Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12]([CH:15]=[CH:16][CH3:17])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2].[Na+].C1(S([O-])=O)C=CC=CC=1.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]2[CH:8]3[CH2:14][CH2:13][CH:12](/[CH:15]=[CH:16]/[CH3:17])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:20])[CH3:2]
Reactant: CC=CC1CCC2c3ccc(OCC)c(F)c3OC2C1
Agent: Cl
Agent: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C/C=C/C1CCC2c3ccc(OCC)c(F)c3OC2C1
Reaction time: 1 h

Procedure:
6.0 g (about 21.7 mmol) of (E/Z) isomer mixture of (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-propenyl-1,2,3,4,4a,9b-hexahydrodibenzofuran (see 1.9) are refluxed in 60 ml of toluene together with 1.15 g (7.0 mmol) of benzene-sulfinic acid sodium salt and 21.4 ml of 1 N hydrochloric acid. After 1 h, the mixture is added to water, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and concentrated to dryness. Repeated recrystallisation from isopropanol gives (±)-(3R*, 4aR*, 9bS*)-7-ethoxy-6-fluoro-3-((E)-propenyl)-1,2,3,4,4a,9b-hexahydrodibenzofuran as colourless solid (melting point 145° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[C:27]3[CH:31]=[C:32]([CH3:34])[CH:33]=[C:25]([CH3:24])[CH:26]=3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cc(C)cc(C)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3,5-dimethyl-benzoic acid to yield (3aR,4S,7aR)-4-(3,5-dimethyl-benzoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=8.590 min; LC/MS Method III
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:14]([Li])[CH2:15][CH2:16]C.C(Br)C=C.Cl.[Cl-].[NH4+].[BH4-].[Na+]>O1CCCC1>[CH2:11]([CH:10]([CH2:16][CH:15]=[CH2:14])[CH:4]([OH:3])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:12][CH3:13]
Reactant: [Li]CCCC
Reactant: CCCCC(=O)CC(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(CCC)C(O)CC(=O)OC
Reaction time: 0.42 h

Procedure:
Sodium hydride (>63% oil, 2.09 g, 55 mmol) was added to a tetrahydrofuran solution (50 mL) of methyl 3-oxoheptanoate (7.91 g, 50 mmol) under ice cooling, and the mixture was stirred in this state for 25 minutes. To the reaction solution, n-butyllithium (1.58 M hexane solution, 34.8 mL, 55 mmol) was added dropwise, and the mixture was further stirred for 1 hour under ice cooling. Then, allyl bromide (4.7 mL, 55 mmol) was added thereto, and the mixture was stirred in this state for 1 hour and then further stirred overnight at room temperature. To the reaction solution, 1 N hydrochloric acid and a saturated aqueous solution of ammonium chloride were added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol (35 mL). To the solution, sodium borohydride (0.61 g, 16.1 mmol) was added under ice cooling, and the mixture was stirred in this state for 1 hour. 1 N hydrochloric acid (50 mL) was added thereto, and the mixture was stirred for 30 minutes. Then, saturated saline was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (3.24 g, 33%, mixture of diastereomers).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH2:18])[CH:16]=[CH2:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20](=[CH2:23])[CH:21]=[O:22].B(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:18][CH2:19][C:20]([CH3:23])([CH:21]=[O:22])[CH2:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=C)c1ccc(OCc2ccccc2)cc1
Reactant: C=C(C)C=O
Agent: FB(F)F
Solvent: ClCCl
Product: CC1(C=O)CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Reaction time: 3 h

Procedure:
1-benzyloxy-4-(1-methylene-allyl)-benzene (0.40 g, 1.694 mmol) and 2-methyl-propenal (0.355 mL) in DCM (10 mL) was cooled to −10° C. BF3.OCH2CH3 (0.322 mL, 1.778 mmol) was added and the reaction mixture stirred for 3 h. The mixture was then quenched by aqueous saturated NaHCO3 solution. After extraction with ethyl acetate (2×100 mL), the reaction mixture was dried over MgSO4 and purified on SiO2 to yield 4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-ene carbaldehyde.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[O:22][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1ccc(O)c(C)c1
Reactant: O=[N+]([O-])c1cccc2nc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 97.5 %

Procedure:
A mixture of 2-bromo-7-nitro-1,3-benzothiazole (200 mg, 0.772 mmol), 2,4-dimethylphenol (0.093 ml, 0.772 mmol) and potassium carbonate (128 mg, 0.772 mmol) in DMF (10 ml) was stirred at 80° C. for 15 h. The mixture was diluted with water and extracted with ethyl acetate (AcOEt). The extract was washed with saturated NaHCO3 solution and brine, dried over Magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 10% AcOEt in n-hexane to afford 226 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][C@H:10]([NH:12][C:13]1[C:14]2[S:31][C:30](=[O:32])[NH:29][C:15]=2[N:16]=[C:17]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:18]=1)[CH3:11].CC([Si](C)(C)[O:38][CH2:39][CH:40]=O)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:28][C:22]1[C:23]([F:27])=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:19][C:17]1[N:18]=[C:13]([NH:12][C@H:10]([CH3:11])[CH2:9][NH:8][CH2:40][CH2:39][OH:38])[C:14]2[S:31][C:30](=[O:32])[NH:29][C:15]=2[N:16]=1
Reactant: C[C@H](CN)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)sc12
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CNCCO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(=O)sc12
Reaction time: 1 h

Procedure:
To a solution of the product from example 12 step f) (100 mg) in dry THF (5 ml) was added [[(1,1-dimethylethyl)dimethylsilyl]oxy]-acetaldehyde (49 mg) followed by sodium triacetoxyborohydride (61 mg) and the mixture stirred for 1 hour. The mixture was acidified with concentrated hydrochloric acid, stirred at room temp for 1 hour then evaporated to dryness. The product was purified (HPLC, Novapak® C18 column, 0.1% aqueous TFA:acetonitrile, gradient elution 75:25 to 5:95 over 15 minutes) to afford the title compound (0.021 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH2:10])[CH:7]([CH3:9])[CH3:8].O>CCOCC>[CH2:6]([NH:10][C:3](=[O:4])[CH2:2][Cl:1])[CH:7]([CH3:9])[CH3:8]
Reactant: O=C(Cl)CCl
Reactant: CC(C)CN
Solvent: O
Solvent: CCOCC
Product: CC(C)CNC(=O)CCl
Yield: 94.4 %

Procedure:
Chloroacetyl chloride (37.58 g) was added dropwise over 1 hour to a solution of isobutylamine (46.8 g) in ether (500 ml) maintaining the temperature below 5° C. Water (100 ml) was then added, and the organic layer was separated and washed with dilute hydrochloric acid, sodium hydroxide, and brine and dried (MgSO4). The solvent was removed in vacuo to yield N-isobutylchloroacetamide (47 g).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16]Br)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:24]=[N:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C.CO>C(O)C>[NH2:2][C:3]1[S:4][C:5]([CH2:15][CH2:16][N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:22]4[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=4[N:25]=[N:24]3)[CH2:31][CH2:30]2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(CCBr)s1
Reactant: Fc1ccc2c(c1)nnn2C1CCNCC1
Agent: Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Nc1nc(-c2ccc(F)cc2)c(CCN2CCC(n3nnc4cc(F)ccc43)CC2)s1
Temperature: 25 °C

Procedure:
A mixture of 0.917 g of 2-amino-5-(2-bromoethyl)-4-(4-fluorophenyl)thiazole hydrobromide, 0.441 g of 4-(5-fluoro-1H-benzotriazol-1-yl)piperidine, 1 ml of diisopropylethylamine and 4 ml of methanol was stirred with heating under reflux for 12 hours. After the reaction mixture was cooled to room temperature, ethanol was added thereto and the crystals were collected by filtration. The crystals were recrystallized from chloroform-ethanol to obtain 0.56 g of 2-amino-4-(4-fluorophenyl)-5-[2-[4-(5-fluoro-1H-benzotriazol-1-yl)piperidin-1-yl]ethyl]thizole.
Reaction SMILES: Cl.[CH2:2]([NH:6][NH2:7])[CH2:3][CH2:4][CH3:5].[CH3:8][N:9]=[C:10]=[O:11]>O1CCCC1>[CH3:8][NH:9][C:10]([N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[NH2:7])=[O:11]
Reactant: CN=C=O
Reactant: CCCCNN
Agent: Cl
Solvent: C1CCOC1
Product: CCCCN(N)C(=O)NC
Yield: 82.7 %

Procedure:
A suspension of 2.42 g n-butylhydrazine hydrochloride in 15 mL tetrahydrofuran was degassed and stirred under nitrogen with cooling (water bath) while 1.68 g of powdered potassium hydroxide was added. Stirring and cooling continued as 0.86 g (0.015 mole) methyl isocyanate in 15 mL tetrahydrofuran was added dropwise. The resulting mixture was allowed to stir at room temperature overnight. The solution was filtered and the filtrate evaporated to yield a colorless liquid. Vacuum distillation gave 82.7% N-methyl-1-butylhydrazine-carboxamide, b.p. 116°-118° C. at 0.06 torr. The compound crystallized upon standing m.p. 48°-50° C. Its structure was confirmed by NMR analysis.
Reaction SMILES: [CH2:1]([N:5]([CH2:22][C:23]#[N:24])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19](Cl)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:25][C:26]1[C:35]([O:36][CH3:37])=[CH:34][C:29]2[NH:30][C:31](=[O:33])[S:32][C:28]=2[CH:27]=1>>[CH2:1]([N:5]([CH2:22][C:23]#[N:24])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19]([NH:25][C:26]4[C:35]([O:36][CH3:37])=[CH:34][C:29]5[NH:30][C:31](=[O:33])[S:32][C:28]=5[CH:27]=4)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC#N)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: CCCCN(CC#N)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
100 mg (276 μmol) (RS)—N-butyl-4-chloro-N-(cyanomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 88a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 15.9 mg (10%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22](O)=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1.Cl.[OH:27][C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.CN1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([N:30]4[CH2:31][CH2:32][C@H:28]([OH:27])[CH2:29]4)=[O:23])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:25]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Reactant: O[C@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
70.36 g of 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylic acid are dissolved in 1600 ml of N,N-dimethylformamide under argon, whereupon 45 ml of 4-methylmorpholine, 27.2 g of (S)-3-hydroxypyrrolidine hydrochloride and 83.4 g of O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate are added in succession. The mixture is stirred at room temperature for about 18 hours and the yellow solution obtained is poured into 6000 ml of water and treated slowly with 2500 ml of saturated sodium hydrogen carbonate solution. The product obtained is filtered under suction and washed with 1000 ml of water. After drying in a vacuum at 70° there are obtained 83.3 g of crude product. By repeated recrystallization from a 120-fold amount of isopropanol and chromatography of the combined mother liquours on 1000 g of silica gel with methylene chloride/diethyl ether (9:1) and subsequently with methylene chloride/acetone (9:1), there are obtained 74.2 g (88%) of (S)-1-[ (10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbonyl]-3-hydroxypyrrolidine with a m.p. of 257°-259° .
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[CH:8][C:7]([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)=[N:6]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:8][C:7]([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1CC1CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Reaction time: 1 h

Procedure:
2-Cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one (540 mg, 1.81 mmol) was dissolved in methylene chloride (12 mL), and triethylamine (238 mg, 2.35 mmol) and methanesulfonyl chloride (249 mg, 2.17 mmol) were added to the solution under cooling with ice, followed by stirring for one hour. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, and the residue was recrystallized from chloroform-hexane, to thereby yield 607 mg of the title compound as a pale yellow crystalline powder (89.1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:39])[C@@H:18](NC(=O)C(C4N=C(NC(OC(C)(C)C)=O)SC=4)=NOC)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:40]Cl)=[O:10])=[CH:5][CH:4]=1.[I-:44].[Na+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:39])[CH2:18][C@H:15]3[S:14][CH2:13][C:12]=2[CH2:40][I:44])=[O:10])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CCl)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3CC(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.9 %

Procedure:
To a solution of 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (652 mg: 1 mMol.) in acetone (7 ml) is added sodium iodide (450 mg: 3 Eq.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to give 7β-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-methoxyimino) acetamido]-3-iodomethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (730 mg). Yield: 98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:10])[CH3:9].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:15][C@@H:16]1[O:18][CH2:17]1)(=O)=O.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][CH2:15][C@H:16]1[CH2:17][O:18]1)[CH3:9]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: C[C@@H](O)c1ccccc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
(R)-1-(2-Bromophenyl)ethanol (30.0 g) and (R)-glycidyl nosylate(50.3 g) were dissolved in N,N-dimethylformamide (300 ml), sodium hydride (7.76 g, 60% in oil) was added and the mixture was stirred at room temperature for 2 hr. 10% Aqueous citric acid (600 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1) to give the title compound (32.9 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.Cl>>[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:15][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(Cl)c3)c[nH]2)CC1
Agent: Cl
Solvent: ClCCl
Product: Clc1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Reaction time: 1 h

Procedure:
Dissolve 4-[4-(3-Chloro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (171 mg; 472.54 μmoles) in dichloromethane (3 mL; 46.80 mmoles) and slowly add hydrogen chloride (4 mL; 16.00 mmoles) (4M HCl in dioxane) at room temperature. Stir the solution 1 h. Concentrate in vacuo (2×DCM) to give 4-[4-(3-Chloro-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride salt.
Reaction SMILES: [Mg].[N+:2]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].C1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>CCOCC>[C:18]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1)(=[O:20])[CH3:19]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(=O)Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
Magnesium turnings (1.2 g) were added to a solution of m-nitrophenol (6.95 g), benzene (40 ml) and acetyl chloride (4 g) and the solution heated for 1 hour at 90° C. The reaction mixture was diluted with ether and decanted from unreacted magnesium. The ether layer was washed successively with water, dilute NaOH and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to give m-nitrophenyl acetate. m.p. 55°-56° C. 1H n.m.r. δ2.4, s, 3H, H3C--CO--; 7.4-8.4, m, 4H, ArH. υmax 1770 cm-1.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1.[CH3:21][C:22]([CH3:33])([C:28](OCC)=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH2:26]([O:25][C:23](=[O:24])[C:22]([CH3:33])([CH3:21])[C:28]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:29])[CH3:27]
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
sec-Butyl lithium (5.85 mL, 7.6 mmol) was added to a solution of 1-bromo-4-benzyloxy-benzene (2.0 g, 7.6 mmol) in THF (10 mL) cooled to −78° C. under nitrogen. The reaction was stirred for 1 h and diethyl dimethylmalonate (4.29 g, 22.8 mmol) was added rapidly. This was stirred for an additional 0.5 h and then allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give an oil. The product was purified by flash column chromatography (FCC) on silica gel eluting hexane:ethyl acetate (90: 10, v:v) to give 3-(4-benzyloxy-phenyl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester (1.25 g, 50%) as an oil. MS found: (M+H)+=327.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[CH2:5]([O:12][C:13]([N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH:17]([CH:25]=O)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH2:5]([O:12][C:13]([N:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH:17]([CH:25]=[N:4][O:3][CH3:2])[CH2:16]1)=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=CC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=CC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
3.42 g of O-methylhydroxylamine hydrochloride are added to a solution of 600 mg of N-benzyloxycarbonyl-2(R,S)-formyl-3,4-dihydro-2H-1,4-benzoxazine (Rf =0.31; prepared by means of Swern oxidation (Example 1g) from Example 87c) in 30 ml of pyridine and the reaction mixture is then stirred at room temperature for 36 h and subsequently concentrated. The crude product is dissolved in ethyl acetate and the solution is washed with a 1N sodium bicarbonate solution, water and saturated sodium chloride solution. N-Benzyloxycarbonyl-2(R,S)-methoxyiminomethyl-3,4-dihydro-2H-1,4-benzoxazine is obtained (540 mg): Rf (A)=0.61. A further reaction analogously to Example 87a) and purification of the crude product by means of FC over 50 g of silica gel (mobile phase N) gives 2(R,S)-methoxyiminomethyl-3,4-dihydro-2H-1,4-benzoxazine: Rf (A)=0.51.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: OCCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCc2ccsc2)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution 6-chloro-2-iodopyridin-3-ol (6.75 g, 26.4 mmol), 2-(3-thienyl)ethanol (3.79 mL, 34.4 mmol), and triphenylphosphine (9.01 g, 34.4 mmol) in tetrahydrofuran (140 mL) was added diisopropyl azodicarboxylate (6.76 mL, 34.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column on silica gel (eluted at EtOAc/Hexanes=1:20) to give 5.5 g of 6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine. Yield: 58%. 1H NMR (DMSO, 400 MHz): δ7.50-7.43 (m, 3H), 7.34 (d, J=1.6 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 4.29 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H). LC-MS (ESI): m/z=366 [M+H]