Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].B1(/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.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>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC/C=C/c1cccc(N)c1C#N
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-6-bromobenzonitrile (1.0 g, 5.0 mmol), (E)-2-(3-methoxypropenyl)-4,4,5,5-tetramethyl-(1,3,2)-dioxaboroane (1.2 g, 6.0 mmol), and K2CO3 (1.38 g, 10.0 mmol) in DME/H2O (4:1, 20 mL) was added Pd(PPh3)4 (289 mg) at room temperature under nitrogen. The reaction mixture was warmed to 85° C. and stirred at that temperature under nitrogen overnight. After it was cooled down to room temperature, the reaction solution was diluted with EtOAc, washed with brine (2×), and dried over Na2SO4. After removal of the solvent, the residue was purified by chromatography on silica gel eluting with 30% EtOAc in hexanes to give the title compound as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ 3.40 (s, 3H), 4.12 (dd, J=6.0, 1.8 Hz, 2H), 4.42 (s, 2H), 6.42 (dt, J=16.0, 5.8 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.85 (d, J=16.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H). 13C NMR (CDCl3) δ 58.2, 72.7, 95.4, 113.6, 115.0, 116.6, 128.5, 130.9, 133.4, 140.3, 150.1. MS 189 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH:13]([N:17]2[CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:19]=[N:18]2)[CH2:14][C:15]#[N:16])[CH2:12][CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[CH:19]=[N:18][N:17]([CH:13]([CH:9]3[CH2:12][CH2:11][CH2:10]3)[CH2:14][C:15]#[N:16])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CCC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCC(C1CCC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
A mixture of 2,4-dichloropyrimidine (4.8 g, 0.032 mol), 3-cyclobutyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (8.10 g, 0.0269 mol), tetrakis(triphenylphosphine)palladium (2.0 g, 0.002 mol), and potassium phosphate (17 g, 0.081 mol) in 1,4-dioxane (80 mL) and water (8 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 80%, to give the desired product (5.51 g, 71.2%). LCMS (M+H) 288.3.
Reaction SMILES: [CH3:1][I:2].[N:3]1([C:8]([NH:10][C@:11]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][C@H:12]2[CH:14]=[CH2:15])=[O:9])[CH:7]=[CH:6][N:5]=[CH:4]1>C(#N)C>[I-:2].[CH2:19]([O:18][C:16]([C@@:11]1([NH:10][C:8]([N:3]2[CH:7]=[CH:6][N+:5]([CH3:1])=[CH:4]2)=[O:9])[CH2:13][C@H:12]1[CH:14]=[CH2:15])=[O:17])[CH3:20]
Reactant: CI
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1ccnc1)C(=O)OCC
Solvent: CC#N
Product: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen, methyl iodide (1.9 mL, 4 eq.) was added to a solution of compound 33 (2 g, 1 eq.) in ACN (16 mL). The reaction mixture was stirred at room temperature for 2 hrs. The solvent was removed under reduced pressure to yield compound 34 as yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccccc3O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3OS(C)(=O)=O)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 16 h

Procedure:
Sulfonylation of 1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (12 mg) with methylsulfonyl chloride (6.5 μl) was performed in pyridine (1 ml). TLC analysis after stirring for 16 h showed conversion to a higher-running product. The mixture was concentrated, the residue was dissolved in dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography. Eluent: heptane/ethyl acetate=8/2 (v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:22])[C:12]([S:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[N:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[OH:23]O.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:22])[C:12]([S:15]([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:23])=[N:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)CCCSc1ncc(C(=O)c2ccc(Cl)cc2)n1C
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCCS(=O)c1ncc(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-Chloro-phenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone (135 mg) in glacial acetic acid (4.00 mL) was added at room temperature H2O2 (82.0 μL; 30 wt. % in water). The reaction solution was stirred for 48 h at room temperature, and water (10.0 mL) was added. The solution was brought to pH=12 using sodium hydroxide (25% in water) and extracted with dichloromethane (250 mL, 2×50.0 mL). The combined organic layers were washed with water (3×20.0 mL) and were dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (CHCl3/NH3, 2 M in methanol) to give the title compound (121 mg). M calc=353; M+H found=354. 1H NMR (400 MHz, CD3OD): δ 7.91-7.87 (m, 2H), 7.70 (s, 1H), 7.60-7.55 (m, 2H), 4.21 (s, 3H), 3.61-3.48 (m, 2H), 2.54-2.43 (m, 2H), 2.21 (s, 6H), 2.04-1.94 (m, 2H). The compound demonstrated useful biological activity when assessed with a [3H]-N-methylhistamine binding assay (see Table in Example XVI II). Step B: Additional Compounds Prepared Following Scheme XI, and Example XVI, Step A. The following compounds of Formula I were prepared following Scheme XI and Example XVI, Step A; and substituting reagents, and adjusting reaction conditions as needed.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:14]([O:18][C:19]([NH:21][C@H:22]1[C@H:25]([CH3:26])[NH:24][C:23]1=[O:27])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][C@H:22]1[C@H:25]([CH3:26])[N:24]([C:2]([NH:3][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:1])[C:23]1=[O:27])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: N#C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)NCC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 20.8 %

Procedure:
To a suspension of potassium cyanate (186 mg, 2.3 mmol) in 2 ml of dimethylformamide was added t-butyl bromoacetate (0.356 ml, 2.2 mmol). The mixture was heated to 100° C. for 1 hour and cooled to room temperature. (3S-trans)-3-[[(t-Butyloxy)carbonyl]amino]-4-methyl-2-azetidinone (400 mg, 2.0 mmol) was then added, and the mixture was heated to 140° C. for 1 hour. Upon cooling to room temperature, the crude product was extracted from ice cold 5% HCl with three portions of ethyl acetate. The combined organic layers were extracted twice with water, once with aqueous potassium bicarbonate, and dried over sodium sulfate. The volatiles were removed, and the residue was subjected to chromatography on silica gel (eluting with 40% ethyl acetate-hexane) yielding 149 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:8](=[O:9])[CH:7]=[CH:6][C:5]2=[O:14].[Br:15]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:15][C:6]1[C:5]([C:4]2[C:10]([C:8](=[O:9])[CH:7]=1)=[CH:11][C:12]([CH3:13])=[C:2]([CH3:1])[CH:3]=2)=[O:14]
Reactant: BrBr
Reactant: Cc1cc2c(cc1C)C(=O)C=CC2=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)C(Br)=CC2=O
Reaction time: 2 h

Procedure:
A solution of 6,7-dimethyl naphtho-1,4-quinone (20.0 g.; 0.107 mole) in glacial acetic acid (250 ml) was stirred during the dropwise addition of bromine (5.6 ml; 17.2 g; 0.107 mole) in acetic acid (10 ml.) at 15° C. and allowed to stir at this temperature for a further 2 hours. Anhydrous sodium acetate (20 g) was added and the mixture stirred at 100° C. for 11/2 hours after an initial half hour period at room temperature; cooled, poured into water (2.5 l) and the yellow bromo product filtered off. It had m.p. (ethanol, chloroform) 156°-159° C. (Found; C, 53.47; H, 3.39; Br, 30.23; C12H9BrO2 requires; C, 54.36; H, 3.42; Br, 30.14%):
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=2)[CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: Clc1ncccn1
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncccn4)CC3)nc3ccccc32)cc1
Yield: 61 %

Procedure:
A mixture of 34.5 parts of 2-chloropyrimidine, 110 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 25 parts of sodium hydrogen carbonate and 1200 parts of ethanol was stirred and refluxed overnight. The reaction mixture was cooled and filtered over Hyflo. The filtrate was evaporated. The residue was purified by HPLC over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 82 parts (61%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(2-pyrimidinyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 168.4° C. (compound 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12]([OH:14])=O)=[CH:7][CH:6]=1.Cl.Cl.[CH3:26][N:27]([CH3:38])[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:26][N:27]([CH3:38])[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:12](=[O:14])/[C:11](/[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:33][CH:32]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To a mixture of 3 (2.90 g, 9.28 mmol), 4-(2-(dimethylamino)ethoxy)benzenamine dihydrochloride (2.58 g, 10.2 mmol), 4-Dimethylaminopyridine (56.7 mg, 0.464 mmol) in CH2Cl2 (100 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (3.87 g, 10.2 mmol) under ice cooling, and the mixture was stirred at 0° C. for 10 min. Then N,N-Diisopropylethylamine (4.19 g, 32.4 mmol) was added under ice cooling. The mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by Biotage (eluent: CH2Cl2 to CH2Cl2/MeOH, 6:1) gave the colorless solid. The solid was triturated with Et2O-hexane to give 4 (65%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.C1COCC1.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:14][CH2:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1ccccc1)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc(N2CCN(C(=O)c3ccccc3)CC2)c1
Reaction time: 16 h
Yield: 75.8 %

Procedure:
A solution of 3-iodo-nitrobenzene (3.0 g, 12.0 mmol), piperazine (1.6 g, 18.1 mmol), copper (I) iodide (0.23 ml, 1.2 mmol) and potassium carbonate (3.3 g, 24.1 mmol) in 40 ml DMSO was stirred at 45° C. for 16 hours. The run was quenched with 10 ml water and extracted with ethyl acetate (3×30 ml). The extraction was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. 1-(3-Nitrophenyl)piperazine hydrochloride (2.0 g, 80%) was obtained when bubbling the HCl gas in ether solution. A solution of 1-(3-nitrophenyl)piperazine (1.50 g, 7.2 mmol), benzoyl chloride, and triethylamine (5.0 ml, 36.1 mmol) was stirred at 0° C. for 2 hours. The mixture was washed with water (2×30 ml) and dried over anhydrous sodium sulfate. (4-(3-Nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 73%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). The obtained (4-(3-nitrophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 3.8 mmol) was dissolved in 30 ml ethanol and 10 ml THF, followed by the addition of platinum oxide (0.12 mg, 10%) and stirred under hydrogen gas for 16 hours. The reaction was filtered with the aid of celite. (4-(3-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.81 g, 80%) was obtained by flash column chromatograph (90% ethyl acetate in hexanes), and its hydrochloride was made by bubbling HCl gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.25 (s, br, 4H), 3.53 (d, br, 4H), 6.83 (dd, J=1.2, 7.7 Hz, 1H), 6.99 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 7.44-7.48 (m, 5H), 10.35 (s, br, 2H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 42.4, 48.1, 110.0, 112.8, 115.1, 120.2, 127.1, 127.2, 128.4, 129.6, 129.9, 130.2, 135.7, 151.0, 169.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)[C:10]([CH2:22][CH3:23])=[C:9]([CH3:24])[N:8]=2)=[CH:4][CH:3]=1.C[Si](C)(C)[O:27][C:28]1[CH2:31][CH2:30][C:29]=1[O:32][Si](C)(C)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]4[C:28](=[O:27])[CH2:31][CH2:30][C:29]=4[OH:32])=[CH:16][CH:15]=3)[C:10]([CH2:22][CH3:23])=[C:9]([CH3:24])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(C=O)cc1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(C2=C(O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
A 18-mL vial was charged with 4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzaldehyde (139 mg, 0.39 mmol, 1 eq.), trimethyl-(2-trimethylsilyloxycyclobuten-1-yl)oxy-silane (140 mg, 0.6 mmol, 1.53 eq.), and dichloromethane (2 ml). To the mixture was added BF3/Et2O (80 μL, 0.63 mmol, 1.6 eq.). The mixture was stirred at room temperature overnight and then added to sodium bicarbonate solution (10 ml). The mixture was extracted with ethyl acetate (3×5 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using 2˜3% of methanol in dichloromethane as eluent to give the title compound as a solid (22 mg, 13% yield). MW=425.93. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (brs, 1H), 8.52 (brs, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.56 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 3.34 (m, 4H), 2.73 (q, J=7.2 Hz, 2H), 2.40 (s, 3H), 1.11 (t, J=7.2 Hz, 3H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C@@H:17]1[C:33](=[O:34])[N:19]2[C:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:21]([CH2:24][CH3:25])[CH2:22][S:23][C@H:18]12.[C:35]1([CH2:41][C:42](O)=[S:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N=C=N>C(Cl)Cl>[CH2:24]([C:21]1[CH2:22][S:23][C@@H:18]2[C@H:17]([NH:16][C:42](=[S:43])[CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:34])[N:19]2[C:20]=1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH3:25]
Reactant: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: OC(=S)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C=N
Solvent: ClCCl
Product: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=S)Cc3ccccc3)[C@H]2SC1
Reaction time: 2 h

Procedure:
A solution of N,N'-dicyclohexylcarbodiimide (620 mg, 3 mmole) in dry methylene chloride (15 ml.) was added to a stirred solution of t-butyl 7β-amino-3-ethylceph-3-em-4-carboxylate (853 mg. 3 mmole) in dry methylene chloride (10 ml.). A solution of phenylthioacetic acid (505 mg. 3 mmole) in dry methylene chloride (10 ml.) was added over 5 minutes to the mixture which was stirred at ca. 20° for 2 hours. A further portion of carbodiimide (124 mg., 0.6 mmole) was added, and the mixture was stirred for a further 30 minutes and filtered from precipitated N,N'-dicyclohexylurea. The filtrate was washed successively with 3% aqueous sodium hydrogen carbonate solution (50 ml.), water (50 ml.), 2N-hydrochloric acid (25 ml.) and water (25 ml.), dried (MgSO4) and evaporated to a yellow oil which was dissolved in ethyl acetate (8 ml.). The solution was cooled, the precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated to give the title ester as a pale yellow foam (1.45 g.), [α]D23 + 67° (c 1.05; CHCl3), λmax. (EtOH) 250.5 nm (E1 cm.1% 256), contaminated with ca. 15% by weight of N,N'-dicyclohexylurea and/or the corresponding N-acylurea. The infra red (CHBr3) and p.m.r. (CDCl3) spectra of the product were in accord with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22]Br)([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][N:9]1[CH2:8][CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=2)[CH2:10]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Clc1ccc(CC2CNC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CC(Cc2ccc(Cl)cc2)C1

Procedure:
A solution of 3-(4-chloro-benzyl)-azetidine (1.0 g, 5.50 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (1.31 g, 5.50 mmol) and diisopropylethylamine (1.91 ml, 11.0 mmol) in dry dimethylformamide (20 ml) is stirred at ambient temperature for 18 hours. The reaction mixture is partitioned between ethylacetate and water. The organic phase is washed with water and brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 5% methanol in dichloromethane as eluent to afford {3-[3-(4-Chloro-benzyl)-azetidin-1-yl]-propyl]-carbamic acid tert-butyl ester. [M+H] 339.15
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F.[I:43][Si](C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][I:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: C[Si](C)(C)I
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1nsc(N)n1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CI)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7β-[(Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (790 mg) was suspended in methylene chloride (10 ml), followed by an addition of N-methyl-N-(trimethylsilyl)trifluoroacetamide (2.1 ml). The resulting mixture was stirred at room temperature for 1 hour. After ice-cooling, iodotrimethylsilane (660 μl) was added and the resulting mixture was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the silylated derivative of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: F.F.F.[CH2:4](N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH2:36][C@H:37]1[O:41][C@@:40](C)([N:42]2[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:51][CH2:52][CH2:53][O:54][N:55]([CH3:57])[CH3:56])[C@@H:38]1[OH:58])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.C(Cl)Cl>[CH3:57][N:55]([CH3:56])[O:54][CH2:53][CH2:52][O:51][C@@H:39]1[C@H:38]([OH:58])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:4])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: CCN(CC)CC
Reactant: CN(C)OCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O[C@@]1(C)n1ccc(=O)[nH]c1=O
Agent: F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).