Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[F:39][C:40]1([F:47])[CH2:42][C:41]1([CH3:46])[C:43](Cl)=[O:44]>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:43]([C:41]3([CH3:46])[CH2:42][C:40]3([F:47])[F:39])=[O:44])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1(C(=O)Cl)CC1(F)F
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3(C)CC3(F)F)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, a solution of 2,2-difluoro-1-methylcyclopropanecarbonyl chloride (25 mg, 165 μmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions. Once analysis of the reaction by HPLC showed substantial conversion (3 h), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (26.8 mg, 76% of theory).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[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)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 100 °C
Yield: 21.3 %

Procedure:
A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (50 mg, 0.123 mmol) from Step 4 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (42 mg, 0.369 mmol), and DIEA (46 mg, 0.369 mmol) in anhydrous DMA (1 mL) was heated in a sealed vessel at 100° C. for 15 h. The reaction was allowed to cool to rt and then was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (12 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.98-8.10 (m, 2H), 7.64 (d, J=1.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.31 (m, 1H), 7.18 (dd, J=1.6, 8.2 Hz, 1H), 5.46 (s, 2H), 4.79 (br s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.04 (m, 1H), 1.87 (m, 1H), 1.65-1.67 (m, 2H), 1.12-1.34 (m, 4H). LCMS (ESI) m/z 458 and 460 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[C:43]1([CH:49]([NH2:51])[CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:51][CH:49]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH3:50])=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: CC(N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(NC(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)c1ccccc1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-phenyl-ethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]([OH:11])=O.CCN(C(C)C)C(C)C.[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:9](=[O:11])[CH2:8][O:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12]
Reactant: Cc1ccccc1OCC(=O)O
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1OCC(=O)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a stirred mixture of 2-(o-tolyloxy)acetic acid (100 mg, 0.60 mmol) in DCM (5 mL) was added DIEA (116 mg, 0.90 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (124 mg, 0.60 mmol) and Bop-Cl (183 mg, 0.72 mmol). The mixture was stirred at 25° C. for 16 hours then quenched by addition of water (20 mL). The resulting mixture was extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the product (79 mg, Yield 37%). 1H NMR (400 MHz, MeOD) δ 7.14-7.01 (m, 6H), 6.95-6.82 (m, 2H), 4.55 (s, 2H), 4.04-4.01 (m, 1H), 3.72-3.63 (m, 2H), 3.55-3.46 (m, 1H), 3.42-3.34 (m, 1H), 2.93-2.84 (m, 2H), 2.83-2.74 (m, 2H), 2.57 (d, J=6.3 Hz, 2H), 2.27 (s, 3H). LCMS (m/z): 355.1 (M+1).
Reaction SMILES: N[C:2]1([C:27]([O-:29])=[O:28])[CH2:7][CH2:6][CH:5]([C:8]2[CH:16]=[CH:15][C:14]([NH:17]C(OC(C)(C)C)=O)=[C:13]3[C:9]=2[CH2:10][N:11]([CH3:26])[C:12]3=[O:25])[CH2:4][CH2:3]1.[Na+].CO.C=O.[CH:35](O)=O.[C:38]([BH3-])#[N:39].[Na+]>>[NH2:17][C:14]1[CH:15]=[CH:16][C:8]([CH:5]2[CH2:4][CH2:3][C:2]([N:39]([CH3:38])[CH3:35])([C:27]([OH:29])=[O:28])[CH2:7][CH2:6]2)=[C:9]2[C:13]=1[C:12](=[O:25])[N:11]([CH3:26])[CH2:10]2
Reactant: O=CO
Reactant: [BH3-]C#N
Reactant: CN1Cc2c(C3CCC(N)(C(=O)[O-])CC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1Cc2c(C3CCC(C(=O)O)(N(C)C)CC3)ccc(N)c2C1=O

Procedure:
Sodium 1-amino-4-{7-[(tert-butoxycarbonyl)amino]-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl}cyclohexanecarboxylate (Compound 285B, 50.0 mg, 0.118 mmol) was taken up in MeOH (1.0 mL, 25 mmol) and over the course of about 5 days was treated repeatedly with formaldehyde (52.5 uL, 0.705 mmol) and Formic acid (26.6 uL, 0.705 mmol) followed by several hours of stirring and then sodium cyanoborohydride (73.8 mg, 1.18 mmol) addition. The reaction was eventually driven to completion after which, the reaction mixture became a suspension. This was filtered and the solid washed a little MeOH. The MeOH filtrate was concentrated to yield a waxy white material which was triturated with DCM and filtered. The DCM filtrate was concentrated to a clear oil and dried in vacuo. 1H NMR (400 MHz, CHLOROFORM-d) d 9.52 (s, 1H), 8.10-8.15 (m, 1H), 7.42 (d, J=8.59 Hz, 1H), 4.36 (s, 2H), 3.18 (s, 3H), 2.93 (s, 6H), 2.82 (dd, J=4.67, 8.72 Hz, 1H), 2.23 (t, J=4.55 Hz, 4H), 1.97-2.07 (m, 2H), 1.83-1.94 (m, 2H), 1.50 (s, 9H). MS (ES+): m/z=432.2303 [MH+]. HPLC: tR=1.12 min (UPLC TOF, polar—3 min). The crude product was taken up in DCM and treated with TFA, stirred for 15 min. The reaction mixture was concentrated to an oil and used without further purification and characterization.
Reaction SMILES: O1CCCC1.[C:6]([O:14][CH2:15]C)(=[O:13])[CH2:7][C:8]([O:10]CC)=[O:9].[Cl:17]CC=O.N1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl.O>[C:8]1(=[O:9])[O:10][CH:15]([C:24]([CH2:25][CH3:26])([CH2:23][CH3:22])[Cl:17])[O:14][C:6](=[O:13])[CH2:7]1
Reactant: O=CCCl
Reactant: CCOC(=O)CC(=O)OCC
Reactant: c1ccncc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC(Cl)(CC)C1OC(=O)CC(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
A solution of titanium (IV) chloride (11 ml, 0.1M) in carbon tetrachloride (25 ml) was added dropwise to anhydrous tetrahydrofuran (200 ml) at 0° under nitrogen. On completion of the addition, diethyl malonate (7.6 ml, 50 mM) and anhydrous chloroacetaldehyde (5 g, 63 mM) were added, then a solution of pyridine (16 ml, 0.2M) in anhydrous tetrahydrofuan (35 ml) was added dropwise over 2 hours at 0°. On completion of the addition, the dark mixture was allowed to warm to room temperature, stirred at this temperature for 2 hours, then heated under reflux overnight. The reaction mixture was cooled, water (500 ml) added and the mixture extracted with diethyl ether (2×250 ml). The combined extracts were washed with water (500 ml), saturated sodium bicarbonate solution (500 ml) and brine (500 ml), dried (MgSO4) and evaporated to give a brown oil. Column chromatography of this oil on silica (eluent 1:1 hexane:dichloromethane) afforded the title compound as a pale yellow oil 4.9 g, 44%.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[O:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15]1.[C:25](=[O:27])=[O:26]>CCCCCC.O>[O:14]1[C:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CCCCO2
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCCCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 17.6 ml n-butyllithium (2.5 M, 0.044 mol) in 63 ml hexane is added dropwise (0.044 mol) 5.1 g tetramethylethylenediamine (TMEDA) and 5 g (0.034 mol) of 2,3,4,5-tetrahydro-1-benzoxepin. The reaction mixture is stirred overnight. The reaction mixture is then chilled to 0° C. and carbonated with dry ice for an hour. Water (110 ml) is added and the mixture is filtered and the aqueous phase acidified with 4N HCl. The resultant oil is extracted into methylene chloride and dried (MgSO4). After filtering and concentrating in vacuo, 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid results as a tan solid.
Reaction SMILES: [Na].Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[C:12](#[N:15])[CH:13]=[CH2:14]>C(O)C>[NH2:15][C:12]1[CH2:13][CH2:14][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[N:11]=1
Reactant: NNc1cccc(F)c1
Reactant: C=CC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2cccc(F)c2)CC1
Reaction time: 0.25 h

Procedure:
A 1.38 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 8.1 g. of m-fluorophenylhydrazine hydrochloride is added followed in 15 minutes by 2.75 g. of acrylonitrile. The reaction mixture is refluxed for 5 hours, then is evaporated to dryness in vacuo. Water is added and the separated solid is collected by filtration. The solid is dissolved in dichloromethane and the solution is passed through a short column of a hydrous magnesium silicate. The effluent is heated to reflux on a steam bath and hexane is added to precipitate a product. The solid is collected, dissolved in acetone, treated with activated charcoal and filtered. Hexane is added to the filtrate to crystallize 2.95 g. of the product of the Example as off-white needles, m.p. 146°-147° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON([C:9](=[O:26])[C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)C.O>C(OCC)C.O1CCCC1>[O:26]=[C:9]([CH2:1][CH3:2])[C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: CON(C)C(=O)[C@@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)[C@@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
50 cm3 of a 3N solution of ethyl magnesium bromide dissolved in diethyl ether are added over 1 hour to a mixture, under an inert atmosphere, of 14 g of tert-butyl N-{2-[N-methoxy-N-(methyl)amino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamate in 350 cm3 of tetrahydrofuran, cooled to a temperature in the region of 0° C. After stirring for 48 hours at 0° C., water is added to the reaction medium, the resulting mixture is extracted with dichloromethane and the extracts are washed with water. The organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 10.5 g of tert-butyl N-[(1R)-2-oxo-1-(4-pyridylmethyl)butyl]carbamate are obtained in the form of a yellow oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.94 (t, J=7 Hz: 3H); 1.32 (s: 9H); from 2.40 to 2.65 (mt: 2H); 2.70 (dd, J=14 and 10.5 Hz: 1H); 3.06 (dd, J=14 and 4.5 Hz: 1H); 4.22 (mt: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 7.44 (broad d, J=8 Hz: 1H); 8.45 (broad d, J=5.5 Hz: 2H)].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[N-:12]=[N+:13]=[N-:14].[Na+].[I-].[K+].CCOCC.O>CN(C=O)C>[N:12]([CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCCCOC1CCCCO1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: [N-]=[N+]=NCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(3-chloro-propoxy)-tetrahydro-pyran (6.28 g, 35.2 mmol), NaN3 (11.4 g, 176 mmol) and potassium iodide (584 mg, 3.52 mmol) in DMF (50 mL) was stirred at RT for 18 h. The reaction mixture was poured into a mixture of Et2O/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 15:85 as the eluent to afford the title compound as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].ClC1C=C2C(=C(Cl)C=1)CN(C)CC2C1C=CC(N)=CC=1.[NH2:41][C@@H:42]([CH2:48][CH2:49][C:50]([O:52]CC)=[O:51])[C:43]([O:45]CC)=[O:44].N[C@@H](CC(OC)=O)[C:57](OC)=[O:58]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:17][C:57](=[O:58])[NH:41][C@@H:42]([CH2:48][CH2:49][C:50]([OH:52])=[O:51])[C:43]([OH:45])=[O:44])[CH:18]=[CH:19][CH:20]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)N[C@@H](CCC(=O)O)C(=O)O)c2)C1

Procedure:
Following the procedures outlined in Example 34, substituting 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)aniline (intermediate 31.5) for 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)aniline and (S)-diethyl 2-aminopentanedioate for (S)-dimethyl 2-aminosuccinate gave, after purification by preparative HPLC, the title compound as a TFA salt. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.74 (s, 1H), 7.67 (s, 1H), 7.42 (m, 1H), 7.27-7.25 (m, 2H), 6.79 (m, 2H), 6.52-6.49 (m, 1H), 4.63-4.58 (m, 1H), 4.44 (m, 2H), 4.20-4.16 (m, 1H), 3.72-3.64 (m, 2H), 2.99 (s, 3H), 2.34-2.27 (m, 2H), 2.01-1.97 (m, 2H), 1.82-1.77 (m, 2H). MS 480 [M+H]+.
Reaction SMILES: COCCOCCOC.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18].[OH:21][C:22]1[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]2[C:23]=1[C:24](=[O:35])[CH2:25][C:26]([CH3:34])([CH3:33])[O:27]2>[I-].[K+]>[OH:21][C:22]1[CH:31]=[C:30]([O:32][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:29]=[C:28]2[C:23]=1[C:24](=[O:35])[CH2:25][C:26]([CH3:33])([CH3:34])[O:27]2
Reactant: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Product: CC(C)COc1cc(O)c2c(c1)OC(C)(C)CC2=O
Temperature: 100 °C
Yield: 79 %

Procedure:
In 50 of diethylene glycol dimethylether (DIGLIM) 4.2 g (20 millimoles) of 5,7-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 3.0 g (22 millimoles) of potassium carbonate and 0.2 g of potassium iodide and thereafter 3.3 g (2.6 ml, 24 millimoles) of isobutyl bromide are added. The reaction mixture is heated at 100° C. for 10 hours and worked up according to Example 19. Thus 4.1 g of the desired compound are obtained, yield 79%. Mp.: 77°-79° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.[NH2:9][CH:10]1[C:42](=[O:43])[N:12]2[C:13]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:14]([C:17]3[S:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[N:20][N:21]=3)[CH2:15][S:16][C@H:11]12.[Cl-].[Na+]>ClCCl.N1C=CC=CC=1>[Br:7][CH2:6][C:2](=[O:1])[CH2:3][C:4]([NH:9][CH:10]1[C:42](=[O:43])[N:12]2[C:13]([C:26]([O:28][CH:29]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:14]([C:17]3[S:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[N:20][N:21]=3)[CH2:15][S:16][C@H:11]12)=[O:5]
Reactant: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: BrBr
Reactant: C=C1CC(=O)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)CC(=O)CBr)[C@H]3SC2)s1
Temperature: 0 °C
Yield: 58 %

Procedure:
In 10.5 ml of dichloromethane there were dissolved 2.1 g of diketene and, under stirring, a solution of 4.00 g of bromine in 12.5 ml of dichloromethane was added dropwise at a temperature not exceeding -20° C. After the dropwise addition was completed, the mixture was maintained at 0° C. for 10 minutes. Separately, 0.5 g of benzhydryl 7-amino-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate was suspended in 15 ml of dichloromethane and, under stirring, 1.37 ml of the above acid bromide solution were added at a temperature not exceeding -40° C. Following this dropwise addition, the mixture was stirred at room temperature for one hour. Then, a solution of 0.085 g of pyridine in 2 ml of dichloromethane was added and the mixture was further stirred for 30 minutes. A saturated aqueous solution of sodium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure and the residue was loosened up with the addition of ether. The resultant powder was recovered by filtration and dried. By the above procedure 0.383 g of benzhydryl 7-(4-bromo-3-oxobutyrylamino)-3-(5-acetylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate was obtained.
Reaction SMILES: [I:1][CH2:2][C:3]([NH2:5])=[O:4].[OH:6][C@@H:7]([C@H:9]1[C:38](=[O:39])[N:11]2[C:12]([C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])=[C:13]([C:16]3[S:20][C:19]4=[C:21]([C:24]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)=[O:25])[N:22]=[CH:23][N:18]4[CH:17]=3)[C@H:14]([CH3:15])[C@H:10]12)[CH3:8].C(OCC)(=O)C>CO>[I-:1].[C:3]([CH2:2][N+:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:24]([C:21]2[N:22]=[CH:23][N:18]3[CH:17]=[C:16]([C:13]4[C@H:14]([CH3:15])[C@@H:10]5[C@@H:9]([C@H:7]([OH:6])[CH3:8])[C:38](=[O:39])[N:11]5[C:12]=4[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[S:20][C:19]=23)=[O:25])[CH:27]=1)(=[O:4])[NH2:5]
Reactant: NC(=O)CI
Reactant: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4cccnc4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(c2cn3cnc(C(=O)c4ccc[n+](CC(N)=O)c4)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 40 °C
Reaction time: 22 h
Yield: 88.9 %

Procedure:
2-Iodoacetamide (1.13 g) was added to a solution of 1.46 g of allyl (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonyl-imidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate in 4.5 ml of methanol, and the mixture was stirred at 40° C. for 22 hr. Methanol (8 ml) was added thereto for dilution. The diluted reaction mixture was added dropwise to 180 ml of ethyl acetate, and the resultant powder was collected by filtration to give 1.80 g of allyl (1S,5R,6S)-2-[7-(1-carbamoylmethylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate iodide.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[O:31]>CN(C)C=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:31])[CH2:32][CH2:33][CH2:34][C:35]1=[O:37]
Reactant: O=C(O)CCCC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCCC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 50 h
Yield: 65.2 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.087 g, 0.27 mmol) and diisopropylethylamine (0.079 ml, 0.46 mmol) were added sequentially at ambient temperature to a stirred solution of 4-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoyl]butyric acid (0.08 g, 0.21 mmol) in dimethylformamide (2 ml), the mixture was stirred at ambient temperature for 50 hours, then it was added dropwise to ice-cold water (10 ml). The resulting solid was collected by filtration and dried in vacuo to give 1-[2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperidine-2,6-dione (0.05 g) as a white solid, m.pt. 259–263° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.8–2.1 (m, 2H) (—CH2CH2CH2—), 2.7–2.9 (m, 4H) (—CH2CH2CH2—) 4.35 (s, 2H) (ArCH2—), 7.1–7.35 (m, 2H) (2×ArH), 7.4–7.5 (m, 1H) (ArH), 7.8–8.05 (m, 3H) (3×ArH), 8.3 (d, 1H) (ArH), 12.65 (s, 1H) (CONH); m/z (M+H)+ 366, 100% purity.
Reaction SMILES: [C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:36].[C:1]1([N:7]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][C:16]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:26](=[NH:44])[NH2:27])=[CH:24][CH:25]=4)=[N:15][C:14]=3[CH:28]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CCc3ccc(C#N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Yield: 80 %

Procedure:
Prepared analogously to Example 9 from 2-[2-(4-cyanophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 80% of theory, C28H28N4O3S (500.62) Rf value: 0.30 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) EKA mass spectrum: (M+H)+ =501