Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:20]=[CH:19][CH:18]=[C:16]([NH2:17])[CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: Nc1cccc(Br)c1
Reactant: CCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1ccc(-c2cccc(N)c2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
4-ethoxyphenyl boronic acid (0.115 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 68% yield.
Reaction SMILES: [Cl:1][C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:18])[C:3]([O:5][CH3:6])=[O:4].OO.C(=O)(O)[O-:28].[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH2:16][C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH2:18])=[O:28])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C([O-])O
Reactant: C=C(CSc1ccccc1NN=C(Cl)C(=O)OC)c1ccccc1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=C(CS(=O)c1ccccc1NN=C(Cl)C(=O)OC)c1ccccc1
Reaction time: 5 h

Procedure:
The compound of Step B (5 g) was stirred with occasional warming in acetic acid (45 ml) and treated with 30% aqueous hydrogen peroxide (2.0 ml). After stirring for 5 h, water (200 ml) was added and the P.h. was adjusted to 6 with sodium bicarbonate. Saturated sodium bisulfite solution (3 ml) was added and the mixture was extracted with dichloromethane (200 ml). The organic layer was dried and evaporated to give the title compound (4.9 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=O>C1C=CC=CC=1>[N:9]1[CH:8]=[C:7]([CH2:5][NH:3][CH2:2][CH2:1][NH2:4])[CH:12]=[N:11][CH:10]=1
Reactant: O=Cc1cncnc1
Reactant: NCCN
Solvent: c1ccccc1
Product: NCCNCc1cncnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
Ethylenediamine (60 g) was dissolved in benzene (200 ml), and 5-formylpyrimidine (21.6 g) was added at room temperature. Subsequently, the mixture was heated, and refluxed for 3 hours while removing water as an azeotrope. After the reaction, benzene and the excess of ethylenediamine were distilled off under reduced pressure. The residue was dissolved in ethanol (200 ml). Sodium borohydride (8.4 g) was added portionwise to this solution at room temperature, and subsequently the mixture was stirred at room temperature for 5 hours. Ethanol was distilled off under reduced pressure. Dichloromethane (100 ml) was added to the residue, and a dichloromethane-soluble portion was separated. Dichloromethane was distilled off from the dichloromethane layer under reduced pressure to give N-(5-pyrimidinylmethyl)ethylenediamine (25.8 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([Cl:16])=[CH:4][C:3]=1[Cl:17].[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:17][C:3]1[C:2]([C:20]2[C:19]([Cl:18])=[CH:24][N:23]=[C:22]([F:25])[CH:21]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:5]([Cl:16])[CH:4]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Clc1cc(Cl)c(NCC2CCOCC2)nc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cc(-c2nc(NCC3CCOCC3)c(Cl)cc2Cl)c(Cl)cn1
Temperature: 25 °C

Procedure:
A mixture of 6-bromo-3,5-dichloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (1 g, 2.94 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.774 g, 4.41 mmol), PdCl2(dppf).CH2Cl2 adduct (0.240 g, 0.294 mmol) in DME (12 mL) and 2M aqueous Na2CO3 solution (4 mL, 2.94 mmol) in a sealed tube was heated at 90° C. for 2 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc (˜100 mL) and saturated aqueous NaHCO3. The separated organic layer was washed with saturated aqueous NaHCO3 (2×), brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane=0/100 to 30/70 over 25 min] providing 3,5,5′-trichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine as a colorless liquid. Yield: 510 mg. LCMS (m/z): 391.9 [M+H]+; Retention time=1.14 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OC1(C2C=CC(OC)=C(OC)C=2)CCNCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[CH2:46][CH2:47][CH2:48][NH:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C:53]1=[O:57])=[O:51].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:16][CH2:15][N:14]([CH2:46][CH2:47][CH2:48][NH:49][C:50]([N:52]3[CH2:56][CH2:55][CH2:54][C:53]3=[O:57])=[O:51])[CH2:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C1CCCN1C(=O)NCCCCl
Reactant: COc1ccc(C2=CCNCC2)cc1OC
Agent: COc1ccc(C2(O)CCNCC2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2=CCN(CCCNC(=O)N3CCCC3=O)CC2)cc1OC
Temperature: 25 °C
Reaction time: 144 h
Yield: 32 %

Procedure:
To a solution of 3.76 g of 4-(3,4-dimethoxyphenyl)-1,2,5,6-tetrahydropyridine (V-7), which was prepared by the reaction of 4-hydroxy-4-(3,4-dimethoxyphenyl)piperidine and p-toluenesulfonic acid, and 2.94 g of 1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine in 35 ml of DMF is added 3.98 g of K2CO3 and 3.22 g of NaI. The reaction mixture is stirred at 100°-105° C. for 6 days under nitrogen gas. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed with brine and dried over MgSO4. After removal of the solvent, the residue is subjected to column chromatography with silica gel, eluting with CH2Cl2 /MeOH (20/1) to prepare 1.78 g (Yield: 33.4%) of the compound (Ia-105) as solid. The oxalate is recrystallized from iPrOH-MeOH to prepare needles. mp. 178.0°-182.0° C.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.[OH-].[Li+].ON1C2C=CC=CC=2N=N1.[CH:62]1([NH2:72])[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][CH2:64][CH2:63]1.Cl.C(N=C=NCCCN(C)C)C.Cl>O1CCCC1.O.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([C:43]([NH:72][C:62]3[C:71]4[CH2:70][CH2:69][CH2:68][CH2:67][C:66]=4[CH:65]=[CH:64][CH:63]=3)=[O:44])[CH:47]=[CH:48][CH:49]=2)=[N:17]1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: NC1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c1CCCC2)c1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Yield: 13 %

Procedure:
The title compound was prepared as described in Example 381, using methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.401 g, 0.621 mmol) and lithium hydroxide (0.048 g, 2.00 mmol) in tetrahydrofuran (2.5 mL) and water (1.5 mL); 1-hydroxybenzotriazole (0.252 g, 1.86 mmol), 1,2,3,4-tetrahydro-1-naphthylamine (0.288 mL, 1.96 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.360 g, 1.88 mmol), and additional tetrahydrofuran (2.5 mL); 4 N hydrochloride solution in dioxane (10 mL). The final crude product was purified by preparative HPLC (30–80% acetonitrile in H2O, 20 min.) (0.035 g, 13% yield over 3 steps): 1H NMR (CD3OD) δ 8.82 (s, 1H), 8.59 (s, 1H), 8.37 (br s, 1H), 8.26 (dt, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.72 (t, 2H), 7.24 (d, 1H), 7.15 (t, 1H), 7.05 (d, 1H), 2.81 (m, 4H), 1.81 (m, 4H); ES-MS (m/z) 435 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH:14]([C:12]#[N:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC#N
Reactant: Brc1ccc2ccccc2c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)C(C#N)c1ccc2ccccc2c1
Yield: 917 %

Procedure:
Method A of the above general procedure was followed using 2-bromonaphthalene (208 mg, 1.00 mmol), ethyl cyanoacetate (123 mg, 1.09 mmol), pentaphenylferrocenyl ligand (14.0 mg, 0.020 mmol) and Pd(dba)2 (6.0 mg, 0.010 mmol). The reaction mixture was purified by column chromatography on silica gel (1:3 dichloromethane/hexanes) to give the desired product (2194 mg, 91%) as a colorless oil: 1H NMR (CDCl3) δ 7.94 (s, 1H), 7.89-7.82 (m, 3H), 7.55-7.50 (m, 3H), 4.88 (s, 1H), 4.29-4.20 (m, 2H), 1.26 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.00, 133.21, 133.16, 129.35, 128.07, 127.76, 127.51, 127.21, 127.08, 126.96, 124.81, 115.75, 63.38, 43.90, 13.89.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.C(C(C(O)=O)(O)C(C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1>CCO>[NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Agent: COc1ccc(C(=O)C(O)(C(=O)O)C(O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@@H]1CCCNC1
Temperature: 25 °C
Yield: 25.3 %

Procedure:
To a solution of tert-butyl piperidin-3-ylmethylcarbamate (162 g, 0.758 mol) in EtOH was added (+)-dianisoyltartaric acid (316 g, 0.756 mol). The suspension was heated until clear and allowed to cool to room temperature overnight. The precipitated salt was recrystallized three times from EtOH. The salt was washed with EtOH (2×200 mL) and air-dried. Residual solvent was removed in vacuo. The salt was taken up in tert-butyl methyl ether and 10% aq. NaOH. The organic layer was separated, and the aqueous layer was extracted with tert-butyl methyl ether (3×200 mL). More product was extracted after addition of 30% aq. NaOH to the aqueous layer. The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to give (R)-tert-butyl piperidin-3-ylmethylcarbamate as a white crystalline solid (41.3 g, 0.192 mol, 25%). For ee determinations, samples of the salt were taken up in CH2Cl2 and 1 N aq. NaOH. The organic layer was washed with water, dried over Na2SO4, and filtered. A drop of 1-naphthyl isocyanate was added, and after 15 minutes a drop of morpholine was added to quench excess isocyanate. Volatiles were evaporated after another 15 minutes. The sample was dissolved in EtOH for chiral HPLC (Chiralcel OD-H; heptane/EtOH/Et2NH 90/10/0.2; 0.5 mL/min; Rt (R): 46 min, Rt (S): 57 min, Rt (N-(naphthalen-1-yl)morpholine-4-carboxamide): 64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([N:24]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH:25]3[CH3:34])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([N:24]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH:25]3[CH3:34])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:35]([F:37])([F:38])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N1c2ccccc2OCC1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: CC1COc2ccccc2N1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of crude 4-chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2 h. Upon cooling to room temperature, the mixture was concentrated and the residue was purified via preparative TLC (50% EtOAc in hexane) to afford 11 mg of 4-chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS m/z: 546.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[O:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[N:31]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:43]1([NH:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:45][CH2:44]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[O:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[N:31]=3)=[C:13]2[C:24](=[O:25])[N:46]([CH:43]2[CH2:44][CH2:45]2)[CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cccc(CNC2CC2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)co3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO[Si](C)(C)C(C)(C)C)co3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.2 %

Procedure:
To a sol. of compound D5 (10 g, 14.7 mmol) in CH2Cl2 (200 mL) was added cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination from 2,3-dichlorobenzaldehyde and cyclopropylamine, 7.95 g, 36.8 mmol), DIPEA (10.1 mL, 58.8 mmol), DMAP (449 mg, 3.68 mmol), HOBt (2.48 g, 18.4 mmol), and EDC.HCl (8.45 g, 44.1 mmol). This mixture was stirred at rt for 3 days. EDC.HCl (2.83 g, 14.7 mmol) and DIPEA (2.5 mL, 26 mmol) were added, and the reaction mixture was stirred at rt for 24 h. EDC.HCl (2.82 g, 14.7 mmol) and cyclopropyl-(2,3-dichlorobenzyl)amine (3.10 g, 14.7 mmol) were added, and the mixture and was stirred for 48 h. CH2Cl2 was added, and the organic layer was washed with aq. 1M HCl (3×), and with aq. sat. NaHCO3 (1×). The org. layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→2:3) yielded the title compound (7.72 g, 65%). LC-MS: tR=1.31 min; ES+: 802.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][C:13]([OH:15])=[O:14].[CH2:20]([Mg]Br)[CH2:21]CCCC>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCCCCC[Mg]Br
Reactant: CCCCC(CC(=O)O)c1ccc(OC)cc1OC
Product: CCCCCCC(CC(=O)O)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 42a, but using hexylmagnesium bromide instead of butylmagnesium bromide, the title compound was obtained as an oily substance.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][O:20][C:21]1[CH:35]=[CH:34][C:24]([CH2:25][NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27](=[O:33])[CH:28]([CH3:32])[C:29]([NH:1][CH:2]2[C:8](=[O:9])[N:7]([CH3:10])[C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]2=3)=[O:30])=[CH:34][CH:35]=1
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc1

Procedure:
The title compound, MS: m/e=458.3 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(4-methoxy-benzyl)-2-methyl-malonamic acid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:13][N:12]=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1.[CH2:21]([N:23]=[C:24]=[O:25])[CH3:22].Cl>C(OCC)(=O)C>[CH2:21]([NH:23][C:24]([N:13]1[C:9]([CH3:8])=[CH:10][C:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:12]1)=[O:25])[CH3:22]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccccc2)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccccc2)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) was added to a solution of 5-methyl-3-phenyloxypyrazole (0.20 g, 1.2 mmol) in ethyl acetate (5 ml), and the mixture cooled to 0° C. Then, ethyl isocyanate (0.09 g, 1.3 mmol) was added, and the mixture was stirred for 30 minutes at an ambient temperature. And, the mixture was stirred for 4 hours while it was allowed to have room temperature gradually. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-ethyl-5-methyl-3-phenyloxypyrazole-1-carboxamide (0.16 g, yield: 56.4%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.58 (d, J=0.8 Hz, 3H), 3.38 (dq, J=1.3 and 7.3 Hz, 2H), 5.67 (q, J=0.8 Hz, 1H), 6.99-7.07 (br s, 1H), 7.12-7.19 (m, 3H), 7.33-7.39 (m, 2H).
Reaction SMILES: [OH:1][C@H:2]([C@@H:11](O)[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][C@@H:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C1C=CC=CC=1.CCOCC>[Br:36][C@H:11]([CH2:12][CH:13]([CH3:15])[CH3:14])[C@@H:2]([OH:1])[CH2:3][C@@H:4]([CH:8]([CH3:10])[CH3:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](O)[C@@H](O)C[C@H](C(=O)O)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(C)C[C@@H](Br)[C@@H](O)C[C@H](C(=O)O)C(C)C
Reaction time: 0.5 h

Procedure:
A stirred solution of the γ-lactone of (2S,4S,5S)-4,5-dihydroxy-2-isopropyl-7-methyloctanoic acid from Preparation IIIA (0.214 g., 1 mmol) and triphenylphosphine (0.289 g., 1.1 mmol) in benzene (3 ml) is cooled in an ice bath and treated during 5-10 minutes with N-bromosuccinimide (0.196 g., 1.1 mmol). The mixture is kept cold for an additional 30 minutes and then at ambient temperature for 4 hours. It is diluted with Et2O and filtered. The filtrate is con-centrated and the residue chromatographed on silica gel (100 g.) with 7.5% EtOAc-hexane. The product, the γ-lactone of (2S,4S,5R)-5-bromo-4-hydroxy-2-isopropyl-7-methyloctanoic acid, thus obtained was crystallized from cold pentane to give 0.061 g., m.p. 62.5°-63.5° C. and 0.054 g., m.p. 60°-62.5° C.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:30][O:31][CH3:32])[C:11]([NH:13][CH:14]2[C:28](=[O:29])[N:16]3[C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1)=O.[OH-].[Na+].C>CO.O>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:30][O:31][CH3:32])[C:11]([NH:13][CH:14]2[C:28](=[O:29])[N:16]3[C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CCCCOC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 4.25 h
Yield: 92.9 %

Procedure:
Conc-Hydrochloric acid (4 ml) was dropwise added to a suspension of n-butyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 7.5 g) in methanol (120 ml) over 5 minutes under ice cooling, and stirred at room temperature for 4.25 hours. The resultant solution was poured into chilled water (75 ml), and adjusted to pH 5.5 with 4N aqueous solution of sodium hydroxide at 5° C. After treating the solution with activated charcoal (0.38 g), the solution was concentrated in vacuo. The aqueous residue was stirred under ice cooling for 30 minutes. The precipitates were collected by filtration, washed with water (10 ml×2), and then dried over phosphorus pentoxide to give yellow powder (6.55 g) of n-butyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).
Reaction SMILES: S(O)([O:4][CH2:5][CH2:6][NH2:7])(=O)=O.O1[CH:11]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1.[OH-].[Na+].C1(C)C=CC=CC=1>O.CO>[O:13]([CH2:12][CH:11]1[O:4][CH2:5][CH2:6][NH:7][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCOS(=O)(=O)O
Reactant: c1ccc(OCC2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: c1ccc(OCC2CNCCO2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
2-Aminoethyl hydrogen sulphate (49 g, 0.347 mol) was added in portions to a mixture of (±)-1,2-epoxy-3-phenoxypropane (11.2 ml, 0.083 mol), sodium hydroxide (26.4 g, 0.66 mol) in water (50 ml) and methanol (20 ml). After addition the reaction mixture was stirred at 40° C. (oil bath temperature) for 2 hours. The reaction mixture was cooled, sodium hydroxide pellets (20.65 g, 0.516 mol) and toluene (80 ml) were added, then the reaction mixture stirred, whilst heating at 65° C. (oil bath temperature) for 7.5 hours. The reaction mixture was cooled, toluene (40 ml) and water (140 ml) were added. The toluene phase was extracted with 2M hydrochloric acid (2×60 ml). The acid extracts were combined, 40% sodium hydroxide solution added to pH=11, then extracted with toluene (2×60 ml). The combined organics were dried (sodium sulphate) then evaporated to give a colourless gum (10 g) which was purified by column chromatography on silica, using neat ethyl acetate to remove the lipophilic impurities then ethyl acetate/methanol/ammonia (9:1:0.1) to elute the required product as a colourless oil (7.0 g, 44%). Rf 0.22 in dichloromethane/methanol (9:1) on silica plates MS CI+, m/z=194 for (M+H)+. 1H NMR (360 MHz, CDCl3) δ2.54-2.85 (2H, m), 2.92 (1H, ddd, J1 =2, J2 =J3 =12 Hz), 3.05 (1H, dd, J1 =2, J2 =12 Hz), 3.67 (1H, ddd, J1 =2, J2 =J3=12 Hz), 3.83-4.03 (4H, m), 6.88-6.97 (3H, m), 7.23-7.30 (2H, m).