Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([NH:11][C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:14][N:13]=2)[CH:8]=[N:7][C:6]=1[CH3:26])C.CO.O.[Li+].[OH-]>C1COCC1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:14]=[N:13][C:12]([NH:11][C:9]3[CH:8]=[N:7][C:6]([CH3:26])=[C:5]([CH:10]=3)[C:4]([OH:27])=[O:3])=[N:17][CH:16]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc(Nc2ncc(-c3ccc(OC)cc3)cn2)cnc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc(Nc3cnc(C)c(C(=O)O)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of the 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid ethyl ester 9 (0.9 mmol) in THF:MeOH:H2O=3:2:1 (7 mL), is added 6M LiOH (2.7 mmol). The reaction mixture is stirred at rt for 12 h. After this time the solvent is removed under vacuum, the residue is diluted with H2O (6 mL) and the pH neutralized with 6M HCl. The solid formed is filtered, washed with water and dried in a vacuum oven for 12 h to afford 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-2-methyl-nicotinic acid 10 as off white solid, which is used in the next step without further purification. MS (m/z) (M+1)+: 337.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C@@H:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][C@H:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(F)cc4)cc3OC)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (45 mg, yield 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])=[O:6].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([NH:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])=[O:6])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](CCC(=O)NCCS(=O)(=O)O)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: O=C(CC[C@H](NC(=O)c1ccccc1)C(=O)O)NCCS(=O)(=O)O

Procedure:
25.4 mg. (0.1 mmoles) of gamma-L-glutamyl-taurine are treated with 13 μl. of benzoyl chloride as described in Example 12. The reaction mixture is processed as described in Example 12 to obtain N-benzoyl-gamma-L-glutamyl-taurine, which is purified by paper electrophoresis using a pH 6.5 buffer solution. Relative motility (related to cysteinic acid): 1.06. Rf =0.47 (in a 15:10:3:12 mixture of n-butanol, pyridine, glacial acetic acid and water).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH3:14][C@@H:15]([CH2:23][CH2:24][CH3:25])[CH:16]([CH2:19][C:20](=O)[CH3:21])[CH:17]=O.Cl.C(=O)(O)[O-].[Na+]>O.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][N:7]1[CH:14]=[C:15]([C@@H:16]([CH3:17])[CH2:19][CH2:20][CH3:21])[CH:23]=[C:24]1[CH3:25])=[O:5]
Reactant: CCC[C@H](C)C(C=O)CC(C)=O
Reactant: CSc1ccc(C(=O)NN)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](C)c1cc(C)n(NC(=O)c2ccc(SC)cc2Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
The compound prepared in Example 76 (1.65 g) and (3S)-3-methyl-2-(2-oxopropyl)hexanal (1.86 g) were dissolved with tetrahydrofuran (10 mL), and 5N hydrochloric acid (0.2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate and water were added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed by water and a saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=85/15→65/35) to obtain the title compound (1.6 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17]2.CO.C([Cl:34])(=O)C>C1COCC1>[ClH:34].[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][NH:16][CH2:17]2
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Solvent: CO
Solvent: C1CCOC1
Product: Cl
Product: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A solution of tert-butyl 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.73 g, 5.98 mmol) in 12 mL THF was treated with methanol (2.421 ml, 59.8 mmol) and was cooled to 0° C. Acetyl chloride (4.25 ml, 59.8 mmol) was added, and the reaction mixture was allowed to stir overnight. LC/MS showed mostly product, so the reaction mixture was concentrated yielding 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.32 g, 5.91 mmol). [M+H]+=357.9.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13](=[CH2:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:18].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl.S([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]2([O:18][CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC2(CO2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution 3-methylen-pyrrolidine-1-carboxylic acid benzyl ester (WO9624593) in 5 ml of dichloromethane was treated with 2.16 g sodium bicarbonate (MW: 84.01 26.28 mmol) and 2.47 g of 80% m-chlor-perbenzoic acid (MW: 172.57, 11.48 mmol). The reaction mixture was stirred at room temperature for three hours. The reaction mixture was diluted with 20 ml of a saturated aqueous sodium sulfite solution and 45 ml of dichloromethane. The organic layer was successively washed with 30 ml of an aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate. The residue was purified by chromatography on silica (1/1 ethyl acetate/n-hexane) to afford a off white solid. Yield: 440 mg, 57%. MS: 234.1 (M+H)+, Method ESI+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@@H:6]([OH:13])[CH2:7]2.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)C>[CH3:21][S:22]([O:13][C@@H:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=2[F:1])[CH2:7]1)(=[O:24])=[O:23]
Reactant: O[C@@H]1CCc2c(F)cc(F)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.8 %

Procedure:
A mixture of (R)-5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (59.0 g, 0.32 mol), prepared as in Example 3, and triethylamine (13.8M, 74.2 mL, 0.53 mol) in 1.78 L of diethyl ether was cooled using a methanol/ice bath. Methanesulfonyl chloride (12.9M, 37.2 mL, 0.48 mol) was added under argon over 5-10 minutes and the mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and ether and the ether layer was separated and the aqueous layer was extracted with ether. The combined ether layers were washed once with each of 1N hydrochloric acid, saturated sodium bicarbonate solution and brine and then dried over magnesium sulfate. Evaporation gave crude (R)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl methanesulfonate as an off-white solid (87.12 g), m.p. 79°-80° C. [α]D25 =+16.77° (c=2.0, CHCl3).
Reaction SMILES: Cl.CN(CC[CH2:7][NH:8][C:9]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])C.[CH2:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH3:28].[C:34]([Cl:37])(=[O:36])[CH3:35]>ClCCl>[ClH:37].[CH2:27]([N:29]([CH2:32][CH2:33][CH2:7][NH:8][C:9]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]2[C:18]([C:19]=1[O:20][C:34](=[O:36])[CH3:35])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:30][CH3:31])[CH3:28]
Reactant: CCN(CC)CC
Reactant: CN(C)CCCNC(=O)c1c(O)c2ccccc2n1-c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCCNC(=O)c1c(OC(C)=O)c2ccccc2n1-c1ccccc1
Reaction time: 0.5 h
Yield: 57 %

Procedure:
1.66 g of 2-[3-(N,N-dimethylamino)propylaminocarbonyl]-3-hydroxy-1-phenylindole hydrochloride are dissolved in 25 ml dichloromethane and mixed successively under vigorous agitation with 0.6 ml of triethylamine and 0.3 ml of acetyl chloride. The reaction mixture is boiled for 30 min under reflux. After cooling, the mixture is washed with a small amount of a saturated solution of sodium chloride, the organic phase dried over sodium sulfate and evaporated under vacuum. Following recrystallization from isopropanol, 1.00 g (57% of theoretical) 2[3-(N,N-diethylamino)-propylaminocarbonyl]-3-acetoxy-1-phenylindole hydrochloride is obtained. Melting point: 174°-176° C.
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C2C(COC([N:54]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[CH:55]3[C:63]([OH:65])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.CNC>C(Cl)Cl.CCO>[CH3:2][N:3]([CH3:4])[C:63]([CH:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:62][NH:54]1)=[O:65]
Reactant: O=C(O)C1c2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)C1NCc2ccccc21
Reaction time: 0.25 h
Yield: 204.6 %

Procedure:
1.66 g of DIPEA and then 5.73 g of BOP are added to a solution of 5 g of 2-(9-fluorenylmethoxycarbonyl)isoindoline-1-carboxylic acid (commercial) in 100 ml of DCM and the mixture is left stirring for 15 minutes at AT. 4.6 ml of a 5.6M solution of dimethylamine in EtOH are subsequently added and the mixture is left stirring for 30 minutes at AT. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted with DCM, the organic phase is washed with a 5% KHSO4 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (70/30, v/v) mixture. 5 g of the expected product are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16](O)=[O:17].O>C(OCC)C.O1CCCC1>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[CH2:16][OH:17]
Reactant: O=C(O)c1cc2ccccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCc1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
Lithium aluminium hydride (467 mg, 12.3 mmol) was suspended in diethyl ether and the suspension was heated under reflux. The suspension was added dropwise with 1-benzofurane-2-carboxylic acid (2.00 g, 12.3 mmol), dissolved in tetrahydrofuran (10 ml) and further heated under reflux for 20 minutes. The reaction mixture was cooled to 0° C., and then added with water (0.8ml) and stirred at the same temperature for 30 minutes. Insoluble solids were removed by filtration using Celite, and then the solvent was evaporated under reduced pressure to obtain the title compound as yellow oil (1.72 g, yield: 94%).
Reaction SMILES: [CH:1]1[C:6]([NH:7][NH2:8])=[CH:5][CH:4]=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:2]=1.Cl.[CH3:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=O)[CH:20]([C:26](=O)[C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:18]2>C(O)C>[CH3:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]3[N:7]([C:6]4[CH:1]=[CH:2][C:3]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:4][CH:5]=4)[N:8]=[C:26]([C:27]([F:28])([F:29])[F:30])[C:20]=3[CH2:19][CH2:18][C:17]=2[CH:16]=1
Reactant: Cc1ccc2c(c1)CCC(C(=O)C(F)(F)F)C2=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)CCc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Reaction time: 14.8 h
Yield: 63.9 %

Procedure:
4-Sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0 mmol) was added to a stirred solution of the diketone from Step 1 (1.86 g, 7.3 mmol) in ethanol (10 mL). The reaction was heated to reflux and stirred for 14.8 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, washed with water and with brine, dried over MgSO4 and reconcentrated in vacuo to give the pyrazole as a brown solid (1.90 g, 64%): mp 215°-218° C. 1H NMR (acetone-d6) 300 MHz 8.10 (d, 2H), 7.80 (d, 2H), 7.24 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 2H), 6.88 (d,1H), 3.02 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H). 19F NMR (acetone-d6) 282 MHz −62.46 (s). High resolution mass spectrum Calc'd. for C19H17F3O2S: 408.0994. Found: 408.0989.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20].C[N:22]1[CH:29]=[CH:28][C:26](=O)[N:25](C)C1=O.ClCC#N.[CH2:35]1[CH2:39][O:38][CH2:37][CH2:36]1>CCO.C(#N)C>[NH2:22][C:29]1[C:39]2[CH:35]=[CH:36][C:37](=[O:38])[N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[Cl:11])[C:19]=2[S:20][C:28]=1[C:26]#[N:25]
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: S=C=Nc1ccccc1Cl
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#CCCl
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Product: N#Cc1sc2c(ccc(=O)n2-c2ccccc2Cl)c1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetonitrile (10 ml) was added to a solution of sodium bis(trimethylsilyl)amide (100 ml, 1.0M in THF, 100 mmol) in THF (50 ml) at −78° C. to give a thick white precipitate. 2-Chlorophenyl isothiocyanate (7.72 g, 45.45 mmol) was added to give a brown solution. The mixture was allowed to warm to r.t. over 1 h then diluted with EtOH (50 ml). 1,3-Dimethyluracil (6.4 g, 45 mmol) was added and the mixture heated at reflux for 24 h. Volatiles were removed in vacuo and the residue dissolved in acetonitrile (100 ml). Chloroacetonitrile (2.85 ml, 45 mmol) was added and the mixture heated at 50° C. for 1 h, a second charge of chloroacetonitrile (2.85 ml, 45 mmol) was added and heating continued for 1.5 h. Some of the acetonitrile (˜50 ml) was removed in vacuo and water was added to precipitate the product. The brown solid was filtered off, washed with water (50 ml) and Et2O (50 ml) and dried to give the title compound as a brown solid (14.3 g, quantitative). δH (DMSO-d6) 8.10 (1H, d, J 9.7 Hz), 7.75-7.73 (1H, m), 7.65-7.54 (3H, m), 7.14 (2H, br s, Hz), 6.54 (1H, d, J 9.7 Hz). LCMS (ES+) RT 2.97 minutes, 302 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Fc1ccc([C@@H]2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@H]1c1ccc(F)cc1

Procedure:
The title compound, white solid, m.p. 120° C. and MS: m/e=339 (Me) was prepared in accordance with the general method of example 1e from (S)-2-(4-fluoro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.C1(C)C=CC(S(O[CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:22][C:21]=3[CH2:20]2)(=O)=O)=CC=1>CN(C)C=O>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:18][CH:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:23]=[CH:22][C:21]=2[CH2:20]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)CCC(Cc1ncc[nH]1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
0.56 g of 50% sodium hydride was suspended in 60 ml of anhydrous dimethylformamide, and 0.79 g of imidazole was added thereto. The mixture was stirred at room temperature for 20 minutes and 4.5 g of ethyl 6-(p-toluenesulfonyloxymethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was added portionwise thereto. The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the residue was extracted with chloroform. The extract was washed with water and dried over sodium sulfate and then concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of methanol and chloroform (2:98 by volume) for elution to give 2.31 g of ethyl 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][CH:30]=1)=[O:28]>N1CCCCC1.C(O)C>[O:17]=[C:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[NH:31][CH:30]=1)=[O:28]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1c(C(=O)NCCCN2CCCC2=O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)NCCCN2CCCC2=O)c[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 4-piperidin-4-yl-1,3-dihydroindol-2-one (35.6 mg, 0.165 mmol), 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid [3-(2-oxo-pyrrolidin-1-yl)propyl]-amide (48 mg, 0.173 mmol) and piperidine (2 drops) in ethanol (0.5 mL) was stirred at room temperature for 7 days. The reaction was concentrated and ether was added to the residue. The precipitate which formed was collected by vacuum filtration, washed with ethanol and ether and dried to give the title compound.
Reaction SMILES: [OH:1][N:2]([CH3:16])[C:3]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([SH:13])[N:7]2[N:6]=1)=[O:4].CC(O[CH2:21][C:22]1[CH2:31][S:30][C@@H:25]2[C@H:26]([NH2:29])[C:27](=[O:28])[N:24]2[C:23]=1[C:32]([OH:34])=[O:33])=O.B(F)(F)F.CCOCC.ClCCl>ClCCl.S1(CCCC1)(=O)=O>[NH2:29][C@@H:26]1[C:27](=[O:28])[N:24]2[C@@H:25]1[S:30][CH2:31][C:22]([CH2:21][S:13][C:12]1[N:7]3[N:6]=[C:5]([C:3](=[O:4])[N:2]([OH:1])[CH3:16])[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=1)=[C:23]2[C:32]([OH:34])=[O:33]
Reactant: Cc1cc(S)n2nc(C(=O)N(C)O)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)N(C)O)nc2n1
Temperature: 10 °C
Yield: 73.1 %

Procedure:
N-Hydroxy-7-mercapto-N,5-dimethyl-s-triazolo[1,5-a]pyrimidine-2-carboxamide (53 mg) (0.22 mmol) and 54 mg (0.2 mmol) of 7-aminocephalosporanic acid are suspended in 1 ml of dichloromethane/sulpholane (1:1 v/v). 0.5 ml of boron trifluoride diethyl etherate is added thereto at 10° C. while stirring and the mixture is stirred at room temperature for a further 20 hours. Subsequently, about 10 ml of dichloromethane are added thereto, the insoluble material is filtered off under suction, dissolved in water and the product is precipitated by the addition of sodium hydrogen carbonate (pH→4). The precipitate is filtered off under suction and washed with water and ethanol. There are obtained 66 mg of (6R,7R)-7-amino-3-[[[2-(N-hydroxy-N-methylcarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4,2,01oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH3:10].C(Cl)(Cl)Cl.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Cu+2].N1C=CC=CC=1>[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:12]=1)[CH3:10]
Reactant: Oc1cccc(Br)c1
Reactant: CCc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCc1ccc(Oc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 102.2 %

Procedure:
A suspension of 3-bromophenol (2.3 g, 13.3 mmol), 4-ethylphenyl boronic acid (1.0 g, 6.67 mmol), molecular sieve 4A (14.7 g), Cu(OAc)2 (1.21 g, 6.67 mmol) and chloroform (25 mL) was stirred at room temperature for three minutes and added with triethylamine (3.6 mL) and pyridine (2.7 mL). The insolubles were filtered off with celite after the mixture was stirred for 15 hours. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain 1.89 g of a colorless oily title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: C[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (22 g, 100 mmol), L-alanine (8.9 g, 100 mmol), and potassium carbonate (17.5 g, 125 mmol) in ethanol (250 ml), and water (200 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water, and acidified with 1N hydrochloric acid. The precipitate was collected on a funnel and dried to afford N-(5-bromo-2-nitrophenyl)-alanine (28.9 g, 100%). A sample was recrystallized from ethanol: m.p. 183-187° C.; 1H-NMR (DMSO-d6) δ1.44 (d, J=6.9 Hz, 3H), 4.56 (m, 1H), 6.87 (d, J=6 Hz, 1H), 7.21 (d, J=1.7 Hz, 1H), 7.99 (d, J=7 Hz, 1H), 8.36 (d, J=7 Hz, 1H), 13.27 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH2:22])[CH:10]=2)[O:5]1.[CH:24](O)=[O:25]>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1([CH3:23])[CH:13]([OH:14])[CH:12]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:22][CH:24]=[O:25])[CH:10]=2)[O:5]1
Reactant: COCC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)C1O
Reactant: O=CO
Solvent: c1ccncc1
Product: COCC1(C)Oc2ccc(NC=O)cc2C(n2ccccc2=O)C1O

Procedure:
A solution of 1 g of 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromanol in 15 ml of formic acid and 1 ml of pyridine is boiled for 24 hours and evaporated. Customary working up gives 2-methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-formamido-3-chromanol.