Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:30])[C:13](=[O:29])[C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br>CN(C)C=O.ClCCl>[Br:31][C:16]1[CH:15]=[C:14]2[C:19]([C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[C:11]([CH:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])[N:12]([CH3:30])[C:13]2=[O:29])=[CH:18][CH:17]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Reactant: BrBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
An ice cold mixture of methyl 2-(tert-butoxy)-2-(4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (187 mg, 0.459 mmol) in N,N-Dimethylformamide (DMF) (2.0 mL) was treated with a solution of bromine (0.071 mL, 1.377 mmol) in dichloromethane (DCM) (2.0 mL). The ice bath was removed and the mixture, which was excluded from light by wrapping the reaction vessel with aluminum foil, was allowed to stir at ambient temperature overnight. The mixture was quenched by adding saturated sodium bicarbonate and then extracted with ethyl acetate. The extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel to afford the title compound as a thick colorless oil (123 mg, 55%) that solidified upon standing. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.63 (d, J=2.1 Hz, 1 H), 7.56 (ddd, J=2.2, 6.0, 8.6 Hz, 1 H), 7.31-7.22 (m, 1 H), 7.20-6.88 (m, 3 H), 5.20 (s, 1 H), 3.83-3.74 (m, 3 H), 3.69 (m, 3 H), 2.37 (s, 3 H), 2.31 (s, 3 H), 1.01 (m, 9 H); LC/MS (m/z) ES+=486 (M+1).
Reaction SMILES: [ClH:1].[C:2]([O:5][CH:6]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24]CC3C=CC=CC=3)[CH:20]=2)[CH:15]=1)[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:4])[CH3:3]>[C].[Pd].C(O)C>[ClH:1].[C:2]([O:5][CH:6]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=2)[CH:15]=1)[CH2:7][O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])(=[O:4])[CH3:3]
Reactant: CC(=O)OC(COCCN(C)C)c1ccc2cc(OCc3ccccc3)ccc2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)OC(COCCN(C)C)c1ccc2cc(O)ccc2c1
Yield: 47.7 %

Procedure:
A mixture of 2.0 g of 1-acetoxy-1-(6-benzyloxy-2-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethane hydrochloride, 0.5 g of 5% palladium-carbon and 40 ml of ethanol was subjected to hydrogenation at room temperature under atmospheric pressure. After the completion of the reaction, the palladium-carbon was removed by filtration. The solvent was removed by distillation under reduced pressure. Acetone was added to the residue thus obtained. The resulting crystals were collected by filtration and dried to obtain 0.76 g of 1-acetoxy-1-[6-hydroxy-2-naphthyl)-2-(2-(N,N-dimethylamino)ethoxy]ethane hydrochloride (compound No. 287).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]([N:31]([CH3:39])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][CH3:38])=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:40](N)([NH2:43])(=[O:42])=[O:41]>O1CCOCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]([N:31]([CH3:39])[CH2:32][CH2:33][O:34][CH2:35][CH2:36][N:37]([CH3:38])[S:40](=[O:42])(=[O:41])[NH2:43])=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: CNCCOCCN(C)C(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1C
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCC(=O)N(C)CCOCCN(C)S(N)(=O)=O)n(C)c2c1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of intermediate 6 (620 mg, 1.16 mmol) and sulfamide (900 mg, 9.36 mmol) in dioxane (10 mL) was heated at 100° C. in a microwave oven for 60 minutes. The reaction mixture was cooled down to room temperature, and then evaporated under vacuum. The residue was triturated in water, filtered and washed with water. The powder was reconstituted in AcOEt. The solution was dried over anhydrous Na2SO4, filtered and the filtrate evaporated to yield 610 mg (86%) of methyl 3-cyclohexyl-1-methyl-2-(2-{2-[methyl(2-{2-[methyl(sulfamoyl)amino]ethoxy}ethyl)amino]-2-oxoethoxy}phenyl)-1H-indole-6-carboxylate 7 as a yellowish powder: m/z=615 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54](=[O:65])[CH2:55][CH2:56][C:57]1([C:62](O)=[O:63])[CH2:61][CH2:60][CH2:59][CH2:58]1)([CH3:52])([CH3:51])[CH3:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:8]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:62]([C:57]3([CH2:56][CH2:55][C:54]([O:53][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:65])[CH2:61][CH2:60][CH2:59][CH2:58]3)=[O:63])=[O:24])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Reactant: NCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC1(C(=O)NCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)CCCC1
Reaction time: 0.17 h
Yield: 124.7 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl 5-aminopentylcarbamate (0.683 g, 2.105 mmol) in 15 ml DMF was added HATU (0.800 g, 2.105 mmol), 1-(3-tert-butoxy-3-oxopropyl)cyclopentanecarboxylic acid (0.425 g, 1.754 mmol) in 5 ml DMF, and DIEA (1.532 mL, 8.77 mmol). The solution was stirred for 10 minutes and material purified by HPLC using a gradient of 0-50% acetonitrile in DCM. Solvents were removed under reduced pressure to give 1.2 g crude tert-butyl 3-(1-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)-pentylcarbamoyl)cyclopentyl)propanoate. The crude material was dissolved in 20 ml DCM and 10 ml TFA was added to remove t-Bu group. Solvent was removed under reduced pressure and material purified by reverse phase chromatography to give 3-(1-(5-(((9H-fluoren-9-yl)methoxy)carbonylamino)pentylcarbamoyl)cyclopentyl)propanoic acid (16 mg, 0.032 mmol, 1.852% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]2[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]=12.[H-].[Na+].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[S:35](Cl)(=[O:37])=[O:36]>CN(C=O)C.O>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[S:35]([N:9]1[C:10]2[C:6](=[C:5]3[CH:12]([CH3:24])[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][O:16][C:4]3=[C:3]([O:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COc1cc2[nH]ccc2c2c1OCCN(C(=O)OC(C)(C)C)C2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(ccn2S(=O)(=O)c2c(F)cccc2F)c2c1OCCN(C(=O)OC(C)(C)C)C2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
tert-Butyl 6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 36, 25 mg, 0.059 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,6-difluorobenzenesulfonyl chloride (24.0 mg, 0.113 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight and a few drops of water were added. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,6-difluorophenyl)sulfonyl]-6-methoxy-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (6.6 mg, 0.013 mmol ) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and evaporated to give the title compound (6.8 mg). MS m/z 409 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[NH:9][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=C1CCc2ccc(Cl)cc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To solution of 7-chloro-3,4-dihydroquinolin-2(1H)-one (110-1; 2.92 g, 0.016 mol) in N,N-dimethylformamide (30 mL), was added N-bromosuccinimide (3.14 g, 0.0176 mol) portion-wise at room temperature. The resulting mixture was stirred at room temperature for 16 h. After 16 h, the reaction mixture was diluted with cold water, solid get precipitated, filtered the solid, washed the solid with water and dried under reduced pressure to afford the compound. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 7.56 (s, 1H), 7.01 (s, 1H), 2.87-2.84 (t, J=7.2 Hz, 2H), 2.45-2.41 (t, J=7.6 Hz, 2H); MS (M+1): 259.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([O-:3])=[O:2].CI.[C:24](=O)([O-])[O-].[K+].[K+]>O>[CH3:24][N:12]1[C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:21]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the stirred reaction mixture containing the crude 3-(4-nitrophenyl)-6-trifluoromethyluracil (14.5 grams--0.048 mole) from the preceding step was added 13.6 grams (0.096 mole) of methyl iodide and 3.3 grams (0.096 mole) of potassium carbonate. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about five hours, after which the reaction mixture was poured into water, and the resultant solid was collected by filtration. The solid was washed with petroleum ether and dried, yielding 13.0 grams of 1-methyl-3-(4-nitrophenyl)-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[CH:13](/[N:17]=[CH:26]/[C:25]1[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:30])[F:31])=[CH:29][CH:28]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(N)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: CCCC(/N=C/c1ccc(C(F)(F)F)cc1)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A mixture of 1-[2,5-bis(trifluoromethyl)phenyl]butan-1-amine (2.95 g, 10.3 mmol) and 4-trifluoromethyl benzaldehyde (1.8 g, 10.3 mmol) was swirled together for 30 minutes. M/Z (ES+) 442 (ME).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][C:38]1[N:39]=[C:40]([CH3:43])[S:41][CH:42]=1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:37][C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)[C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccccc1N1C(=O)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: Cc1nc(CCl)cs1
Product: Cc1nc(CN2C(=O)N(c3ccccc3C)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)cs1

Procedure:
The title compound, MS: m/e=611.0 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione and 4-chloromethyl-2-methylthiazole.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: C#Cc1cccc(C)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Cc1cccc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-3-methylbenzene (Aldrich, 58 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 7.37 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 7.67 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 7.74-7.84 (m, 3H), 8.38 (dt, J=7.9, 2.0 Hz, 1H), 8.76 (dd, J=4.7, 1.7 Hz, 1H), 9.15 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 237 (M+H)+.
Reaction SMILES: [Cl:1][C:2](Cl)(Cl)[C:3]1[CH:8]=[CH:7][C:6]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(O)(=[O:19])C.N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[F:10][S:9]([F:14])([F:13])([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([C:2]([Cl:1])=[O:19])=[CH:4][CH:5]=1
Reactant: CC(=O)O
Reactant: FS(F)(F)(F)(F)c1ccc(C(Cl)(Cl)Cl)cc1
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(Cl)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 56.1 %

Procedure:
Into a 25 mL flask equipped with a stirrer were placed 10.0 g (31.2 mmol) of the 4-trichloromethyl(pentafluorosulfanylbenzene) prepared in Example 1 and 0.15 g (3 mol %) of FeCl3. To the mixture, 1.87 g (31.2 mmol) of acetic acid was added dropwise at an oil bath temperature of 70° C. in a N2 atmosphere for 3 hours. After the addition was complete, the mixture was heated with stirring at an oil bath temperature of 70° C. for 17 hours. After the mixture was cooled to room temperature, it was mixed with 0.49 g (6 mol %) of triphenylphosphine and was stirred for 3 hours. This mixture was distilled under reduced pressure to yield 4.67 g of 4-pentafluorosulfanylbenzoic chloride (product yield: 56%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:19][CH:20]=2)[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH:12]1([C:15]2[CH:20]=[N+:19]([O-:9])[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1ccc(C2CC2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(C2CC2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
m-Chloroperbenzoic acid (55 g) was added to a solution of ethyl 5-cyclopropylpyridine-2-carboxylate (15.5 g) in chloroform (300 mL) under ice-cooling, and the mixture was stirred at room temperature for four hours. The reaction solution was poured into a mixed solvent of saturated aqueous sodium bicarbonate and a saturated sodium thiosulfate solution, and the mixture was stirred at room temperature for 30 minutes. After extraction with chloroform, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give ethyl 5-cyclopropylpyridine-2-carboxylate 1-oxide (15.4 g) as a pale yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[S:22][C:23]=1[CH3:24]>>[CH3:18][C:19]1[N:20]=[C:21]([N:25]2[CH2:26][CH2:27][N:28]([C:7]([C:6]3[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=3[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:29][CH2:30]2)[S:22][C:23]=1[CH3:24]
Reactant: Cc1nc(N2CCNCC2)sc1C
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: Cc1nc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)sc1C
Yield: 65 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(4,5-dimethyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 65%). MS (m/e): 584.3 (M+H+, 100%), 601.4 (M+NH4+, 60%).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]2[N:42]=[CH:3][C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=3[N:41]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: COC(=O)C1CCCCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: COC(=O)C1CCCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude methyl 3-[1-dimethylamino-methylidene]-2-oxo-cycloheptanecarboxylate (85 mg, 0.38 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow oil (7 mg, 8%). MS ISP (m/e): 408.5 [(M+H)+].
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:57])[C@@H:24]([NH:25][C:26](=[O:56])/[C:27](/[C:49]4[N:50]=[C:51]([NH2:55])[S:52][C:53]=4[Cl:54])=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2Cl)=[O:16])C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[SH2:60].[Na].P(O)(O)([O-])=O.[Na+]>CN(C=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:57])[C@@H:24]([NH:25][C:26](=[O:56])/[C:27](/[C:49]4[N:50]=[C:51]([NH2:55])[S:52][C:53]=4[Cl:54])=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[SH:60])=[O:16])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Cl)CS[C@H]23)c(Cl)s1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S)CS[C@H]23)c(Cl)s1
Yield: 190.7 %

Procedure:
To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate diphenylmethyl ester (4.0 g, 4.72 mmol) in DMF (30 mL) cooled to -20° C. was added in one portion powdered sodium hydrogen sulfide hydrate (1.1 g, 19.6 mmol). After 15 min the reaction mixture was poured into 0.5M monosodium phosphate (about 100 mL), extracted with ethyl acetate and the organic layer was washed thoroughly with water. After concentrating in vacuum the crude title product was obtained as yellow foam 3.8 g (95%). 1H NMR (CDCl3 /CD3OD) δ 3.38 (d, 1H, J=15), 4.43 (d, 1H, J=15), 5.03 (d, 1H, J=5), 5.80 (d, 1H, J=5), 5.99 (br s, 1H), 6.80 (s, 1H), 7.05-7.50 (m, 25H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:30]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:28][CH:27]=2)=[O:31])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (45.8 mg, 0.167 mmol) in CH2Cl2 (2 mL) was added 4-(trifluoromethyl)phenyl isocyanate (0.28 μL, 0.196 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 137 as a colorless solid (25.1 mg, 33%). LCMS m/z (%)=462 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 9.11 (bs, 1H), 8.75 (bs, 1H), 7.65 (d, J=9.08 Hz, 2H), 7.62 (d, J=9.35 Hz, 2H), 7.47 (dd, J=9.09, 2.78 Hz, 1H), 7.45 (d, J=1.77 Hz, 1H), 7.39 (d, J=2.78 Hz, 1H), 7.10 (d, J=8.84 Hz, 1H), 6.24 (d, J=1.77 Hz, 1H), 3.98 (t, J=6.32 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.07 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:13](=O)[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>CN(C)C=O.CCOCC>[CH3:14][C:13]1[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(=Cc1ccccc1)C(C)=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-[(phenyl)methylene]-3-oxobutanoic acid, methyl ester (13.0 g., 63.7 mmole) in dry dimethylformamide (20 ml.) is treated dropwise with 2-aminothiophenol (8.85 g. of 90%, 63.7 mmole). A slight release of heat is noted. The reaction is stirred at room temperature for 6 hours and then heated at 65° for 72 hours. It is cooled to room temperature and diluted with ether. The resulting solution is thoroughly washed with water, sodium bicarbonate and brine. After drying over anydrous magnesium sulfate, the solvent is stripped off to give a yellow solid. It is triturated with isopropyl ether and filtered off to provide 6.93 g. of light yellow crystals. Recrystallization from isopropyl ether-dichloromethane gives an analytically pure sample of 2,5-dihydro-4-methyl-2-phenyl-1,5-benzothiazepine-3-carboxylic acid, methyl ester; m.p. 154°-156°. TLC(silica gel, hexane:acetone, 70:30) Rf =0.35.