((Example 3: step b) 92 mg, 0.3 mmol), Na2CO3 (2M, 0.4 mL, 0.8 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.4 mL) and toluene (0.8 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (25% EtOAc in hexanes) yielded the title compound (29 mg, 49%) as a colorless glass. 1H-NMR (CDCl3): δ 7.98 (dt, 1H, J=1.6, 7.6 Hz), 7.93 (m, 2H), 7.79 (t, 1H, J=1.7 Hz), 7.58 (t, 1H, J=7.6 Hz), 7.53 (dt, 1H, J=1.6, 7.6 Hz), 7.36 (s, 1H), 7.30 (d, 1H, J=4.5 Hz), 5.27 (heptet, 1H, J=6.2 Hz), 2.58 (s, 3H), 2.35 (s, 3H), 1.51 (s, 9H), 1.39 (d, 1H, J=6.2 Hz). ESI-MS (m/z): Calcd. for C28H32N2O6S3: 588.8; found: 588.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([O:10]CC)=[O:9].[C:30]([N:34]=[C:35]=[O:36])([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:30]([NH:34][C:35]([NH:1][CH2:2][C:3]1[N:4]=[C:5]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH3:29])=[C:25]([Cl:28])[C:26]=3[Cl:27])=[O:21])[CH2:15][CH2:14]2)[S:6][C:7]=1[C:8]([OH:10])=[O:9])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)N=C=O
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNC(=O)NC(C)(C)C)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.7 %

Procedure:
Ethyl 4-(aminomethyl)-2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 246; 200 mg; 0.424 mmol) was dissolved in DCM (4 ml). tert-Butyl isocyanate (130 mg; 1.28 mmol) was added and the mixture stirred at room temperature for 1 h. The solvent was removed in vacuo and the ester (215 mg), LCMS:561 was treated with LiOH/THF in a manner analogous to Example 31 to give the title compound (290 mg).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10](I)[CH:9]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[N:19]1>CN(C=O)C>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([N:19]2[N:20]=[CH:21][CH:22]=[N:18]2)[CH:9]=1
Reactant: c1c[nH]nn1
Reactant: O=C(O)c1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(Cl)cc1-n1nccn1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (12.0 g, 37 mmol) was added portionwise to a rt solution of commercially available 4-chloro-2-iodobenzoic acid (5.22 g, 18.5 mmol) in DMF (25 mL) followed by 1H-1,2,3-triazole (1.61 mL, 27.8 mmol) and Cu(I)I (210 mg, 1.1 mmol). The resulting blue suspension was stirred at 120° C. for 30 min, then the rxn mixture was quenched with 2M aq. HCl and filtered through a celite plug before being extracted with DCM (3×). The combined org. layers were dried (Na2SO4), filtered and evaporated in vacuo to give the crude product that was purified by FC (Biotage SP1: eluting with DCM/MeOH 95:5+0.1% AcOH) to give the title compound A-1-1 as a brown solid. LC-MS A: tR=0.66 min; [M(35Cl)+H]+=224.10.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl.O.O.N>C(O)C>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CCOC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccc2[nH]ncc2c1
Yield: 48 %

Procedure:
The resulting ethyl 1-acetyl-1H-indazole-5-carboxylate was stirred in a mixture of concentrated hydrochloric acid (15 ml), water (15 ml) and ethanol (30 ml) for 15 hours at a room temperature. The resulting mixture was rendered faintly alkaline with a 25% ammonia water. The faintly alkalified mixture was subjected to extraction with chloroform. The extract was crystallized from n-hexane, and then the resulting crystal was separated by filtration and dried to give the title compound (6.45 g, 48%) as a light-brown powder.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:25])[CH3:22].C([BH3-])#N.[Na+].O>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([N:35]3[CH2:34][CH2:33][N:32]([C:29]4[CH:28]=[CH:27][C:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])=[CH:31][CH:30]=4)[CH2:37][CH2:36]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCCCCCOc1ccc(N2CCC(=O)CC2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: CCCCCCOc1ccc(N2CCC(N3CCN(c4ccc(C(=O)OCC)cc4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A mixture of 1-(4-n-Hexyloxyphenyl)-4-piperidone (0.823 g), 1-(4-Ethoxycarbonylphenyl)piperazine (0.7 g), and titanium(IV) isopropoxide (1.11 ml) was stirred at room temperature. After 1 hour, the IR spectrum of the mixture showed no ketone band, and the viscous solution was diluted with absolute ethanol (3 ml). Sodium cyanoborohydride (0.121 g) was added, and the solution was stirred for 3 hours. Water (3 ml) was added with stirring, and the resulting in organic precipitate was filtered and washed with ethanol. The filtrate was extracted with ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure to give Ethyl 4-[4-[1-(4-n-hexyloxyphenyl)piperidin-4-yl]piperazin-1-yl]benzoate (331 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][NH:7][C:8]([NH2:10])=[O:9])[NH:4][C:3]1=[O:11].C(=O)(O)[O-].[Na+].Cl.[Cl:18][CH2:19][C:20]([NH:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:32]/[O:33][C:34]([CH3:49])([C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:37])[CH3:35])/[C:29](Cl)=[O:30])[N:27]=1)=[O:21]>O.O1CCCC1>[Cl:18][CH2:19][C:20]([NH:22][C:23]1[S:24][CH:25]=[C:26](/[C:28](=[N:32]/[O:33][C:34]([CH3:49])([C:36]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=2)=[O:37])[CH3:35])/[C:29]([NH:1][C@H:2]2[C@@H:5]([CH2:6][NH:7][C:8]([NH2:10])=[O:9])[NH:4][C:3]2=[O:11])=[O:30])[N:27]=1)=[O:21]
Reactant: CC(C)(O/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)NC[C@H]1NC(=O)[C@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N[C@@H]1CNC(N)=O)c1csc(NC(=O)CCl)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 66.4 %

Procedure:
A 350 mg portion of the thus-obtained cis-3-amino-4-ureidomethyl-2-azetidinone (433 mg) is dissolved in a mixture of 25 ml of water and 25 ml of tetrahydrofuran and, under ice-cooling and stirring, 628 mg of sodium bicarbonate is added. Then, 1.43 g of 2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acetyl chloride hydrochloride is added and the mixture is stirred at room temperature for 2 hours. The tetrahydrofuran is distilled off under reduced pressure, 50 ml of water is added to the residue, and the mixture is stirred. The crystalline precipitate is collected by filtration, washed with aqueous sodium bicarbonate, water and hexane in that order, and dried to give 1.1 g of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acetamido]-4-ureidomethyl-2-azetidinone as colorless crystals.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([Mg]Cl)([CH3:11])([CH3:10])[CH3:9].O>CCOCC>[CH3:9][C:8]([CH3:11])([C:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:10]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C(Cl)C1CCC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C(=O)C1CCC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Cuprous iodide (1.0 gm) was added to a solution of cyclobutane carboxylic acid chloride (15.0 gms) in dry ether (40 mls) under an argon atmosphere. The suspension was stirred and cooled to -70° C. A solution of t-butyl magnesium chloride in ether (61.4 mls of 2M solution) was then added dropwise, whilst the temperature was maintained below -70° C. After the addition was complete, stirring was continued at -70° C. for 1 hour and then for several hours whilst the temperature was allowed to reach 20° C. Water was carefully added to the mixture. The ether layer was separated, combined with an extract of the aqueous phase and washed with dilute caustic soda. Drying and evaporation gave 4.9 gms of yellow oily product. Gas chromatography showed 80% of a major component. The product was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:11][CH3:12])[CH:10]=1)=[O:5])C.[OH-].[Li+]>C1COCC1.O>[CH2:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[C:8]1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCOC(=O)c1cn(CC)c(-c2cccc3ccccc23)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(C(=O)O)nc1-c1cccc2ccccc12
Temperature: 50 °C

Procedure:
1-Ethyl-2-naphthalen-1-yl-1H-imidazole-4-carboxylic acid ethyl ester (2.2 g, 7.48 mmol) is dissolved in THF (20 ml), followed by the addition of aqueous lithium hydroxide solution (2.0 N, 7.5 ml, 2.0 eq.). The mixture is heated at 50° C. overnight. THF is stripped off under reduced pressure, and the residue is diluted with water (10 ml), basified to pH=4˜5. The solid precipitate is collected, washed with water and ether, dried under high vacuum to give the title compound. LCMS 267 (M+1).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 41 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-octyl chloroformate. Yield: 41% of theory, C36H44N6O5 (640.8) Rf value: 0.43 (silica gel; dichloromethane/ethanol=19:1) ##EQU66##