Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1CN=C(C2C=CC=CN=2)C2C=C([Br:19])C=CC=2N=1.[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21].BrCC(=O)C(OCC)=O.C(OCC)C>O1CCCC1>[BrH:19].[CH2:20]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH3:21]
Reactant: NC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Agent: CCOC(=O)C(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Br
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
A suspension of 52 g of 2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepine in 1.5 l of tetrahydrofuran was treated in succession with 58 ml of N-ethyldiisopropylamine and 44 ml of ethyl bromopyruvate and the mixture was stirred at 65° C. for 20 min. Then, a further 5.8 ml of N-ethyldiisopropylamine and 44 ml of ethyl bromopyruvate were added and the mixture was stirred at 65° C. for a further 20 min. After cooling in an ice bath 0.5 l of diethyl ether was added and the crystals were filtered off. 49.5 g of N-ethyldiisopropylamine hydrobromide were obtained. The filtrate was evaporated in a vacuum, the residue was taken up in dichloromethane and shaken twice with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate and chromatographed over 2 kg of silica gel. With dichloromethane/ethanol 197:3 and 196:4 there were firstly eluted small amounts of impurities, then with dichloromethane/ethanol 97:3, 95:5 and 94:6 there were isolated a total of 58.2 g of ethyl 3-[2-amino-7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-1-yl]pyruvate. This was dissolved in 11 of acetic acid and stirred at 100° C. for 3.5 h. The solution was then evaporated in a vacuum and the residue was partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution (11 of each). The dichloromethane phase was separated, dried over sodium sulphate and chromatographed over 2 kg of silica gel. 17.2 g of ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate were obtained as dark red crystals by elution with ethyl acetate. This was again chromatographed over 2 kg of silica gel. Strongly coloured impurities were eluted with ethyl acetate/dichloromethane 1:1 and 2:1. The desired ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate was eluted with ethyl acetate. There were obtained 11.7 g of ethyl 8-bromo-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate of m.p. 227-230° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[O:11]C.B(Br)(Br)Br>ClCCl>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:10])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc(I)c(OC)cc1I
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(I)c(O)cc1I
Yield: 81.3 %

Procedure:
1,4-Diiodo-2,5-dimethoxy-benzene (3.65 g, 9.36 mmol) was added to 100 mL of dichloromethane and stirred under nitrogen at ice bath temperature. Boron tribromide (10.3 mL, 10.3 mmol) was added dropwise, and the reaction mixture was stirred at ice bath temperature for 20 hours. The reaction was quenched by dropwise addition of methanol, and the reaction mixture was poured into water and extracted into dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2.86 g of 2,5-Diiodo-4-methoxy-phenol, MS (M+H)=377.
Reaction SMILES: [C:1](=[N:14][OH:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:17][NH:18][CH2:19][CH2:20][CH2:21]Cl>>[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][O:15][N:14]=[C:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCCCl
Reactant: ON=C(c1ccccc1)c1ccccc1
Agent: Cl
Product: CNCCCON=C(c1ccccc1)c1ccccc1
Yield: 62 %

Procedure:
Benzophenone O-(3-methylamino-propyl)oxime was prepared in 62% yield from benzophenone oxime and N-methyl-3-chloropropylamine hydrochloride by the procedure described above for the preparation of benzophenone O-(2-N-methylaminoethyl)oxime (Preparation 13, Step 1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1.C([O-])(=O)C.[K+].O1CCOCC1>CS(C)=O>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: Fc1ccc(Br)cc1-c1ccccn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: OB(O)c1ccc(F)c(-c2ccccn2)c1
Temperature: 85 °C
Reaction time: 15 h

Procedure:
To 2-(5-bromo-2-fluorophenyl)pyridine (544 mg, 2.16 mmol) and bis(neopentyl glycolato)diborane (585 mg, 2.60 mmol) under nitrogen was added dry potassium acetate (450 mg, 4.58 mmol), anhydrous 1,4-dioxane (8 ml) and DMSO (1 ml). The mixture was degassed with nitrogen, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (50 mg, 3 mol %) was added. After stirring at 85° C. under nitrogen for 15 h, the mixture was cooled to room temperature, and sodium hydroxide solution (20 ml of a 1 M solution) was added. The mixture was stirred for 10 min, and was then extracted twice with diethyl ether. The combined ether extractions were washed with water, then the combined aqueous layers were filtered through a glass fibre filter paper. The pH of the filtrate was adjusted to 6 by the addition of 2 N hydrochloric acid, precipitating a white solid. This was collected by filtration, washed with water and dried in vacuo at 60° C., and was found to be 4-fluoro-3-(pyridin-2-yl)phenylboronic acid (455 mg, 97%): 1H NMR (400 MHz, DMSO) δ 7.30 (1H, dd, J 8.2, 11.7 Hz), 7.41 (1H, m), 7.77 (1H, m), 7.90 (2H, m), 8.16 (2H, s), 8.36 (1H, dd, J 1.6, 8.6 Hz), 8.72 (1H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=S)=[CH:4][CH:3]=1.CI.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>CC#N.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:25]\[C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1
Reactant: S=c1ccccn1-c1ccc(I)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(/N=c2\ccccn2-c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (192 mg, 0.61 mmol) in CH3CN (5 mL), CH3I (0.40 mL, 6.4 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give a solid. The solid was dissolved in DMF (3 mL). To the solution, p-anisidine (317 mg, 2.6 mmol) was added. After being stirred at 100° C. overnight, the mixture was purified by HPLC to give (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)-4-methoxybenzenamine (90 mg).
Reaction SMILES: CO[CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.B(Br)(Br)[Br:18].O>C(Cl)Cl>[Br:18][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[S:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: COCc1ccc2sc(S(N)(=O)=O)cc2c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-methoxymethyl-2-sulfamoylbenzo[b]thiophene, (7.4 g, 0.029 mol) in 300 ml of dry methylene chloride cooled to -30° C. was added boron tribromide (30 ml of a 1M solution in methylene chloride, 0.03 mol) over a 20 minute period. The resulting solution was stirred for 11/2 hours as the temperature rose to ambient. The solution was cooled to 0° C. and there was added dropwise 150 ml of water keeping the temperature below 20° C. The methylene chloride layer was separated and the aqueous suspension was extracted with three portions (200 ml) of methanol-chloroform (50/50). The combined extracts were washed with ice water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 8.8 g of tan solid (quantitative yield of crude product) which after recrystallization from 1,2-dichloroethane had m.p. 171°-173° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22](I)[CH:23]=[C:24]([Cl:26])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Cu]I>[Cl:19][C:20]1[CH:21]=[C:22]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: Clc1cc(Cl)cc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2)cc1Nc1cc(Cl)cc(Cl)c1
Yield: 9.3 %

Procedure:
Prepared according to the procedure of Example 33 using 3-amino-4-methoxy-N-phenyl-benzamide (2.0 g, 8.3 mmol), 3,5-dichloroiodobenzene (4.5 g, 16.5 mmol), potassium carbonate (2.9 g, 21.0 mmol), and copper(I) iodide (0.5 g, 2.6 mmol) to give a gummy residue which was subjected to chromatography on a column of silica gel in dichloromethane to afford the product (0.3 g); m.p. 207-208° C. after recrystallization from ethanol.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]([C@@H:11]1[CH2:14][C@H:13]([CH:15]([C:26]([O:28][CH3:29])=[O:27])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:10].Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]([C:15]([C@H:13]1[CH2:14][C@@H:11]([C:9]([O:8][CH3:7])=[O:10])[CH2:12]1)([CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:27]
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)C(C(=O)OCc1ccccc1)[C@H]1C[C@@H](C(=O)OC)C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cccc2ccccc12)(C(=O)OCc1ccccc1)[C@H]1C[C@@H](C(=O)OC)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred suspension of potassium t-butoxide (0.44 g, 3.93 mmol) in dry tetrahydrofuran (20 ml) cooled to 0° C. under a nitrogen atmosphere was added dropwise a solution of benzyl methyl cis-3-methoxycarbonylcyclobutylmalonate (1.25 g, 3.9 mmol) in dry tetrahydrofuran (20 ml) followed by dropwise addition of 1-(bromomethyl)naphthalene (2.58 g, 11.7 mmol) in dry toluene (15 ml). Stirring was continued at 0° C. for 4 hours, aqueous hydrochloric acid (2M, 15 ml) was then added and the mixture extracted with diethyl ether. The organic phase was dried, filtered and evaporated to an oil (2.5 g). The oil was dissolved in dichloromethane and filtered through a pad of flash silica, the solvent was removed and the resulting oil (2.0 g) purified by chromatography on silica using a Biotage Flash 40 eluting with dichloromethane to give the title compound as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCC(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.1 %

Procedure:
To a stirred suspension of 4-bromo-3-methoxybenzoic acid (2.0 g) in THF (100 mL) was added 2,2,2-trifluoroethylamine (1.26 g), HATU (3.87 g), and DIPEA (1.7 ml). The mixture was stirred at room temperature for 12 h. Water (350 ml) and saturated sodium bicarbonate solution (350 ml) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 2.57 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18](Br)[CH:19]=1>CS(C)=O>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:19]=1
Reactant: COc1ccc(CO)cc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(COc2cncc(Br)c2)cc1
Temperature: 90 °C
Reaction time: 1.25 h
Yield: 47.8 %

Procedure:
To a solution of 4-methoxybenzyl alcohol (1.73 g) in DMSO (10 mL) at room temperature was added sodium hydride (500 mg). The reaction mixture was stirred for 75 min and then a solution of 3,5-dibromopyridine (3.0 g) in DMSO (15 mL) was added. The reaction mixture was then heated at 90° C. for 2.5 h and then allowed to cool to room temperature, quenched with water (60 mL) and extracted into diethyl ether (3×60 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 3-bromo-5-(4-methoxy-benzyloxy)-pyridine as a white solid (1.76 g).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:25]=NNC=5)=[CH:22][N:23]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[NH2:32][C:33]([C:35]1[S:36]C=C(B(O)O)[CH:39]=1)=[O:34]>>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:39]=[C:35]([C:33]([NH2:32])=[O:34])[S:36][CH:25]=5)=[CH:22][N:23]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: NC(=O)c1cc(B(O)O)cs1
Reactant: c1nc2c(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)ncc(-c3cn[nH]c3)n2n1
Product: NC(=O)c1cc(-c2cnc(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)c3ncnn23)cs1

Procedure:
This compound may be prepared using methods as described for Compound 46, using 2-(aminocarbonyl)thiophene-4-boronic acid. LCMS: Rt=0.93 (95%), m/z (ESI) 475 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:41])[C:8]=2[N:17]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)N1CCOCC1

Procedure:
2-(Ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c]quinoline (6.9 g, 18 mmol) was treated with mCPBA (7.9 g, 35 mmol), concentrated ammonium hydroxide (50 mL of 29%), and p-toluenesulfonyl chloride (6.0 g, 32 mmol) according to a modification of the method described in Part E of Example 3. The mCPBA addition was carried out at 0° C., and the reaction was carried out in dichloromethane (150 mL). The crude product was triturated with 2:1 ethyl acetate:hexane (15 mL), and the resulting solid was isolated by filtration, washed with 30:70 ethyl acetate:hexane, recrystallized twice from methanol:water, and dried overnight in a vacuum oven at 70° C. to provide 2-(ethoxymethyl)-1-(4-morpholin-4-yl-4-oxobutyl)-1H-imidazo[4,5-c]quinolin-4-amine as yellow crystals, mp 201-203° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11](O)(=O)[CH3:12].C(=O)(O)[O-].[Na+]>C1(=O)CCCCC1>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:11][CH2:5][CH2:4][CH2:3][C:8]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C1CCCCC1
Product: Brc1ccc2[nH]c3c(c2c1)CCCC3

Procedure:
Cyclohexanone (1.16 mL, 11.2 mmol) and 4-bromo-phenylhydrazine hydrochloride (2.50 g, 11.2 mmol) were refluxed in cyclohexanone (18 mL) and acetic acid (AcOH) (12 L) for 24 h. The reaction mixture was treated with saturated sodium bicarbonate (Na2CO3) and extracted with ethyl acetate, dried (Na2CO3) and concentrated. The product was purified by column chromatography, giving 479 mg of compound 30 as a solid.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.Cl.[F:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.CCN(C(C)C)C(C)C>C(#N)C>[F:32][C@@H:33]1[CH2:37][CH2:36][N:35]([C:8](/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)=[O:30])[CH2:34]1
Reactant: F[C@@H]1CCNC1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CC[C@@H](F)C2)s1
Temperature: 30 °C
Reaction time: 12 h

Procedure:
(Z)-3-Methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide (Example 81A, 250 mg, 0.45 mmol), (R)-3-fluoropyrrolidine hydrochloride (62 mg, 0.49 mmol) and Hunig's base (0.078 mL, 0.45 mmol) in acetonitrile (5 mL) were stirred at 55° C. for 3 hours. The reaction mixture was then cooled to 30° C. with continued stirring for 12 hours. The mixture was evaporated to dryness and purified by reverse phase HPLC to give the title compound. 1H NMR (CDCl3) δ ppm 2.00 (2H), 2.20 (3H), 3.35-3.85 (4H), 5.10-5.30 (1H), 6.60 (1H), 7.20 (1H), 7.35 (1H), 7.45 (1H); MS (ESI) m/z 436(M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=2)[C:12]([OH:14])=O)[CH2:8][CH2:7]1.[NH2:23][C@@H:24]1[C:39](=[O:40])[N:26]2[C:27]([C:36]([OH:38])=[O:37])=[C:28]([CH2:31][O:32][C:33](=[O:35])[NH2:34])[CH2:29][S:30][C@H:25]12.C[Si](C)(C)NC(=O)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[CH:6]1([O:9][N:10]=[C:11]([C:15]2[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=2)[C:12]([NH:23][C@@H:24]2[C:39](=[O:40])[N:26]3[C:27]([C:36]([OH:38])=[O:37])=[C:28]([CH2:31][O:32][C:33](=[O:35])[NH2:34])[CH2:29][S:30][C@H:25]23)=[O:14])[CH2:7][CH2:8]1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(=O)N[Si](C)(C)C
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: O=C([O-])O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC3CC3)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
Phosphorus oxychloride (0.53 ml) was dropwise added to N,N-dimethylformamide (0.42 ml) under ice-cooling. After stirring for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. To the suspension was added 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (1.12 g). The mixture was stirred at the same temperature for 30 minutes to give an activated acid solution. On the other hand, a mixture of 7β-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.5 g), N-trimethylsilylacetamide (1.4 g) and bis(trimethylsilyl)acetamide (2.2 g) in tetrahydrofuran (26 ml) was stirred at 30° C. for 30 minutes to give a clear solution. To the clear solution was added the activated acid solution prepared above at -30° C. The mixture was stirred for 30 minutes at -20° C. to -15° C. The mixture was poured into ice-water, adjusted to pH 7.2 with saturated aqueous solution of sodium bicarbonate, and washed with ethyl acetate. The aqueous solution was adjusted to pH 2.5 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer) (2.1 g).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:13]12([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([CH2:23][C:24]([N:1]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:25])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: C1COCCOCCOCCN1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)N1CCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and (1-adamantyl)acetyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]#[C:6][CH2:7][CH2:8][O:9]C1CCCCO1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]#[C:6][CH2:7][CH2:8][OH:9])[CH3:2]
Reactant: CCOC(=O)C#CCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)C#CCCO

Procedure:
The title compound was prepared from 5-(tetrahydro-pyran-2-yloxy)-pent-2-ynoic acid ethyl ester employing p-toluenesulfonic acid in ethanol.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:24])([CH3:23])[CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][C:3]([CH3:24])([CH3:23])[CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CN
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CNC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
A solution containing 1-(3-amino-2,2-dimethylpropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.05 mmol) and triethylamine (470 μL, 3.36 mmol) in 1-methyl-2-pyrrolidinone (30 mL) was cooled to 0° C. Benzoyl chloride (345 μL, 3.05 mmol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was combined with 1% aqueous sodium bicarbonate solution (150 mL) and then stirred overnight. A fine white precipitate was isolated by filtration and washed with hexanes. The material was dissolved in dichloromethane, methanol and toluene. The solution was concentrated under vacuum. The material was purified by column chromatography (60 g silica gel eluting with 7.5% methanol in dichloromethane) and then dried in a vacuum oven at 50° C. for 2 days to provide 0.82 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropyl}benzamide as an off white powder, m.p. 103-125° C. Analysis: Calculated for C25H29N5O2.0.30H2O: % C, 68.72; % H, 6.83; % N, 16.03; Found: % C, 68.50; % H, 6.55; % N, 16.02.