Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11]Br)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:14]([NH:21][C:22]([NH2:24])=[NH:23])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[C:17]([O:16][C:14]([N:21]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=2)=[CH:11][N:23]=[C:22]1[NH2:24])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N=[N+]=[N-])cc2)cnc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
To a solution of 1-(4-azidophenyl)-2-bromoethanone (1.50 g, 6.24 mmol) in anhydrous DMF (20 mL) was added Boc-guanidine (3.00 g, 18.7 mmol). The reaction was stirred at ambient temperature for 48 hours upon which the mixture was partitioned between EtOAc (150 mL) and water (75 mL). The organic layer was successively washed with water (3×50 mL) and brine (2×50 mL) before being dried (Na2SO4) and evaporated to dryness. The resulting crude oil was purified via flash column chromatography (10-50% EtOAc/Hexanes) to obtain the target 2-amino-5-(4-azidophenyl)imidazole-1-carboxylic acid tert-butyl ester (1.84 g, 58%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 7.77 (d, 2H, J=8.1 Hz), 7.36 (s, 1H), 7.10 (dd, 2H, J=0.9, 8.1 Hz), 6.61 (br s, 2H), 1.58 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 150.4, 148.9, 137.6, 136.2, 130.5, 126.2, 119.1, 106.2, 84.7, 27.5; HRMS (ESI) calcd for C8H6BrN3O (M+) 300.1335. found 300.1329.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([CH2:25][C:26](=O)[CH3:27])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1>>[O:21]1[C:22]2[CH:23]=[CH:24][C:16]([CH2:15][CH2:25][CH:26]([NH:14][C:9]3[C:10]([CH3:13])=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH3:27])=[CH:17][C:18]=2[O:19][CH2:20]1
Reactant: CC(=O)CCc1ccc2c(c1)OCO2
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc2c(c1)OCO2

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and piperonyl acetone.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=C(C(O)=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>C(Cl)Cl>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[CH:21]=[C:1]([C:2]([Cl:4])=[O:3])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C(O)c1cc(-c2ccco2)nc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2ccco2)nc2ccccc12
Temperature: -10 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
5.2 ml (60.4 mmol) of oxalyl chloride were dissolved in 70 ml of CH2Cl2. The solution was cooled at −10° C. and 8.5 g (35.5 mmol) of 2-(2-furyl)quinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 9.2 g of the title compound, used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([O:22]C)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:24])=[CH:4][N:3]=1>[OH-].[Na+].C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:24])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Yield: 106.2 %

Procedure:
A solution of methyl 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylate (218 mg, 0.67 mmol) in NaOH (8 mL, 2 N) and THF (8 mL) was stirred at 80° Celsius for 48 hours, and then concentrated to dryness. The residue was acidified with 2 N HCl. The precipitate was collected by filtration and washed with water several times, and dried in vacuo to afford the desired product (220 mg, 106%). The crude product was used without further purification. MS (ESI): mass calcd. for C17H12FN3O2, 309.09; m/z found, 309.9 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:12]([CH:13]2[CH2:16][CH:15]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:14]2)=[CH:11][C:10]([NH:25][C:26](=[O:36])[C:27]([CH3:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH3:28])=[N:9]1)=O)(C)(C)C.C(OC(N1C(NC(=O)C(C)(C2C=CC=CN=2)C)=CC(C2CC(OC(=O)NCC3CC3)C2)=N1)=O)(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O.CCOC(C)=O>[CH3:35][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)([CH3:28])[C:26]([NH:25][C:10]1[CH:11]=[C:12]([CH:13]2[CH2:14][CH:15]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16]2)[NH:8][N:9]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)n1nc(NC(=O)C(C)(C)c2ccccn2)cc1C1CC(OC(=O)NCC2CC2)C1
Agent: CC(C)(C)OC(=O)n1nc(C2CC(OC(=O)NCC3CC3)C2)cc1NC(=O)C(C)(C)c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C(=O)Nc1cc(C2CC(OC(=O)NCC3CC3)C2)[nH]n1)c1ccccn1
Reaction time: 4 h

Procedure:
A mixture of 5-(3-cyclopropylmethylcarbamoyloxy-cyclobutyl)-3-(2-methyl-2-pyridin-2-yl-propionylamino)-pyrazole-1-carboxylic acid tert-butyl ester and 3-(3-cyclopropylmethylcarbamoyloxy-cyclobutyl)-5-(2-methyl-2-pyridin-2-yl-propionylamino)-pyrazole-1-carboxylic acid tert-butyl ester (120 mg, prepared by procedures analogous to those described in Example 221, Steps A to E, using appropriate starting materials) was dissolved in TFA (0.19 mL) and CH2Cl2 (1.25 mL) at room temperature. After 4 h, the solution was diluted with EtOAc and the solution was washed sequentially with saturated aqueous NaHCO3 solution (2×), water, and saturated aqueous NaCl solution. The organic layer was dried over Na2SO4 and concentrated. Purification of the residue by silica gel chromatography afforded the title compound as a solid. MS (M+H)+=398.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6]>CC(O)=O.CCOC(C)=O.[Fe]>[NH2:15][C:14]1[CH:13]=[CH:12][C:4]([C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)NCC(=O)O)cc1F
Temperature: 87.5 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
To a suspension of iron powder (231 mg, 4.13 mmol) in AcOH (2 mL) was added 2-(3-fluoro-4-nitrobenzamido)acetic acid (100 mg, 0.413 mmol) at rt and stirred at 85-90° C. for 15 min. The reaction mixture was attained to rt and diluted with EtOAc (20 mL). The solution was stirred for 5 min and filtered through celite. The celite bed was washed with EtOAc (10 mL) and the combined organic layer was evaporated under reduced pressure. The residue was chromatographed over silica gel column using chloroform:methanol (70:30) as eluents to give the product as an off-white color solid (62 mg, 71%), 198-200° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH:16]C(OC(C)(C)C)=O)([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([OH:13])[CH:7]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:15][NH2:16])([CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:8]([OH:13])[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OC)cc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold reaction mixture containing compound 108 (0.17 g, 0.5 mmol) and TEA (0.07 mL, 0.5 mmol) in dichloromethane (5 mL) was added ethyl chloroformate (0.025 mL, 0.5 mmol). The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for 1. After concentration, the residue was partitioned with 10% citric acid and ethyl acetate. The organic phase was separated and dried over MgSO4. After removing the solvent under reduced pressure, the resulting residue was treated with 50% trifluoroacetic acid in dichloromethane at room temperature for 30 min. Removal of the solvent and purification by reverse phase preparative HPLC afford 73 mg of a 1:1 mixture of the title compounds 123 and 124. 1H NMR (CD3OD, 400 MHz): 1.35 (q, 3H), 1.46 (d, 3H), 2.98 (dd, 2H), 3.80 (d, 3H), 4.28 (q, 4H), 6.60–6.98 (m, 3H). MS (ESI) m/z 313.25 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:14](C3CCCCO3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(-c2c(C#N)cnn2C2CCCCO2)cc1Cl
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(-c2[nH]ncc2C#N)cc1Cl
Reaction time: 8 h

Procedure:
To a solution containing 5-(3-chloro-4-cyanophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbonitrile (2.686 g, 8.59 mmol) dissolved in ethanol (25 ml), 10% HCl solution in ethanol (50 ml) was added and the resulting mixture was stirred overnight. The crude product was extracted with DCM/water. The pH of the aqueous phase was adjusted to 12 by adding 2 M NaOH. The aqueous phase was again extracted with DCM. The combined organic phases were dried with Na2SO4, filtered and evaporated. The product was purified by flash chromatography. 1H-NMR (400 MHz; DMSO-d6): δ 8.00-8.05 (m, 1H), 8.13-8.19 (m, 2H), 8.75 (s, 1H), 14.24 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:2]([CH3:1])([CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Yield: 84.3 %

Procedure:
A reaction mixture of ethyl 2,2-dimethyl-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (8.5 g, 26.6 mmol) and Pd/C (0.283 g, 2.66 mmol) in MeOH (50 mL) was hydrogenated using an H-cube apparatus (settings: 50° C., 50 psi, 24 h). The mixture was filtered, and the filtrate was concentrated. The crude material was purified by silica column chromatography (PE/EA=10:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.4) were combined and concentrated to yield an off white solid of ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (7 g, 22.42 mmol, 84% yield): 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 6.71 (dd, J=2.4, 8.4 Hz, 1H), 4.15 (q, J=6.8 Hz, 2H), 3.00 (s, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.14 (s, 6H); ES-LCMS m/z 290 (M+H).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH:19]1([CH2:25][NH:26][CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:25][N:26]([CH3:27])[C:2]([Cl:1])=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNCC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CC1CCCCC1)C(=O)Cl
Reaction time: 8 h

Procedure:
To a solution of triphosgene (77 mg, 0.259 mmol) in CH2Cl2 (1 mL) at −78° C. is added dropwise pyridine (63 μl, 0.786 mmol) followed by a solution of cyclohexylmethyl-methylamine (100 mg, 0.786 mmol) in CH2Cl2 (1 mL). The yellow mixture is allowed to reach RT and stirred overnight. The solvent is concentrated, and the residue taken up in AcOEt. An aqueous saturated solution of NaHCO3 is added, the layers are separated and the aqueous one is extracted twice with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow oil. TLC, Rf (CH2Cl2/MeOH 95:5)=0.95. MS (LC-MS): 189.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:17](Cl)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[C:20]1([CH:19]=[CH:18][CH2:17][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: ClCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCC=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (0.396 g, 1.97 mmol) was dissolved in DMF (5 ml), to which sodium hydride (0.086 g, 2.16 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Cinnamyl chloride (0.300 g, 1.97 mmol) was added to the mixture while cooling in an ice-bath, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1) to afford tert-butyl 4-(3-phenyl-2-propenyloxy)piperidine-1-carboxylate (0.314 g, yield 50%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C1C=CC=CC=1.[CH3:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([CH3:40])[C:35]=1[O:36][CH2:37][O:38][CH3:39])[C:30](Cl)=[O:31]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:30](=[O:31])[C:29]2[CH:28]=[C:27]([CH3:26])[C:35]([O:36][CH2:37][O:38][CH3:39])=[C:34]([CH3:40])[CH:33]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: COCOc1c(C)cc(C(=O)Cl)cc1C
Solvent: O=C(Cl)c1ccccc1
Product: COCOc1c(C)cc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)cc1C

Procedure:
An amidation reaction and post-treatment were carried out according to the conditions of Example 1, using 1.06 g (4.9 mmol) 4-amino-1-benzyl-5-imidazolecarboxamide prepared in Reference Example 2 and, instead of benzoyl chloride, 3,5-dimethyl-4-methoxymethoxybenzoyl chloride which was separately prepared by a conventional method, to obtain 1.40 g of 1-benzyl-4-(3,5-dimethyl-4-methoxymethoxybenzoyl-amino)-5-imidazolecarboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[Cl:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34](Cl)(=[O:36])=[O:35])[CH:33]=1)([Cl:27])[C:23]([F:26])([F:25])[F:24]>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:36])=[O:35])[CH:33]=1)([Cl:27])[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccc(C(Cl)(Cl)C(F)(F)F)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(Cl)(Cl)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxybenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 374 mg of benzo[b]thiophene-2-sulfonic acid [2-(5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxy-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.40 min; MS: 625.8 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:20]([O:22][CH3:23])=[O:21])[N:9]2[C@@H](C2C=CC=CC=2)C)[CH2:6]1)(=[O:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:7]([C@@H:8]([C:20]([O:22][CH3:23])=[O:21])[NH:9]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OC(C)=O)C2)N1[C@H](C)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1N[C@@H]2C[C@H]1C[C@H]2OC(C)=O

Procedure:
A solution of methyl (1R,3S,4S,6R)-6-acetyloxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-4 (1.25 g) in methanol (20 mL) containing 20% Pd(OH)2 (250 mg) was stirred at room temperature for 17 hrs under 4 atm pressure with hydrogen.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-])=O)[CH:15]=2)[N:10]=1>CO.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH2:3][N:2]2[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:19])[CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1ccc2nc(N3CC4CCC3CC4)ccc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2nc(N3CC4CCC3CC4)ccc2c1
Reaction time: 6 h

Procedure:
The product of Step A and palladium hydroxide on carbon (1.3 g, 20% by wt) was suspended in methanol (100 mL) and ethyl acetate (100 mL). The resulting mixture was degassed then stirred under hydrogen atmosphere (balloon) for 6 h. The reaction mixture was filtered through filter aid and the solvent removed under vacuum. The resulting oil was dissolved in ethyl acetate and the solvent removed under vacuum. The resulting oil was suspended in ether and triturated until crystallization occurred. The solids were filtered and washed with ice-cold ether then dried under vacuum to afford the product as a brown solid, MS: m/z 254 (MH+), which was used without further purification
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](Cl)=[O:7].[CH2:14]([N:16]([CH2:29][CH3:30])[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:27][CH3:28])[CH3:15].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][N:16]([CH2:29][CH3:30])[CH2:14][CH3:15])=[C:21]([O:27][CH3:28])[CH:22]=1)=[O:7]
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1OC

Procedure:
A solution of 70 mg (0.290 mmol) of (2,4-dichloro-phenoxy)-acetylchloride in 0.5 mL dichloromethane was added to a solution of 66 mg (0.278 mmol) of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine (intermediate product Z6b) and 96 μL (0.56 mmol) of ethyl-diisopropylamine in 1.5 mL abs. dichloromethane and the mixture was stirred for 15 hours at RT. The reaction mixture was evaporated down i. vac. and the residue was purified by column chromatography (silica gel, dichloromethane/MeOH 9:1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][CH:13]=[C:12]([C:15](=[N:17][OH:18])[NH2:16])[CH:11]=1)(C(C)(C)C)(C)C.[C:19]1([C:25]2[CH:26]=[C:27]([C:34](Cl)=O)[S:28][C:29]=2[C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:19]1([C:25]2[CH:26]=[C:27]([C:34]3[O:18][N:17]=[C:15]([C:12]4[CH:11]=[C:10]([CH2:9][OH:8])[S:14][CH:13]=4)[N:16]=3)[S:28][C:29]=2[C:30]([F:33])([F:31])[F:32])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cs1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1e) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxythiophene-3-carboximidamide (0.43 g, 1.5 mmol) that was obtained in Example 3 (3b), 4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyl chloride (0.52 g, 1.8 mmol), N,N-diisopropylethylamine (0.52 ml, 3.0 mmol), and a 1.0 M solution of tetrabutylammonium fluoride (3.0 ml, 3.0 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2 to 1:1) as the eluent to afford the title compound (0.60 g) as a white crystalline solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2([CH2:22][OH:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:26])=[N-]>CCOCC>[CH3:26][O:23][CH2:22][C:8]1([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1
Reactant: C=[N+]=[N-]
Reactant: OCC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Solvent: CCOCC
Product: COCC1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of 4-(N-phenylamino)-1-(2-phenylethyl)-4-piperidinylmethanol (0.100 g) and silica (0.5 g) in ether (5 ml) at room temperature was added an excess of ethereal diazomethane, and the mixture stirred at room temperature until no more colour remained. The reaction mixture was filtered and the filtrate concentrated to give an oil. Purification on silica gel using chloroform-methanol 38:1 as eluant gave the title compound (0.052 g).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[CH2:5]([N:7](CC)[CH2:8][CH3:9])[CH3:6]>>[CH3:1][N:2]([CH3:4])[C:3]1[CH:9]=[CH:8][N:7]=[CH:5][CH:6]=1
Reactant: CN(C)C
Reactant: CCN(CC)CC
Product: CN(C)c1ccncc1

Procedure:
triethyl amine; and trimethylamine.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13]C(CCC[C@@H](N)C(O)=O)=O)[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=[O:3].CC(OCC1CS[C@@H]2[C@H](NC(CCCC(O)=O)=O)C(=O)N2C=1C(O)=O)=O>>[CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=[O:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCCC(=O)O)[C@H]2SC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1

Procedure:
or enzymatically, e.g. by action of an acylase; or by conversion of cephalosporin C into glutaryl-7-amino-cephalosporanic acid, e.g. by action of a D-amino acid oxidase, enzymatically hydrolysing a glutaryl-7-amino cephalosporanic acid to obtain 7-ACA, e.g. in a basic medium, neutral or slightly acidic medium, optionally purifying the reaction solution with an appropriate ion exchanger or adsorber resin, and precipitating 7-ACA, e.g. by adjustment of the pH (around the isoelectric point), e.g. by addition of an acid, e.g. HCl. In that case precipitated 7-ACA may be, however, in the form of very small, loose, needle-like crystals difficult to be isolated. Increasing purity of 7-ACA may result in still smaller crystals and addition of an organic solvent, e.g. a, e.g. lower, alcohol, e.g. methanol or a ketone, e.g. acetone, to the reaction mixture before the isolation of 7-ACA, which may improve the yield, again may result in considerably smaller crystals.