Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=S1(=O)COc2cc(F)ccc2N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S1(=O)COc2cc(F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.3 %

Procedure:
A mixture of the title compound of Step D (0.5 g, 2.46 mmol), K2 CO3 (1.02 g, 7.38 mmol), benzyl bromide (0.463 g, 2.71 mmol) and TBAB (79 mg) in DMF (5 mL) was stirred at room temperature for 48 h. After the reaction was complete, the reaction mixture was poured into an H2 O/ethyl acetate mixture (10/100 mL). The organic phase was separated, dried and concentrated to give the title compound of Step E as a brown solid (0.76 g). 1H NMR (CDCl3, 300 MHz): δ7.32 (m,6H, aromatic) 6.72 (d,1H, 11 Hz), 6.34 (d, 1H, 8 Hz), 4.82 (s,2H), 4.69 (s,2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].O>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)NC2CCC3CN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC32)cc(-c2nnnn2C)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(NC(=O)NC2CCC3CNCC32)cc(-c2nnnn2C)c1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
N-[3-Ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-N′-[(3aRS,4RS,6aSR)-2-trityloctahydrocyclo-penta[c]pyrrol-4-yl]urea (310 mg, 518 μmol) was dissolved in trifluoroacetic acid (5 mL) to provide a bright yellow solution. This was treated dropwise with water (5 mL) to provide a pale yellow slurry. After 2 hours, the mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and 1.0 N aqueous hydrochloric acid. The aqueous phase was washed with additional ethyl acetate, and then made strongly basic with 50% aqueous sodium hydroxide. The resulting mixture was extracted three times with ethyl acetate, and these organic phases were combined, dried over sodium sulfate, and concentrated under vacuum to provide a white glass (167 mg, 90%). NMR (300 MHz, CDCl3) δ7.71 (s, 1H), 7.69 (s, 1H), 7.29 (s, 1H), 7.18 (s, 1H), 6.49 (d, J=8 Hz, 1H), 4.27 (m, 1H), 4.20 (s, 3H), 2.97 (m, 2H), 2.8-2.6 (m, 6H), 1.90 (m, 1H), 1.70 (m, 2H), 1.36 (m, 1H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C([O:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[C:18]([NH:20][S:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:40]3[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([O:41][Si](C(C)(C)C)(C)C)[CH2:27]1)(=[O:23])=[O:22])=[O:19])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CO.[Pd]>[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[OH:15][C:16]1[CH:52]=[CH:51][CH:50]=[CH:49][C:17]=1[C:18]([NH:20][S:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:40]3[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[CH2:27]1)(=[O:22])=[O:23])=[O:19]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(=O)(=O)NC(=O)c2ccccc2OCc2ccccc2)O[C@H]1n1cnc2c(N)ncnc21
Agent: [Pd]
Agent: CC[NH+](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COS(=O)(=O)NC(=O)c2ccccc2O)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 5′-O—[N-(2-benzyloxybenzoyl)sulfamoyl]-2′-O-tert-butyldimethylsilyl-3′-deoxyadenosine triethylammonium salt (70 mg, 0.092 mmol, 1.0 equiv) in MeOH (10 mL) was added 10% Pd/C (20 mg) and the reaction was stirred under H2 (1 atm) for 8 hours at room temperature. The reaction mixture was filtered through a plug of Celite and the residue was washed with MeOH (4×10 mL). The combined filtrates were concentrated and the crude obtained was treated with 80% aq TFA (2.0 mL) for 8 hours. The reaction was concentrated in vacuo. Purification by flash chromatography (10:90:1 MeOH/EtOAc/Et3N) afforded the title compound (27 mg, 53%) as a viscous oil: Rf 0.3 (1:4 MeOH/EtOAc); [α]20D −10 (c 0.28, MeOH); 1H NMR (600 MHz, CD3OD) δ 1.26 (t, J=7.2 Hz, 9H), 2.05-2.20 (m, 1H), 2.40-2.55 (m, 1H), 3.15 (q, J=7.2 Hz, 6H), 4.32 (dd, J=11.4, 4.2 Hz, 1H), 4.46 (d, J=11.4 Hz, 1H), 4.60-4.80 (m, 2H), 6.00 (s, 1H), 6.70-6.85 (m, 2H), 7.27 (t, J=7.2 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 8.12 (s, 1H), 8.47 (s, 1H); 13C NMR (150 MHz, CD3OD) δ 9.3, 34.9, 47.9, 70.7, 76.9, 79.9, 92.9, 117.9, 119.3, 120.3, 120.7, 131.3, 134.3, 140.7, 150.2, 153.7, 157.3, 162.0, 174.9; HRMS (ESI+) calcd for C17H19N6O7S [M+H]+ 451.1030, found 451.1053 (error 5.1 ppm).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14](O)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C1C=CC2N(O)N=[N:31]C=2C=1.CCN=C=NCCCN(C)C.N>C(Cl)Cl>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[C:5]([C:14]([NH2:31])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Product: N#Cc1c(N2CCOCC2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
4-Cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.050 g, 0.13 mmol), HOBT (0.037 g, 0.274 mmol) and EDCI (50 mg, 0.261 mmol) were suspended in DCM (6.5 mL). After 30 min the reagents dissolved. To the resulting solution was added concentrated aqueous ammonia (0.26 mL, 6.5 mmol) and the solution was allowed to stir vigorously at rt overnight. The reaction mixture was concentrated and the residue was diluted with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4 filtered and concentrated to give a brown solid. The solid was triturated with hexanes and cold EtOAc to give 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxamide (0.024 g, 49%). LCMS: (AA) ES+ 382, ES− 380. 1H NMR (400 MHz, d6-DMSO) δ: 7.78 (s, 1H), 7.54 (d, 2H), 7.43 (d, 2H), 3.79-3.77 (m, 4H) and 3.55-3.52 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([N:14]2[CH2:18][CH2:17][CH2:16]C2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)(=[O:22])C#C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2[NH:14][C:18](=[O:22])[CH:17]=[CH:16][C:12]=2[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Reactant: C#CC(N)=O
Solvent: Cc1ccccc1
Product: O=c1ccc2c([nH]1)CCN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
To a solution of 1-benzyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (2.58 g, 10.65 mmol) in toluene (30 mL) is added propiolamide (1.47 g, 21.29 mmol) and the mixture is refluxed for 4 hr. The mixture is cooled to rt and the solvent is removed in vacuo. The residue is partitioned between NaHCO3 (30 mL) and DCM (30 mL). The layers are separated and the aqueous layer is extracted with DCM (30 ml). The combined extracts are dried and evaporated and the residue is purified by flash column with 5% MeOH in DCM to give the title compound as a light yellow solid. MS (M+1): 241.1.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([CH:10]2[S:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:18]([O:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[CH:26]=[CH:25][C:22]=1[CH2:23]O)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>>[CH2:18]([O:20][C:21]1[CH:28]=[C:27]([O:29][CH2:30][CH3:31])[CH:26]=[CH:25][C:22]=1[CH2:23][N:12]1[C:11](=[O:16])[CH:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[S:14][C:13]1=[O:15])[CH3:19]
Reactant: CCOc1ccc(CO)c(OCC)c1
Reactant: Cc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(CN2C(=O)SC(S(=O)(=O)c3ccc(C)cc3)C2=O)c(OCC)c1

Procedure:
5-(Toluene-4-sulfonyl)-thiazolidine-2,4-dione[U.S. Pat No. 5,605,918; February 1997; Wrobel, et al.] was reacted with 2,4-diethoxybenzyl alcohol in the presence of triphenylphosphine and diethyl diazodicarboxylate to give the title compound as colorless crystals, mp 121-123° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=2)[OH:14])(=O)=O)=CC=1.FC1C=CC(C(=O)C)=CC=1C(F)(F)F.[OH-].[Na+]>CCOCC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:13]2[CH2:12][O:14]2)=[CH:16][C:17]=1[F:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(Cl)c(F)c2)cc1
Agent: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Fc1cc([C@@H]2CO2)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(R)-2-(4-chloro-3-fluorophenyl)-2-hydroxyethyl 4-methylbenzenesulfonate (prepared as previously described in Example 1 (steps a-b) except substituting 1-(3-chloro-4-fluorophenyl)ethanone for 1-(4-fluoro-3-(trifluoromethyl)phenyl)ethanone, 3.35 g, 9.72 mmol) was dissolved in ether (80 mL) and 2N NaOH solution (25 mL) was added. The mixture was stirred at room temperature for 6 h until all starting material was consumed. The mixture was separated and the ether layer was washed with water. The organic layer was dried with sodium sulfate and solvents were removed to afford (R)-2-(4-chloro-3-fluorophenyl)oxirane as a colorless oil which was dried in vacuum (1.66 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.71-2.80 (m, 1H) 3.18 (dd, J=5.31, 4.04 Hz, 1H) 3.82-3.89 (m, 1H) 7.01-7.12 (m, 2H) 7.39 (dd, J=8.46, 7.45 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16]>C1COCC1>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
To 1.35 g (6.12 mmol) of 2-chloro-5-fluoro-1,3-dinitrobenzene in 20 mL of THF at 0° C. was added 6.1 mL (12 mmol) of 2N methylamine in THF. The cold bath was removed and the reaction was stirred at room temperature for 45 minutes. The solution was concentrated, diluted with ether and washed with saturated sodium bicarbonate solution. The resulting organic solution was dried over sodium sulfate, filtered and concentrated giving 1.30 g (99%) of the title compound as a bright orange powder.
Reaction SMILES: CON(C)[C:4](=[O:18])[C@@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].C([Mg]Cl)(C)C.C([Mg]Br)C.I[C:30]1[N:31]=[CH:32][N:33]([CH3:35])[CH:34]=1.[NH4+].[Cl-]>C(Cl)Cl.C1COCC1.CCOCC.O>[CH3:6][C@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([C:30]1[N:31]=[CH:32][N:33]([CH3:35])[CH:34]=1)=[O:18]
Reactant: Cn1cnc(I)c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1cn(C)cn1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (64 mg, 0.24 mmol) in CH2Cl2 (1 mL) was cooled to −20° C. under N2, and isopropylmagnesium chloride (120 μL of a 2.0 M solution in THF) was added dropwise. The mixture was stirred at −20° C. for 20 min. In a separate flask ethylmagnesium bromide (480 μL of a 2.0 M solution in Et2O) was added to a solution of 4-iodo-1-methyl-1-H-imidazole (109 mg, 0.48 mmol) in dry CH2Cl2 (1.5 mL) at room temperature. The resulting mixture was stirred for 20 min and then added by cannula to the solution above slowly. The resulting solution was left to stir overnight. Saturated NH4Cl was added to the reaction solution. The mixture was diluted with water and the aqueous phase was extracted with CH2Cl2 (2×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Flash chromatography of the residue yielded benzyl [(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate. LCMS calc.=288.14; found=288.3 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.65 (s, 1 H); 7.47 (s, 1 H); 7.35-7.28 (m, 5 H); 5.93 (d, J=6.9 Hz, 1 H); 5.29-5.25 (m, 1 H); 5.13 (s, 2 H); 3.73 (s, 3 H); 1.26 (d, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[CH3:20])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:21]([NH:23][CH3:24])=[O:22].[F:25][C:26]1[C:31](OC(=O)C(F)(F)F)=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42].N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[F:25][C:26]1[C:31]([O:7][C:6](=[O:8])[C:5]2[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[CH3:20])=[C:10]([F:11])[C:2]([F:1])=[C:3]([C:21]([NH:23][CH3:24])=[O:22])[CH:4]=2)=[C:30]([F:39])[C:29]([F:40])=[C:28]([F:41])[C:27]=1[F:42]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CNC(=O)c1cc(C(=O)O)c(Nc2ccc(I)cc2C)c(F)c1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc(I)cc2C)c(F)c1F
Reaction time: 17 h
Yield: 45.1 %

Procedure:
To a suspension of 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid (0.13 g, 0.29 mmol) in N,N-dimethylformamide (5 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.055 mL, 0.32 mmol) and pyridine (0.03 mL, 0.32 mmol). After stirring for 17 hours the reaction mixture is diluted with ethyl acetate and transferred to a separatory funnel, washed twice with 1.0 M HCl, twice with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 4,5-difluoro-6-(4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid pentafluorophenyl ester (0.08g, 45.2%). To a suspension of 4,5-difluoro-6-(-4-iodo-2-methyl-phenylamino)-N-methyl-isophthalamic acid pentafluorophenyl ester (0.08 g, 0.13 mmol) in freshly distilled THF (3 mL) is added cyclopropylmethylamine hydrochloride (0.016 g, 0.13 mmol), and N,N-diisopropylethylamine (0.07 mL, 0.39 mmol). After stirring at room temperature for 17 hours the reaction mixture was partitioned between ethyl acetate and 1.0 M HCl solution. The organic layer was washed twice with water, twice with saturated brine solution, dried over MgSO4, filtered and concentrated in vacuo. Purification was performed by silica column chromatography in 2:1 ethyl acetate:hexanes affording N1-cyclopropylmethoxy-4,5-difluoro-6-(4-iodo-2-methyl-phenylamino)-N3-methyl-isophthalamide (0.033, 42.8%); mp 198–202° C.; 1H NMR (400 MHz; DMSO-d6) 8.59 (s, 1H), 8.01 (s, 1H), 7.44 (d, 1H, J=5.2), 7.32 (s, 1H), 7.18 (d, 1H, J=7.6), 6.36 (m,1H), 3.34 (d, 2H, J=6.8), 2.56 (d, 3H, J=4.0), 1.99 (s, 3H), 0.82 (m, 1H), 0.27 (d, 2H, J=8.4), 0.00 (m, 2H); MS(APCI)m+1=516;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])[CH3:34]>O1CCCC1>[CH2:33]([O:35][C:36]([N:38]1[CH2:39][CH2:40][N:41]([C:18](=[O:20])[CH2:17][N:16]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:42][CH2:43]1)=[O:37])[CH3:34]
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'carbonyldiimidazole (2.82 g, 0.0174 mole), and dry tetryhydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of ethyl-1-piperazine carboxylate (6.9 g, 0.0435 mole) in tetrahydrofuran (6 ml) was added dropwise and the reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were removed under reduced pressure and the residual oil was triturated in water (100 ml) overnight. The resulting solid was collected by filtration, rinsed with water, dissolved in hot isopropyl alcohol, and filtered hot. Water was added to the cloud point and upon cooling to room temperature, a solid precipitated, which was collected by filtration, rinsed with water, and dried uner high vacuum to give 4.66 g (63%) of title compound, mp 184°-186° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 29A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give the title compound as colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:6]([S:9][CH2:10][S:11][C:12]3[N:13]=[N:14][NH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12.Cl.CC(C)=O.C(OCC)(=O)C>C(O)=O>[NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([S:9][CH2:10][S:11][C:12]3[N:13]=[N:14][NH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12
Reaction time: 2.5 h
Yield: 81.1 %

Procedure:
To a solution of diphenylmethyl 7β-amino-3-[(1H-1,2,3-triazol-4-yl)thiomethylthio]-3-cephem-4-carboxylate (9.9 g) in formic acid (39.6 ml) was added conc. hydrochloric acid (8.54 ml) at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. The mixture was poured into a mixture of acetone (297 ml) and ethyl acetate (594 ml) under ice-cooling, and the resulting precipitate was collected by filtration. The precipitate was resolved in water, and adjusted to pH 4 with 28% ammonium hydroxide under ice-cooling. The precipitate was collected by filtration to give 7β-amino-3-[(1H-1,2,3-triazol-4-yl) thiomethylthio]-3-cephem-4-carboxylic acid (5.42 g).
Reaction SMILES: II.[Al].[CH2:4](Br)[C:5]#[CH:6].[CH:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[C:10]([C:16]([CH2:18][Cl:19])=[O:17])[CH:9]=1.[Cl-].[NH4+]>O1CCCC1.[Hg](Cl)Cl>[Cl:19][CH2:18][C:16]([C:10]1[CH:9]=[CH:8][C:13]([Cl:14])=[CH:12][C:11]=1[Cl:15])([OH:17])[CH2:6][C:5]#[CH:4]
Reactant: C#CCBr
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: Cl[Hg]Cl
Agent: II
Agent: [Al]
Solvent: C1CCOC1
Product: C#CCC(O)(CCl)c1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
A pinch of mercury(II) chloride and an iodine crystal are added to 13 g (0.48 mol) of aluminum (in the form of flakes), the substances are covered with a layer of 60 ml of tetrahydrofuran and the mixture is stirred for 10 hours at 20° C. The mixture is then warmed to 60° C., and a solution of 84.5 g (0.71 mol) of propargyl bromide in 85 ml of tetrahydrofuran is added dropwise. The mixture is then cooled to -60° C., and a solution of 111.7 g (0.5 mol) of ω-chloro-2,4-dichloroacetophenone in 165 ml of tetrahydrofuran is added dropwise. The mixture is allowed to warm up to 0° C., and after 1 hour hydrolysis is effected with 170 ml of saturated, aqueous ammonium chloride solution. Thereafter, the mixture is filtered, the filtrate is evaporated down in vacuo and 500 ml of ethyl acetate are added to the residue. The organic phase is separated off, washed with three times 300 ml of water and dried over anhydrous sodium sulphate, and the solvent is distilled off under reduced pressure. 113.5 g (86.1% of theory) of 5-chloro-4-(2,4-dichlorophenyl)-pent-1-in-4-ol are obtained as colorless crystals of melting point 55°-57° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C=O)C.C1(C)C=CC=CC=1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1
Reaction time: 0.5 h

Procedure:
5 g (20 mmol) of 4-iodobenzoic acid, 30 ml of toluene and 5 drops of DMF were introduced into a round-bottomed flask. Heating was carried out to 40° C., 1.74 ml (24 mmol) of thionyl chloride was added and stirring was carried out for 30 minutes. Evaporation was carried out to dryness and 5.5 g (100%) of the crude acid chloride were recovered, which compound was employed as is in the continuation of the synthesis.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Na+].[Br-].[O-]Cl.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[CH2:1]([O:8][CH2:9][C:10](=[O:13])[CH2:11][Cl:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)COCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyloxy-3-chloro-propan-2-ol (10.0 g, 50.0 mmol) [prepared according to Journal of Organic Chemistry (1990), 55, 4897] in ethyl acetate (125 mL) was added a solution of NaHCO3 (12.6 g, 150 mmol) and NaBr (5.66 g, 55.0 mmol) in water (75 mL). After cooling of the biphasic mixture to 0° C., 2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl (“TEMPO”) (391 mg, 2.50 mmol) was added in one portion followed by dropwise addition of NaOCl (6 wt % in water, 85.4 mL, 75.0 mmol) to the vigorously stirred solution. After completion of the addition, stirring at 0° C. was continued for 30 min. Subsequently, a solution of aqueous Na2SO3 was added until the reaction mixture had completely discolored. Additional solid Na2SO3 was added to saturate the aqueous phase. The mixture was transferred to a separation funnel and the layers were separated. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure (at 20° C.). The remaining oil was used without further purification. 1H NMR (400 MHz, CDCl3) 4.26 (s, 2H), 4.33 (s, 2H), 4.62 (s, 2H), 7.31-7.45 (m, 5H).