Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:37][N:38]([CH3:69])[NH:39][C:40]([C:42]1([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:47][CH2:46][N:45]([C:48](=[O:61])[CH:49]([NH2:60])[CH2:50][C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[NH:53][CH:52]=2)[CH2:44][CH2:43]1)=[O:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[NH:60][CH:49]([CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1)[C:48]([N:45]1[CH2:44][CH2:43][C:42]([CH2:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)([C:40]([NH:39][N:38]([CH3:69])[CH3:37])=[O:41])[CH2:47][CH2:46]1)=[O:61])([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(N)Cc2c[nH]c3ccccc23)CC1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methylpropionic acid (0.18 g, 0.88 mmol) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.12 mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.12 g, 0.88 mmol) and the mixture was stirred for 30 min. Then 1-(2-amino-3-(1H-indol-3-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide (0.46 g, 0.73 mmol) and diisopropylethylamine (0.50 ml, 2.92 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with methylene chloride/(10% ammonia in methanol) (9:1) to give 0.31 g of (1-(2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamoyl)-1-methylethyl)carbamic acid tert-butyl ester as a colorless oil.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13](=[O:16])([O-])[O-].[K+].[K+].ClC[C:21]1[N:22]=[C:23]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:24][CH:25]=1>CN(C)C=O.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>[C:27]([NH:26][C:23]1[S:24][CH:25]=[C:21]([CH2:13][O:16][C:8]2[CH:9]=[CH:10][CH:11]=[C:4]3[C:3]([NH:2][C:6](=[O:7])[C:5]=23)=[O:12])[N:22]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: ClCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C([O-])[O-]
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(OCc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
8.15 g of N-hydroxyphthalimide was dissolved in 300 ml of N,N-dimethylformamide, 6.91 g of potassium carbonate and 200 mg of dicyclohexyl-18-crown-6 were added, and stirred at room temperature for 2 hours. Thereafter, 9.82 g of 4-chloromethyl-2-tritylaminothiazol was added thereto, and stirred and reacted at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, and, after adding 500 ml of ethyl acetate, washed with 300 ml of water 4 times. The ethyl acetate layer was dried on anhydrous magnesium sulfate, and concentrated to dryness to obtain 12.5 g of (2-tritylaminothiazol-4-yl)methoxyphthalimide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.O[C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.O.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[C:19]1([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:13]4[CH:12]=[C:11]([OH:17])[CH:16]=[CH:15][CH:14]=4)[CH:3]=3)[NH:8][CH:9]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: OB(O)c1cccc(O)c1
Reactant: O=C1CCCCC1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Oc1cccc(-c2cnc3[nH]cc(C4=CCCCC4)c3c2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 8.6 %

Procedure:
To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.507 mmol) in MeOH (1 mL) was added cyclohexanone (52 uL, 1.015 mmol). The reaction mixture was stirred at 80° C. for 16 h then concentrated in vacuo. To the residue was added 3-hydroxyphenyl boronic acid (91 mg, 0.66 mmol), dichlorobis (triphenylphosphino)palladium (II) (18 mg, 0.025 mmol), and 2 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water. The reaction was run in a Personal Chemistry® microwave reactor at 150° C. for 600 s. The reaction mixture was diluted with methanol, filtered, and the filtrate was adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-(3-cyclohex-1-enyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-phenol as an off-white solid (12.6 mg, 12% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.64 (m, 2H), 1.74 (m, 2H), 2.23 (m, 2H), 2.42 (m, 2H), 6.27 (m, 1H), 6.74 (dd, J=2.0, 8.0 Hz, 1H), 7.05 (s, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.51 (broad s, 1H), 11.7 (s, 1H). MS: m/z 291 (M+H+).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7](=[O:28])[CH2:8][S:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]([N:19]2[CH2:23][CH:22]([O:24][CH3:25])[CH2:21][NH:20]2)=[S:18])[C:13]([F:26])=[CH:12][C:11]=1[Cl:27]>C1(C)C=CC=CC=1>[Cl:27][C:11]1[C:10]([S:9][CH2:8][C:7]([O:6][CH3:5])=[O:28])=[CH:15][C:14]([N:16]=[C:17]2[N:19]3[N:20]([CH2:21][CH:22]([O:24][CH3:25])[CH2:23]3)[C:1](=[O:2])[S:18]2)=[C:13]([F:26])[CH:12]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)CSc1cc(NC(=S)N2CC(OC)CN2)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: COC(=O)CSc1cc(N=c2sc(=O)n3n2CC(OC)C3)c(F)cc1Cl
Temperature: 22 °C
Reaction time: 2 h

Procedure:
At 0°-5° C., 4.2 ml of phosgene solution in toluene (20%) are added to a solution of 2.8 g of α-[2-chloro-4-fluoro-5-(4-methoxypyrazolidinyl-thiocarbonylamino)-phenylthio]-acetic acid methyl ester in 20 ml of toluene. After stirring for 2 hours at 22° C., the organic phase is washed with water, dried and concentrated. The product is purified by means of column chromatography to yield 2.21 g of the desired product, 8-(4-chloro-2-fluoro-5-methoxy-carbonylmethylthio-phenylimino)-3-methoxy-7-thia-1,5-diazabicyclo[3.3.0]octan-6-one, in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][N:16]=[N:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[N:17]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=[N:15][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnnn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of crude compound A in N,N-dimethyl-formamide (5 mL) is added K2CO3 (1.16 g, 8.4 mmol) and benzyl bromide (665 uL, 5.6 mmol). The solution is stirred at room temperature for 1 hr. The mixture is diluted with EtOAc and washed with brine. The organic layer is dried and concentrated under vacuum. The residue is purified by flash column chromatography (Hexanes/EtOAc) to provide 404 mg of the title compound M+H+=330, and 401 mg of the other region isomer (S)-2-(1-Benzyl-1H-tetrazol-5-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (C). M+H+=330. Combined yield is 87% for 2 steps.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([OH:30])[CH:29]=1>>[ClH:1].[Cl:31][C:27]1[C:26]([Cl:32])=[CH:25][C:24]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:29][C:28]=1[OH:30]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1cc(O)c(Cl)c(Cl)c1
Agent: Cl
Product: Oc1cc(Nc2ncnc3sc4c(c23)CCNC4)cc(Cl)c1Cl

Procedure:
The title compound was prepared in analogy to Example 65A from tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (300 mg, 0.92 mmol) and 5-amino-2,3-dichlorophenol hydrochloride from Example 68A (296 mg, 1.38 mmol) to yield 395 mg (99%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11](Cl)(=O)=O.S(=O)(=O)(O)O>ClCCl.[Zn]>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[SH:11]
Reactant: COc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: ClCCl
Product: COc1ccc(S)c(Cl)c1Cl
Temperature: 0 °C
Yield: 77.4 %

Procedure:
A mixture of 9.37 g of 2,3-dichloro-4-methoxybenzenesulfonyl chloride, 72 g of crushed ice, 24 g of conc. sulfuric acid and 12 g of zinc dust is stirred under reflux for 16 hours. The mixture is diluted with dichloromethane, cooled and stirred at room temperature for 2 hours. Filtration removes the unreacted zinc and the organic extracts are washed with water, sodium bicarbonate solution and dried over anhydrous magnesium sulfate. Removal of solvent in vacuo leaves a white solid which is recrystallized from ether-pentane to give 5.5 g of 2,3-dichloro-4-methoxy-thiophenol as colorless needles, mp 81.5°-83°.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])#[N:2].[C:16]1([C@H:22]([NH2:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:1]([N:3]=[C:4]([NH:24][C@@H:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])#[N:2]
Reactant: CCOC(Cc1ccccc1C)=NC#N
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCO
Product: Cc1ccccc1CC(=NC#N)N[C@H](C)c1ccccc1

Procedure:
A solution of Example 26B (142 mg, 0.7 mmol) and (R)-1-phenylethylamine (85 mg, 0.7 mmol) in absolute ethanol (1 mL) was stirred at 60° C. for 6 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC on a Waters Symmetry C8 column (40 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile in 10 mM of ammonium acetate over 15 min at a flow rate of 70 mL/min to provide the title compound. MS (ESI+) m/z 277 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.78 Hz, 3H) 2.28 (s, 3H) 3.83 (s, 2H) 5.10 (m, 1H) 6.95 (d, J=8.48 Hz, 1H) 7.16 (m, 3H) 7.29 (m, 1H) 7.35 (m, 5H) 9.37 (d, J=7.46 Hz, 1H).
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33]C)=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 500 mg (20.9 mmol) LiOH in 10 mL water was added to a solution of 6.7 g (13.6 mmol) of (R)-2-(4-amino-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred overnight at RT. To complete the reaction another 300 mg (12.5 mmol) LiOH were added and the reaction solution was stirred for 3 h at 40° C. It was evaporated down i.vac., the residue was taken up in 15% K2CO3 solution and extracted exhaustively with DCM. The aqueous phase was acidified with 4 M HCl, exhaustively extracted with DCM and the combined organic phases were dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was reacted further without purification.
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]2[NH:6][C:7]([N:9]3[CH2:14][CH2:13][C:12]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[O:23])[O:15]4)[CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:2]2[CH:25]=[CH:24][C:5]3[NH:6][C:7]([N:9]4[CH2:14][CH2:13][C:12]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[C:16](=[O:23])[O:15]5)[CH2:11][CH2:10]4)=[N:8][C:4]=3[CH:3]=2)[CH:27]=1
Reactant: O=C1OC2(CCN(c3nc4cc(I)ccc4[nH]3)CC2)c2ccccc21
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1OC2(CCN(c3nc4cc(-c5cccnc5)ccc4[nH]3)CC2)c2ccccc21

Procedure:
Add tetrakistriphenylphosphine palladium(0)(0.1 g, 0.01 mmol) to 1′-(5-iodo-1H-benzimidazol-2-yl)-spiro[isobenzofuran -1,4′-piperidin]-3-one (0.10 g, 0.22 mmol) in ethylene glycol dimethyl ether (2 mL). To this solution, add pyridine-3-boronic acid (0.06 g, 0.45 mmol) and aqueous sodium carbonate (1M, 1 mL) and heat the reaction at 80° C. for 2 hours. Extract the product with EtOAc (20 mL). Wash the combined extracts with brine (20 mL), dry over sodium sulfate, and concentrate in vacuo. Purify by flash column chromatography (5% MeOH—CH2Cl2) to obtain 1′-(5-pyridin-3-yl-1H-benzimidazol-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: COC1C=CC(CN2CCN(CC3N=CC([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:34]5[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=5[Cl:45])=[C:28]5[C:33]=4[N:32]=[CH:31][CH:30]=[CH:29]5)=[O:23])=CC=3)CC2)=CC=1.[CH3:48][N:49]([CH3:59])[CH2:50][C:51]1[N:52]=[C:53]([N+]([O-])=O)[NH:54][CH:55]=1.CO.C1COCC1.CO>[Ni].C(Cl)Cl.CO>[CH3:48][N:49]([CH2:50][C:51]1[N:52]=[C:53]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:34]3[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=3[Cl:45])=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:23])[NH:54][CH:55]=1)[CH3:59]
Reactant: COc1ccc(CN2CCN(Cc3ccc(NC(=O)c4ccc(-c5c(Cl)c(OC)cc(OC)c5Cl)c5cccnc45)cn3)CC2)cc1
Reactant: CN(C)Cc1c[nH]c([N+](=O)[O-])n1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN(C)C)c[nH]3)c3ncccc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Example 170), dimethyl-(2-nitro-1H-imidazol-4-ylmethyl)-amine (Step 22.1) instead of 2-nitroimidazole in Step 14.3, and Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2. The title compound: ESI-MS: 500.0 [M+H]+; tR=3.50 min (System 1); TLC: Rf=0.20 (DCM/MeOH, 9:1).
Reaction SMILES: C([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:25][C@@H:24]1[C:23](=[O:26])[N:22]2[C:17]([C:15]([OH:16])=[O:14])=[CH:18][CH2:19][S:20][C@H:21]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12

Procedure:
36.6 g of 7β-amino-3-cephem-4-carboxylic acid benzhydryl ester in 60 ml of anisole are reacted for 10 minutes at room temperature with 240 ml of trifluoroacetic acid. The reaction mixture is diluted with toluene and evaporated to dryness in vacuo. The residue is dissolved in a mixture of 150 ml of methanol, 250 ml of ether and 10 ml of water and the pH is adjusted to 3.5 with triethylamine. The suspension is cooled for 1 hour to 0° C. and the fine-crystalline precipitate of 7β-amino-3-cephem-4-carboxylic acid is isolated by filtration.
Reaction SMILES: C1COCC1.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([N:23]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24]2)[CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Zn].C(O)(=O)C>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([N:23]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24]2)[CH:17]=[CH:18][C:19]=1[NH2:20])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(-n2cc(F)c(F)c2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.2 %

Procedure:
To a mixture of zinc (33.7 g), THF (40 mL) and acetic acid (80 mL) was added dropwise a mixture of 1-[3-(benzyloxy)-4-nitrophenyl]-3,4-difluoro-1H-pyrrole (8.52 g), THF (80 mL) and acetic acid (40 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized from hexane/ethyl acetate to give the title compound (7.53 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[CH:17][N:16]=2)=[CH:10][CH:9]=1)(C)(C)C>C(Cl)(Cl)Cl.CO.C(OCC)(=O)C>[ClH:29].[ClH:29].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[N:16]=[CH:17][C:18]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cl
Product: Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 25 °C

Procedure:
t-Butyl{4-[5-(3,4-dichlorobenzoylamino)-pyridin-2-yloxy]phenyl}carbamate (4.31 g, 9.09 mmol) was dissolved in a mixed solution of chloroform-methanol-ethyl acetate. The resulting solution was concentrated to a volume of about 20 mL. To the residue solution was added a solution of 4 N hydrogen chloride in ethyl acetate (70 mL), and left to cool for 2 hours at room temperature. The precipitated white powder was filtered, and washed with ethyl acetate, to thereby yield 4.04 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.[CH3:25][N:26]1[C:30]([CH3:31])=[CH:29][C:28]([NH2:32])=[N:27]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:32][C:28]2[CH:29]=[C:30]([CH3:31])[N:26]([CH3:25])[N:27]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cc1cc(N)nn1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)nn1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a solution of tert-butyl 5-[(2,5-dichloropyrimidin-4-yl)amino]-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (1.29 g, 3.46 mmol) and 1,5-dimethylpyrazol-3-amine (0.80 g, 7.20 mmol) in 1,4-dioxane (20 mL) was added trifluoroacetic acid (2.01 g, 17.60 mmol). The reaction mixture was stirred at 100° C. overnight and adjusted to pH=10 with a saturated Na2CO3 solution, then extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a yellow solid (294.5 mg, 19%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:19][C:18]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[Cl:10]
Reactant: Fc1ccccc1CBr
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2F)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
0.5 M solution of 1-bromomethyl-2-fluoro-benzene (1.5 g, 8 mmol) in DMF was added dropwise to a suspension of 3-chloro-4-hydroxy-benzaldehyde (1.14 g, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixture was stirred at 90° C. overnight. After cooling, the solid residue was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate and the organic layer washed twice with NaOH 1M, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, obtaining 1.91 g of the title compound, yield 100%.
Reaction SMILES: [Br-].[C:2]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:31]([O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[C:43](Br)=[C:44]([C:46](=O)[C:47]([F:50])([F:49])[F:48])[S:45][C:39]=2[CH2:38][CH2:37]1)=[O:35])[CH3:32]>C1COCC1.CCOC(C)=O>[CH2:31]([O:33][C:34]([N:36]1[CH2:42][CH2:41][C:40]2[CH:43]=[C:44]([C:46]([C:47]([F:50])([F:49])[F:48])=[CH2:2])[S:45][C:39]=2[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)N1CCc2sc(C(=O)C(F)(F)F)c(Br)c2CC1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(c1cc2c(s1)CCN(C(=O)OCC)CC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Triphenyl phosphonium bromide (393 mg, 1.1 mmol) was stirred in 7 mL THF. KHMDS (199 mg, 1.0 mmol) was added and the yellow solution was stirred for 30 minutes at room temperature. The product of step (a) (180 mg, 0.56 mmol) was dissolved in 7 mL THF and added to the above reaction. The solution was allowed to stir for 1 hour at room temperature, then diluted with EtOAc (25 mL) and washed with water (2×20 mL). The crude product was purified by silica gel chromatography (30% EtOAc in Hex) to give 100 mg of the sub-title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CC(C)=O>[Cl:15][CH2:16][C:17]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: NCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCl)NCc1ccccn1
Temperature: 0 °C

Procedure:
To a solution of 0.5 g (4.6 mmol) 2-(aminomethyl)pyridine in 10 ml acetone at 0° C. were added 1.27 g (9.2 mmol) potassium carbonate and 0.57 g (5.1 mmol) 2-chloro acetylchloride. The reaction was stirred at 0° C. until no starting material remained and then poured onto ice water. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with aqueous NaHCO3 (sat.) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used directly for the next step. MS(ISP): 185.21 ([MH]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Reactant: BrCCCCBr
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCCBr)cc1

Procedure:
In analogy to example 1.4, reaction of (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester with 1,4-dibromobutane yielded [4-(4-Bromo-butoxy)-phenyl]-carbamic acid tert-butyl ester, MS: 344 (MH+, 1Br).