Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].[O:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:23]([NH2:41])=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=3)[CH2:18][CH2:17]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[NH2:41][C:23]1[C:22]([N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])[CH:29]=2)[N:24]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: O=C(c1ccccc1Br)C1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccc(-c3ccccc3C(=O)C3CCOCC3)cc2cc1N1CCOCC1
Temperature: 120 °C

Procedure:
(2-Bromophenyl)(tetrahydro-2H-pyran-4-yl)methanone (0.46 g, 1.69 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.50 g, 1.13 mmol, prepared as in Example 2, Step 1-2), potassium phosphate tribasic (0.37 mL, 4.50 mmol), 2-dicyclohexylphosphino-2′,4′,6′,-triisopropylbiphenyl (0.054 g, 0.113 mmol), and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (0.029 g, 0.028 mmol) were suspended in a mixture of dioxane (3 mL) and water (0.5 mL) and heated in the microwave to 120° C. for 30 min. The crude material was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated, dried with magnesium sulfate and evaporated to dryness under reduced pressure before purification using silica column chromatography (0-5% MeOH in DCM). The isolated material was further purified using silica column chromatography (60-100% ethyl acetate in hexane) to give (2-(2-amino-3-morpholinoquinolin-6-yl)phenyl)(tetrahydro-2H-pyran-4-yl)methanone. MS (ESI, pos. ion) m/z: 418 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[C:17]=[CH2:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCc1c(C)nc2c(OCc3ccccc3C)cccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C=Cc1c(C)nc2c(OCc3ccccc3C)cccn12
Yield: 27.3 %

Procedure:
A solution of 8-(2-methylbenzyloxy)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.99 g) and 1N-sodium hydroxide solution (5.65 ml) in methanol (50 ml) was stirred for 72 hours at room temperature. The mixture was evaporated in vacuo and the residue was dissolved in chloroform. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (14 g) with a mixture of chloroform and ethyl acetate (15:1) as an eluent to give 8-(2-methylbenzyloxy)-3-(1,2-propadienyl)-2-methylimidazo[1,2-a]pyridine (0.27 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25](C)(C)C)=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:48]#[C:49][C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:25][C:5]1[C:6]2[CH:7]=[CH:8][C:9]([C:48]#[C:49][C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)=[CH:10][C:11]=2[C:2]([CH3:1])([CH3:29])[CH2:3][CH:4]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1,1-dimethylethyl)naphth-3-yl)ethynyl]benzoate (Compound 71), 300 mg (0.63 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (colorless oil) using 84 mg (0.94 mmol) of cuprous cyanide, 40 mg (0.94 mmol) of lithium chloride and 41 mg (1.54 ml, 1.88 mmol) of methyllithium (1.22M solution in Et2O).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 150 °C
Yield: 16.1 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (120 mg, 0.346 mmol) from Step 4 of Example 70, (1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol), and DIEA (89 mg, 0.692 mmol) in anhydrous DMA (2.5 mL) was heated in a Biotage microwave synthesizer at 150° C. for 30 min. LCMS analysis indicated that the reaction was incomplete. Additional (1R,2R)-(−)-trans-1-amino-2-indanol (103 mg, 0.692 mmol) and DIEA (89 mg, 0.692 mmol) were added and the mixture was further heated in a Biotage microwave synthesizer at 150° C. for 2 h. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-1-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (24 mg, 16%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.40-8.50 (m, 2H), 8.09 (dd, J=2.6, 9.4 Hz, 1H), 7.73 (d, J=1.1 Hz, 1H), 7.32-7.39 (m, 1H), 7.10-7.31 (m, 5H), 5.47-6.00 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.30 (d, J=3.6 Hz, 1H), 3.16 (dd, J=7.0, 15.6 Hz, 1H), 2.74 (dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 432 (M+H)+.
Reaction SMILES: COC1C=C(C(C2C=CC=C(N)C=2)=CC#N)C=CC=1OC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]([C:36]2[CH:41]=[CH:40][C:39]([N+:42]([O-])=O)=[CH:38][CH:37]=2)=[CH:33][C:34]#[N:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>[Pd].C(OCC)(=O)C>[NH2:42][C:39]1[CH:40]=[CH:41][C:36]([C:32]([C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:33][C:34]#[N:35])=[CH:37][CH:38]=1
Reactant: COc1ccc(C(=CC#N)c2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Agent: COc1ccc(C(=CC#N)c2cccc(N)c2)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=CC#N)c2ccc(N)cc2)cc1OC

Procedure:
3-(4-Aminophenyl)-3-(3,4-dimethoxyphenyl)acrylonitrile was prepared analogously to 3-(3,4-dimethoxyphenyl)-3-(3-aminophenyl)acrylonitrile using 3-(3 ,4-dimethoxyphenyl)-3-(4-nitrophenyl)acrylonitrile (1.24 g, 4 mmol) and 0.15 g of 10% palladium on carbon catalyst in 100 mL of ethyl acetate. The crude mixture was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) to afford 0.19 g (17%) of a mixture of the E and Z isomers as a yellow solid: mp 150-152° C.; 1H NMR (CDCl3) δ 7.38-6.56 (m, 14 H); 5.51 (s, 1 H), 5.44 (s, 1 H), 3.97 (br s, 4 H), 3.93 (s, 3 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.82 (s, 3 H); 13C NMR (CDCl3) δ 162.8, 162.6, 150.8, 150.3, 148.8, 148.7, 148.5, 148.4, 132.4, 131.4, 130.1, 129.5, 129.9, 128.6, 126.7, 123.0, 122.1, 114.4, 114.3, 112.8, 111.6, 110.7, 90.3, 89.9, 56.0, 55.9; Anal. Calcd for C17H16N2O3. Theoretical: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.79; H, 5.83; N, 9.59.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:20]=[C:19]([Cl:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>C(COC)OC>[Cl:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=[C:11]2[CH:20]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(Cl)c2ccccc2n1
Solvent: COCCOC
Product: CCOC(=O)c1cn2c(cc(Cl)c3ccccc32)n1
Reaction time: 0.5 h

Procedure:
4 g of ethyl bromopyruvate were added to a solution of 2 g of 2-amino-4-chloroquinoline [Hardman et al C.S., (1958), p. 614] in 40 ml of dimethoxyethane and the mixture obtained was allowed to stand at room temperature for 30 minutes. The quaternary salt thus precipitated was filtered off, washed with ether and then was dissolved in ethanol. The solution obtained was heated at reflux for 1 hour and then the ethanol was removed under vacuum. The residue was dissolved in chloroform and the solution was washed with dilute sodium carbonate solution and water, was decolorized with charcoal and the solvent was evaporated to leave a white solid. This solid was recrystallized from methanol to obtain fine white needles of ethyl 5-chloroimidazo-[1,2-a]-quinoline-2-carboxylate melting at 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(O)(=O)C.C(O)C>O.[Fe]>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a 100 mL, 3-neck round bottom flask was charged 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2.40 g, 10.7 mmol), acetic acid (4 mL), ethanol (4.8 mL) and water (4.8 mL). The mixture was cooled to 5° C. and iron powder (2.98 g, 53.4 mmol) was added portionwise over ˜15 minutes. The reaction was allowed to stir at 20° C. for 18 hours and diluted to 50 mL with water. It was filtered through Celite® and the filtrate was carefully basified with 50 wt % sodium hydroxide solution. The resulting suspension was filtered through Celite® and the filtrate was extracted with ethyl acetate (3×20 mL). The organic layers were combined and dried over sodium sulfate and concentrated to dryness to afford a tan colored solid, which was further dried under vacuum for 18 hours (2.20 g, quantitative): mp 145-147° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J=2.6, 0.8 Hz, 1H), 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.08 (ddd, J=8.4, 2.7, 1.4 Hz, 1H), 7.91 (s, 1H), 7.49 (ddd, J=8.3, 4.7, 0.8 Hz, 1H), 4.43 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 146.35, 138.53, 135.72, 132.09, 130.09, 124.29, 124.11, 114.09; EIMS m/z 194 ([M]+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])=[O:15])([O-:12])=[O:11].I[CH2:26][C:27]([CH2:29]I)=[CH2:28]>CN(C)C=O>[CH2:26]=[C:27]1[CH2:29][C:13]([N+:10]([O-:12])=[O:11])=[C:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[O:15][CH2:28]1
Reactant: O=C(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Reactant: C=C(CI)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
A mixture of 3-chloro-2-(chloromethyl)prop-1-ene (1.0 g, 8 mmol) and sodium iodide (6.6 g, 44 mmol) in acetone (60 mL) was stirred at room temperature for 20 hours, evaporated under reduced pressure and dissolved in dichloromethane (150 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 3-iodo-2-(iodomethyl)prop-1-ene as a reddish oil (2.45 g). N,N-diisopropylethylamine (0.20 mL) was added to a solution of 2-nitro-1-(2,4,5-trifluorophenyl)ethanone (110 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (170 mg, 0.55 mmol) and the mixture was heated at 60° C. for 2.5 hours, evaporated and purified by chromatography on a Biotage Horizon® system (silica, gradient 0-30% dichloromethane in hexane) to yield 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH2:37])O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([C:36]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH2:37])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: C=C(c1ccccc1)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 50 °C

Procedure:
A sealed tube was charged with 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Preparative Example 3.1, 150 mg, 0.337 mmol), 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (93 mg, 0.405 mmol), PdCl2(dppf)-dichloromethane adduct (27.5 mg, 0.034 mmol), and potassium phosphate (215 mg, 1.012 mmol). The tube was evacuated and backfilled with argon (3×). Fully degassed dioxane (1.53 mL) and water (0.153 mL) were added. The vial was sealed and heated at 50° C. overnight. The mixture was then cooled to room temperature and directly purified via silica gel chromatography (0-100% ethyl acetate/hexanes) to afford 4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-(1-phenylethenyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile as a yellow solid. MS ESI calcd. for C28H26ClN5 [M+H]+ 468. found 468.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][C:15](=[O:18])[C:14]3[S:13][C:12]([C:19]([NH2:21])=[O:20])=[N:11][C:10]=3[C:9]=2[CH:22]=1.[BH4-].[Na+].O>CO>[OH:18][CH:15]1[C:14]2[S:13][C:12]([C:19]([NH2:21])=[O:20])=[N:11][C:10]=2[C:9]2[CH:22]=[C:5]([C:4]#[C:3][C:2]([OH:1])([CH3:23])[CH3:24])[CH:6]=[CH:7][C:8]=2[O:17][CH2:16]1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(=O)CO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (80 mg, 0.23 mmol) in MeOH (5 mL) at 0° C., NaBH4 (9 mg, 0.23 mmol) was added. The mixture was allowed to warm to room temperature, and stirred for 2 h, then water (2 mL) was added. The mixture was extracted with EtOAc (10 mL×3) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4-Hydroxy-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as a white solid (29 mg, 36%). 1H NMR (400 MHz, DMSO-d6): 8.57 (d, J=2.1 Hz, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 7.31 (dd, J1=8.3 Hz, J2=2.2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.38 (d, J=7.2 Hz, 1H), 5.45 (s, 1H), 5.09-5.14 (m, 1H), 4.08-4.35 (m, 2H), 1.49 (s, 6H); LC-MS (ESI & APCI): 345.3 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[CH:27]=[CH:28][CH:29]=[C:30]([C:31](O)=[O:32])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[OH:34][CH:35]1[CH2:38][NH:37][CH2:36]1>>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([N:37]4[CH2:38][CH:35]([OH:34])[CH2:36]4)=[O:32])[C:15]=3[N:14]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)nc3c(C(=O)O)cccc32)c1
Reactant: OC1CNC1
Product: COc1cccc(Cn2c(C(=O)NC3CCN(C(C)C)CC3)nc3c(C(=O)N4CC(O)C4)cccc32)c1

Procedure:
4-(3-Hydroxy-azetidine-1-carbonyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 150 mg (0.287 mmol) 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1-(3-methoxy-benzyl)-1H-benzoimidazole-4-carboxylic acid and 23.0 mg (0.315 mmol) 3-hydroxy-azetidine. The title compound was obtained as its formiate in form a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25].[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])[N:20]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2c-3ccc(F)c2Cl)n1
Yield: 38.7 %

Procedure:
A suspension of 1.11 g (0.0028 mol) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 80 ml of tetrahydrofuran was treated with 7.6 ml (0.056 mol) of dipropylamine. After stirring at reflux for 24 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.50 g (39%) of 7-chloro-3-(4-dipropylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one as white crystals; m.p. 123°-1250.
Reaction SMILES: C[Si](CC(N)=O)(C)C.C[Si](C)(C)Cl.[NH2:14][C@@H:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([S:22][CH2:23][C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[CH2:20][S:21][C@H:16]12.C(=O)=O.C([O-])(=O)C.[Cl:41][C:42]1[S:46][C:45]([NH:47]C=O)=[N:44][C:43]=1/[C:50](=[N:54]/[O:55]C(=O)C)/[C:51](Cl)=[O:52]>ClCCl.CO>[NH2:47][C:45]1[S:46][C:42]([Cl:41])=[C:43](/[C:50](=[N:54]/[OH:55])/[C:51]([NH:14][C@@H:15]2[C:32](=[O:33])[N:17]3[C:18]([C:29]([OH:31])=[O:30])=[C:19]([S:22][CH2:23][C:24]4[CH:28]=[N:27][NH:26][CH:25]=4)[CH2:20][S:21][C@H:16]23)=[O:52])[N:44]=1
Reactant: CC(=O)O/N=C(\C(=O)Cl)c1nc(NC=O)sc1Cl
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cn[nH]c3)CS[C@H]12
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)CC(N)=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cn[nH]c4)CS[C@H]23)c(Cl)s1
Temperature: 0 °C
Reaction time: 12 h
Yield: 40.6 %

Procedure:
Under nitrogen atmosphere, trimethylsilylacetamide (39.4 g) and trimethylchlorosilane (0.76 ml) were added successively to a suspension of 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (9.4 g) in dichloromethane (100 ml) at 0° C. The mixture was refluxed for 1.5 hours, then cooled again to -15° C. with dry ice-acetate. 2-(5-Chloro-2-formylaminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetyl chloride (12.6 g) was added portionwise to the mixture over 10 minutes at the same temperature. The whole mixture was stirred for 12 hours at 0° C., then poured into 100 ml of ice-cooled methanol. After the solvent was concentrated in vacuo, 17 ml of concentrated hydrogen chloride was added at 0° C., and stirred for 7 hours. The mixture was poured into water (400 ml) and the pH was adjusted to between 3.4 and 3.6 with 28% ammonium hydroxide, and stirred for 12 hours at 0° C. The resulting precipitate was collected by filtration, and chromatographed on HP-20 to afford 7β-[2-(2-amino-5-chlorothiazol-4-yl)-2-(Z)-(hydroxyimino)-acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (6.30 g) as crystals. The physical data was identical with that the object compound of Example 3.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[CH2:7]([C:10]1([S:13]([N:16]2[C:20]3[C:21]4[O:25][CH:24]=[CH:23][C:22]=4[C:26]([F:29])=[C:27]([F:28])[C:19]=3[N:18]([C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])C2=O)(=[O:15])=[O:14])[CH2:12][CH2:11]1)[CH:8]=[CH2:9].C(OCC)(=O)C>C1COCC1.CCCCCC>[CH2:7]([C:10]1([S:13]([NH:16][C:20]2[C:21]3[O:25][CH:24]=[CH:23][C:22]=3[C:26]([F:29])=[C:27]([F:28])[C:19]=2[NH:18][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])(=[O:15])=[O:14])[CH2:12][CH2:11]1)[CH:8]=[CH2:9]
Reactant: C=CCC1(S(=O)(=O)n2c(=O)n(-c3ccc(I)cc3F)c3c(F)c(F)c4ccoc4c32)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(F)c(F)c3ccoc23)CC1
Temperature: 30 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
Potassium trimethyl silanolate (0.105 g, 0.82 mmol) was added to a solution of 1-(1-allylcyclopropylsulfonyl)-4,5-difluoro-3-(2-fluoro-4-iodophenyl)-1H-benzofuro[6,7-d]imidazol-2(3H)-one (0.230 g, 0.4108 mmol) in THF (5 mL) at 0° C. The reaction mass was stirred for 4 hours at 20-40° C. The reaction was monitored by TLC (10% ethyl acetate in hexane). The reaction mass was concentrated under reduced pressure and the concentrate was extracted with ethyl acetate. The organic layer was washed with water, brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford the crude compound. Purification by column chromatography on silica gel (10% ethyl acetate in hexane) afforded 0.177 g of the product (78% yield). 1H NMR (CDCl3, 300 MHz): δ 7.54 (d, 1H), 7.40 (dd, 1H), 7.25 (s, 1H), 7.05 (bs, 1H), 6.99 (d, 1H), 6.32-6.39 (m, 1H), 6.22 (s, 1H), 5.65-5.75 (m, 1H), 5.19 (s, 1H), 5.10 (d, 1H), 2.88 (d, 2H), 1.15 (t, 2H), 0.75 (t, 2H). LCMS: 96.32%, m/z=548.8 (M+1). HPLC: 97.19%.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]([Cl:12])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH3:8])[CH3:3].[Br:13]Br>C(Cl)(Cl)Cl.Cl>[CH3:3][C:2](=[CH:4][CH:5]([Cl:12])[C:6]([CH3:11])([CH3:10])[C:7](=[O:9])[CH2:8][Br:13])[CH3:1]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)C(Cl)C=C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)=CC(Cl)C(C)(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
6.03 g (0.032 mol) of 2,5,5-trimethyl-4-chloro-2-hepten-6-one are dissolved in 75 ml of chloroform, 2 drops of an ethereal hydrogen chloride solution are added, and 5.12 g (0.032 mol) of bromine are then added in one portion at 25° C. The mixture is stirred for 2.5 hours at room temperature, and hydrogen bromide and solvent are distilled off in vacuo; the final residues are removed in a high vacuum. 8.7 g are obtained of crude, 2,5,5-trimethyl-4-chloro-7-bromo-2-hepten-6-one, the structure of which is confirmed by the 1H-NMR spectrum. It is used directly in the next stage: