Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH2:7][CH3:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:16]([N:14]1[CH:10]([O:9][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][C:13]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCOC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC1CCC(=O)N1C(=O)c1ccccc1
Yield: 57.9 %

Procedure:
18.6 cm3 of a 1.5M solution of n-butyllithium in hexane is added to a solution of 4 g of 5-(1-propyloxy) pyrrolidin-2-one in tetrahydrofuran at -60° C., while maintaining the temperature between -55° C. and -60° C. After agitation for 15 minutes at -60° C. a solution of 3.93 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added at this temperature. After allowing the mixture to return to ambient temperature, the solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of the expected product is obtained. b.p. =200° C. under 0.1 mbar.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:15]C)=[O:14])=[CH:7][C:6]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[OH-].[Na+]>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([S:17]([CH3:20])(=[O:18])=[O:19])[C:13]([OH:15])=[O:14])=[CH:7][C:6]=1[C:21](=[O:34])[NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1
Reactant: COC(=O)C(Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(C(=O)O)S(C)(=O)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
Into 6 ml of methanol were dissolved 300 mg of methyl 3-[4-methoxy-3-[N-(4-trifluoromethylbenzyl)]carbamoylphenyl]-2-(methylsulfonyl)propionate, 0.7 ml of 1 mol/l aqueous solution of sodium hydroxide were added, and the mixture was stirred for 1 hour at 50° C. The reaction mixture was poured into water and washed with diethyl ether. The aqueous layer was adjusted to pH value of 1 to 2 with 2 mol/l aqueous solution of hydrochloric acid, which was extracted with methylene chloride. The organic layer was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the crystals obtained were recrystallized from diethyl ether-ethyl acetate to obtain 218 mg of aimed product as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:24][N:25]([CH2:28][CH2:29]Cl)[CH2:26][CH3:27].Cl>>[ClH:22].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][N:25]([CH3:24])[CH2:28][CH3:29])[C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CCN(C)CCCl
Agent: Cl
Product: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Yield: 151.7 %

Procedure:
3 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1.7 g of 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride are treated in the same manner as described in Example 5. The product is converted to its hydrochloride and recrystallized from a mixture of ethanol and ether. 3.1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained as colorless needles.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[IH:15].[CH3:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1SC>>[IH:15].[CH3:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[N:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CSC1=NCCN1C
Agent: I
Product: CN1CCNC1=NC(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 31.1 %

Procedure:
A mixture of 1.8 g of benzhydrylamine and 3.4 g of 1-methyl-2-methylmercapto-2-imidazoline.hydroiodide was allowed to stand at room temperature for 2 days. Chloroform was then distilled off to give 1.2 g of 1-methyl-2-benzhydryliminoimidazolidine.hydroiodide having a melting point of 254°-256° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([O:28]C)=[O:27])[N:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:30]=1.[OH-].[Na+].C1COCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=[O:27])[N:21]=4)[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:30]=1
Reactant: COC(=O)c1ncnc(N2CCC(N3CCc4cc(OC)ccc4NC3=O)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)O)n3)CC1)C(=O)N2

Procedure:
0.27 g (0.64 mmol) methyl 4-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-[1,3,5]triazine-2-carboxylate and 0.5 mL (2 mmol) of a 4M NaOH solution were stirred in 0.5 mL water and 4.0 mL THF for 3 days at RT. The organic solvent was eliminated by rotary evaporation and the reaction mixture was combined with 0.5 mL of a 4M HCl solution. The precipitated solid was suction filtered and dried.
Reaction SMILES: C(ON=O)CC(C)C.N[C:10]1[S:11][C:12]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[Cl:49])=[O:42])=[C:13]([C:15]2[N:16]=[N:17][N:18]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:19]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:14]=1>C1COCC1.CCOC(C)=O>[F:40][C:37]([F:38])([F:39])[C:29]1[CH:28]=[C:27]([CH:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=1)[CH2:26][N:18]1[C:19]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:15]([C:13]2[N:14]=[CH:10][S:11][C:12]=2[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[Cl:49])=[O:42])[N:16]=[N:17]1
Reactant: Nc1nc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2cccnc2)c(C(=O)c2ccccc2Cl)s1
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)c1scnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add isoamylnitrite (29 μL, 0.21 mmol) to a solution of {2-amino-4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-thiazol-5-yl}-(2-chloro-phenyl)-methanone (63 mg, 0.103 mmol) in THF (1.5 mL). Stir the solution at RT for 30 min. then warm to reflux for an additional 30 min. Cool solution to RT and dilute with EtOAc (30 mL). Wash the organic solution with saturated NaHCO3 (15 mL) and brine (15 mL) then dry, filter, and concentrate. Purify the crude material by flash chromatography then triturate with ether (2×0.3 mL) and dry to give the title compound: MS (IS) 594.1 (M+1), MS (ES−) 592.0 (M−1); 1HNMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.60 (d, 1H, J=5.0), 8.50 (s, 1H), 7.97 (s, 1H), 7.76 (s, 1H), 7.65 (s, 2H), 7.41 (m, 2H), 7.24 (m, 2H), 7.19 (m, 1H), 5.77 (s, 2H).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.[CH3:16]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOC(C)=O>[CH3:16][C:7]1[CH:2]=[CH:3][C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[C:5]([CH:6]=1)[CH:8]=[O:9]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@H](C)Oc1ccc(C)cc1C=O
Yield: 90.8 %

Procedure:
A mixture (S)-(4-methyl-2-(pent-4-en-2-yloxy)phenyl)methanol (100 mg, 0.485 mmol), Dess-Martin periodinane (247 mg, 0.582 mmol) in DCM (5 mL) was stirred at rt for 1 h. It was then diluted with EtOAc and washed with sat. NaHCO3 and water. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (S)-5-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (90 mg, 91%) as an oil. 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 6.87-6.78 (m, 2H), 5.88 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.21-5.10 (m, 2H), 4.59 (sxt, J=6.1 Hz, 1H), 2.63-2.51 (m, 1H), 2.51-2.42 (m, 1H), 2.40 (s, 3H), 1.40 (d, J=6.1 Hz, 3H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[O:3].[OH-].[Na+].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[F:18]>C(O)C>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:4][C:2](=[O:3])[C:1]([OH:6])=[O:5])=[CH:12][C:11]=1[F:18]
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)C=Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.6 %

Procedure:
A solution of pyruvic acid (1.9 mL, 27.1 mmol) in ethanol (6.0 mL) was added to a 0.5 M sodium hydroxide solution (74.0 mL). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-bromo-3-fluorobenzaldehyde (5.0 g, 24.6 mmol) in ethanol (20.0 mL) was slowly added thereto at room temperature for 1 hour. The reaction mixture was stirred at room temperature for 18 hours and then filtered. The resulting solid washed with ethyl acetate, diluted with a 1N hydrochloric acid solution and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3.2 g of the titled compound as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH:21]([O:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH3:22])=[CH:18][CH:17]=1)#[N:20]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(C#N)cc1
Temperature: 100 °C
Yield: 35 %

Procedure:
To a solution of 6-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(4-cyano-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (VI-B-5) 380 mg (0.93 mmol) dissolved in toluene (10 mL) were added 0.30 mL (2.79 mmol) of 1-chloroethyl chloroformate and 0.47 mL (2.79 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 105 mg (35%) of the title compound as a light yellow oil. ES-MS m/e: 319.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:18])[S:5]([C:8]1[S:12][C:11]([NH:13]C(=O)C)=[N:10][C:9]=1[CH3:17])(=[O:7])=[O:6]>Cl>[OH:1][CH2:2][CH2:3][N:4]([CH3:18])[S:5]([C:8]1[S:12][C:11]([NH2:13])=[N:10][C:9]=1[CH3:17])(=[O:6])=[O:7]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)N(C)CCO)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)N(C)CCO
Temperature: 80 °C
Yield: 67.2 %

Procedure:
A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-methyl-amide (0.85 g,2.9 mmol) in 6N hydrochloric acid (13 ml) was heated for 2 h at 80° C., evaporated, and saturated NaHCO3 solution (50 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (50 ml), dried (MgSO4) and evaporated. The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to yield the title compound (0.49 g, 67%) as a white solid. MS (EI) 251.1 [(M)+]; mp 118° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[O:26][CH3:27])=[CH:14][CH:13]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:28][NH2:29]>C(O)CCC>[F:25][C:21]1[C:22]([F:24])=[CH:23][C:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:7]3[CH:6]=[C:3]4[C:2](=[CH:9][CH:8]=3)[NH:29][N:28]=[C:4]4[NH2:5])=[CH:17][CH:16]=2)=[C:19]([O:26][CH3:27])[CH:20]=1
Reactant: NN
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc(F)c(C#N)c2)cc1
Solvent: CCCCO
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2ccc3[nH]nc(N)c3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-5-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-benzonitrile (150 mg, 0.41 mmol), aqueous hydrazine (excess) and n-butanol (3 mL) was heated to 150° C. for 30 min via microwave reactor. The mixture was then cooled to room temperature. The mixture was then purified by preparative HPLC under neutral conditions to give title compound. LC-MS (ES) calculated for C21H17F2N3O2, 381.39; found m/z 382 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:28])[CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][C:48]([NH2:50])=[O:49]>CN(C=O)C>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]([CH3:28])[CH:22]4[CH2:23][CH2:24][N:25]([CH2:47][C:48]([NH2:50])=[O:49])[CH2:26][CH2:27]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: NC(=O)CBr
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1)C1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-piperidin-4-yl-amino)-thiazol-4-one (Example 17) (80 mg, 0.14 mmol) in DMF (2 mL) was added potassium carbonate (39 mg, 0.28 mmol) followed by 2-Bromo-acetamide (23 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (61 mg, 69%).
Reaction SMILES: [CH2:1]([O:4]C1CCCCO1)[C:2]#[CH:3].C([Mg]Br)C.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17]>CCOCC.O1CCCC1>[OH:4][CH2:1][C:2]#[C:3][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C#CCOC1CCCCO1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(C#CCO)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.9 %

Procedure:
A solution of 3.3 ml (23.2 mmols) of tetrahydro-2-(2-propinyloxy)-2H-pyran [R. A. Earl et al., Organic Syntheses 60, 81 (1981)] in 23 ml of anhydrous tetrahdrofuran was added dropwise to 7.8 ml (23.2 mmols) of a 3 molar solution of ethyl-magnesium bromide in ether at room temperature in the course of 30 minutes. The mixture was then subsequently stirred at room temperature for 1.5 hours. This solution was added dropwise to a well-stirred solution, cooled to -20° C., of 5.0 g (23.2 mmol) of 4-nitrobenzyl chloroformate in 25 ml of tetrahydrofuran in the course of 1.5 hours. The mixture was then subsequently stirred at -15° C. for 30 minutes and at 0° C. for 1.5 hours, and was then left to stand at 0° C. for 12 hours, whereupon the magnesium salts crystallized out. The salts were filtered off, with exclusion of moisture, and washed two times with a little toluene. The filtrate solution was washed 5 times with saturated NaCl solution and dried over MgSO4. The solvent was evaporated off in vacuo, the residue was dissolved in 25 ml of anhydrous methanol and the solution was stirred with 1 ml of the ion exchanger Dowex-50-X4 (H+ form, prewashed with anhydrous methanol) at room temperature for 1 hour. The ion exchanger was separated off, the filtrate solution was concentrated in vacuo and, finally, the residue was dried under a high vacuum. The treatment with the ion exchanger was repeated as described above. The crude product was chromatographed on 300 g of silica gel (toluene:ethyl acetate 4:1) and 2.07 g (38%) of 4-nitrobenzyl 4-hydroxy-2-butinoate were obtained as colorless crystals, melting point: 93°-94° C., RF : 0.27 (toluene:ethyl acetate 4:1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[OH:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][C:4]([O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])=[O:5]
Reactant: COCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
A solution of methoxyacetyl chloride (108.5 g, 1 mol) in absolute dichloromethane (170 mL) was added dropwise at 0° C. to a solution of N-hydroxysuccinimide (115 g, 1 mol) and TEA (111 g, 1 mol) in dichloromethane (900 mL). The reaction mixture was stirred at room temperature for 48 hours, and a saturated NaHCO3 solution (500 mL) was added under stirring. The organic layer was separated, and the aqueous layer was subjected to extraction twice with chloroform. The combined organic extract was washed with saturated NaHCO3 solution (200 mL), brine (200 mL), and dried over Na2SO4. The solution was concentrated in vacuo to afford the title compound as a yellow oil (147.8 g, 79%). Taken directly on to the next step.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1.Cl.CO[C:16](=N)[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.O.Cl>CO>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]2[NH:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=3[N:12]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc2[nH]c(C=Cc3ccc(OC)c(OC)c3)nc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
A mixture of 4-methoxy-1,2-phenylenediamine dihydrochloride (1.55 g; 7.3 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.9 g; 7.3 mmol) in methanol (50 mL) was stirred at ambient temperature for 72 hours. The methanol was concentrated to 25 mL. A yellow solid was separated by filtration. The solid was suspended in MeOH (10 mL), and treated with hydrogen chloride. The precipitate that formed was collected to obtain 515 mg (21% yield) of the title compound as a mono-hydrochloride, hydrate, yellow solid, m.p. 246-249° C. Anal. Calcd. for C18H18N2O3HCl. H2O: C, 61.72, H, 5.20; N, 7.79. Found: C, 61.61; H, 5.37; N, 7.84 . Mass spectrum: (EI; M+) m/z 310. 1H-NMR (DMSO-d6; 400 MHz) δ14.8 (broad s,1H), 8.3-8.5(d,1H), 7.62-7.63 (d, 1H), 7.3 (d,1H), 7.21-7.23 (dd 1H), 7.2 (d, 2H), 7.07-7.16(m, 3H), 3.86-3.88 (d, 6H), 3.82-3.84 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([Cl:8])[S:4][C:3]=1[Cl:9].[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>C1COCC1>[Br:7][C:6]1[C:2]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[CH:17]=2)[OH:20])=[C:3]([Cl:9])[S:4][C:5]=1[Cl:8]
Reactant: Clc1sc(Cl)c(Br)c1Br
Reactant: O=Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cccc(Cl)c1)c1c(Cl)sc(Cl)c1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dibromo-2,5-dichlorothiophene (2.00 g, 6.43 mmol) in THF (18 mL) at −78° C., was added n-BuLi (2.5M in hexane, 2.57 mL, 6.43 mmol) dropwise. After 30 min., 3-chlorobenzaldehyde (0.732 mL, 6.43 mmol) was added dropwise to the yellow solution. The resulting solution was stirred at −78° C. for 30 min. and allowed to warm to 0° C. After 30 min., the reaction was quenched by the addition of 25% aq. NH4OAc. The aqueous layer was extracted with EtOAc and the combined organics were washed with water and brine, dried (Na2SO4) and concentrated. The crude product was purified by chromatography on silica gel (50:50 to 80:20 CHCl3/hexane) to afford the desired product as a pale yellow oil.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:44][O:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])[C:11]([NH:13][CH:14]2[C:42](=[O:43])[N:16]3[C:17]([C:39]([OH:41])=[O:40])=[C:18]([CH:21]([S:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)[CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O>CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:44][O:45][CH2:46][C:47]([OH:49])=[O:48])[C:11]([NH:13][CH:14]2[C:42](=[O:43])[N:16]3[C:17]([C:39]([OH:41])=[O:40])=[C:18]([CH:21]([S:33][C:34]4[NH:38][N:37]=[N:36][N:35]=4)[CH2:22][CH2:23][CH2:24][NH2:25])[CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(CCCNC(=O)OC(C)(C)C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Conc. hydrochloric acid (20.8 g.) was added to a mixture of 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-[1-(3-tert-butoxycarbonylaminopropyl]-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 39.1 g.) in methanol (400 ml.), and stirred at room temperature for 4 hours. After removing the solvent in vacuo, tetrahydrofuran (40 ml.) and anisole (40 ml.) were added to the residue and stirred at room temperature for 4 hours. The reaction mixture was added to ethyl acetate at room temperature. The precipitates were collected by filtration and washed with ethyl acetate to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-[1-(3-aminopropyl)-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers). The product was subjected to column chromatography on macroporous nonionic absorption resin "HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Co.) to give the syn isomer of the objective compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C([C@@H]1COC(=O)N1C(=O)[C@H](CS(N1CCN(C2N=CC(C3C=CC([C:71]([F:74])([F:73])[F:72])=CC=3)=CN=2)CC1)(=O)=O)C(C)C)C1C=CC=CC=1>>[CH3:30][CH:28]([CH3:29])[C@@H:24]([CH2:23][S:20]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:71]([F:74])([F:73])[F:72])=[CH:3][CH:4]=3)=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[C:25]([OH:27])=[O:26]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1)C(=O)O
Yield: 24 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(3-methyl-2-(R)-{4-[5-(4-trifluoromethylphenyl)pyrimidin-2-yl]piperazine -sulfonylmethyl}butyryl)oxazolidin-2-one(0.480 g), to give the title compound as a white solid (0.086 g, 24%).