Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[CH2:12][CH3:13].[CH:16]1[CH:17]=[CH:18][C:19]2[S:24][CH:23]=[CH:22][C:20]=2[CH:21]=1>>[S:24]1[C:23]([CH2:4][C:5]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=2[CH2:12][CH3:13])=[CH:22][C:20]2[CH:21]=[CH:16][CH:17]=[CH:18][C:19]1=2
Reactant: c1ccc2sccc2c1
Reactant: CCc1ccc(Br)cc1C(=O)N(C)OC
Product: CCc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
To a solution of 2-ethylbenzoic acid (10.0 g) in dichloromethane (50 ml) were added oxalyl chloride (7.0 ml) and N,N-dimethylformamide (3 drops) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give a corresponding acid chloride. The acid chloride was dissolved in methanol (60 ml) and the mixture was stirred at room temperature for 3 hours, and then, the solvent was evaporated under reduced pressure. The residue was dissolved in diethyl ether, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2-ethylbenzoate, which was used in the subsequent step without further purification. (2) The above methyl 2-ethylbenzoate was mixed with molecular sieve 13× (powder, 70 g), and while stirring the mixture, bromine (5.2 ml) was added dropwise thereto at 80° C. The mixture was further stirred at the same temperature for 1.5 hours. The mixture was cooled to room temperature, and added thereto were potassium carbonate (7.4 g), water (70 ml) and methanol (350 ml), and the mixture was stirred for 8 hours. Insoluble materials were filtered off, and suspended in a mixed solution of methanol (500 ml)-water (500 ml), and the mixture was stirred at room temperature overnight. Insoluble materials were filtered off and the filtrate was combined with the previously obtained filtrate, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure, to give methyl 5-bromo-2-ethylbenzoate (2.44 g). APCI-Mass m/Z 260/262 (M+NH4). (3) The above methyl 5-bromo-2-ethylbenzoate was treated in a manner similar to Reference Example 4-(1) and (2) to give N-methoxy-N-methyl-5-bromo-2-ethylbenzamide as colorless oil. APCI-Mass m/Z 272/274 (M+H). (4) The above N-methoxy-N-methyl-5-bromo-2-ethylbenzamide and thianaphthene were treated in a manner similar to Reference Example 45 to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-ethylbenzene as oil.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:8])[CH2:6][OH:7].[C:9]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:14]=[CH:13][C:12]([C:15]2[CH:35]=[CH:34][C:18]3[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20](S(C)(=O)=O)=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1.Cl>C1COCC1.O.C(#N)C.O>[C:9]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:14]=[CH:13][C:12]([C:15]2[CH:35]=[CH:34][C:18]3[N:19]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:20]([O:7][CH2:6][C:5]([OH:4])=[O:8])=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)CO
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(-c3ccc(-c4ccccc4)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (6.0 mg, 60% suspension in mineral oil, 0.15 mmol). A solution of hydroxyacetic acid methyl ester (18.0 mg, 0.200 mmol) in THF (2.0 mL) was added dropwise to the vial and the resulting mixture was stirred at rt for 10 min. Then, a solution of 5-biphenyl-4-yl-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (compound 46-1, 51.3 mg, 0.100 mmol) in THF (1 mL) was added. The resulting mixture was stirred at rt for 10 mM, then diluted by dropwise addition of 1:1 ACN/water (2 mL) and left to stir at rt for 30 min. The reaction mixture was then diluted with water (5 mL), acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and washed with 5% aqueous HCl and water, and evaporated to dryness in vacuo to give the title compound as pale yellow solid. LR-MS (API-ES): mixture of two N-SEM isomers, calculated for C27H29ClN2O4Si 508.2, observed m/e 509.0 [(M+H)+, 100%], 465 (Rt 3.74 min). The compound was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:18])([F:19])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: NCC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC(F)(F)F
Yield: 79 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.81 ml (0.013 mol) of triethylamine, 1.1 ml (0.013 mol) of 2,2,2-trifluoroethylamine in 30 ml of DMF were reacted at 40° C. for 48 hours affording 4.71 g of oil. This oil was kugelrohr distilled at 53 Pa, pot temperature 110°-120° C. to give 2.82 g (47.3%) of product as a yellow oil, nD25 1.4496.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN1C(=O)CCC1>[C:33]([CH2:35][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:27][CH2:26]1)=[O:37])#[N:34]
Reactant: N#CCC(=O)O
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(=O)N1CCC(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
The mixture of 4-(2,3-difluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 209) (90 mg, 0.19 mmol), cyanoacetic acid (81 mg, 0.95 mmol), DIEA (330 μL, 1.9 mmol) in 4 mL NMP was stirred at RT. To it was added BOP (360 mg, 0.95 mmol). The mixture was stirred at RT for overnight. To it was added TFA (0.5 mL). The mixture was subjected to reverse phase preparative HPLC to isolate the title compound (81 mg). MS found for C27H26F2N6O2 as (M+H)+ 505.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.05 (1H, s), 7.24 (2H, d, J=8.4 Hz), 7.15 (1H, m), 7.06 (1H, m), 7.04-6.97 (3H, m), 5.71 (1H, s), 4.56 (1H, m), 4.46 (2H, s), 3.91-3.77 (3H, m), 3.16 (1H, m), 2.83-2.69 (2H, m), 1.84 (2H, m), 1.60 (2H, m) ppm.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[O:8])(=[O:3])[CH3:2].O[CH:14]([CH:16]=[CH2:17])[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[C:1]([S:4][CH2:5][C:6]([CH2:15][CH2:14][CH2:16][CH3:17])([CH2:9]/[CH:10]=[CH:11]/[CH3:12])[CH:7]=[O:8])(=[O:3])[CH3:2]
Reactant: CCCCC(C=O)CSC(C)=O
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C/C=C/CC(C=O)(CCCC)CSC(C)=O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
To a stirred solution of 2-(acetylthiomethyl)hexanal (32.6 g, 0.173 mole) in 325 ml of xylenes in a 500-mL RBF fitted with a Dean-Stark trap is added 2-hydroxy-3-butene (22.5 mL, 0.259 mole), followed by pyridinium p-toluenesulfonate (4.34 g, 0.017 mole) at room temperature under nitrogen. The mixture is heated to reflux overnight. After cooling to room temperature, the xylenes solution is washed with 300 mL of saturated NaHCO3 solution. The aqueous phase is extracted with 300 mL of ethyl acetate. The combined organic extract is washed with 200 mL of brine and 200 mL of water. After removing solvents, the product is obtained by vacuum distillation (157-160° C./1.5 mmHg) in 80.5% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](C=O)=[CH:3][CH:2]=1.[C:9](O)(=O)[CH3:10].[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37]C3C=NC=CC=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14].[Na]>ClCCl.ClCCCl>[CH2:13]([N:15]1[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[C:19](=[O:25])[N:18]([CH3:26])[C:17]2[CH:27]=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:36][CH2:37][CH2:4][C:3]3[CH:2]=[N:1][CH:6]=[CH:9][CH:10]=3)[CH:29]=[CH:30][C:16]1=2)[CH3:14]
Reactant: O=Cc1ccncc1
Reactant: CC(=O)O
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Agent: [Na]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCCc3cccnc3)c3ccncc3)ccc21
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4-Pyridinecarbaldehyde (1.18 ml, 12.5 mmol) and a catalytic amount of acetic acid were added to a 1,2-dichloroethane solution (40 ml) of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (4.44 g, 10.5 mmol), and stirred for 30 minutes. Sodium triacetoxyhydroborate (3.33 g, 15.7 mmol) was added to the resulting mixture, and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water and a saturated sodium chloride aqueous solution in this order, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ethyl acetate:methanol=1:0→9:1). The purified product was concentrated under reduced pressure to thereby obtain 4.73 g (yield: 88%) of 1-ethyl-3,3,5-trimethyl-7-{3-[(2-pyridin-3-ylethyl)pyridin-4-yl methylamino]propoxy}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a pale yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH:11]=[CH:10][C:9]2[C@H:4]([C@@H:5]([O:13][C:14](=[O:19])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[CH2:6][C@@H:7]([CH3:12])[CH:8]=2)[C@H:3]1[CH2:20][CH2:21][C:22](=[O:38])[CH2:23][C@@H:24]([O:30][Si](C(C)(C)C)(C)C)[CH2:25][C:26]([O:28][CH3:29])=[O:27].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>O1CCCC1>[CH3:1][C@H:2]1[CH:11]=[CH:10][C:9]2[C@H:4]([C@@H:5]([O:13][C:14](=[O:19])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[CH2:6][C@@H:7]([CH3:12])[CH:8]=2)[C@H:3]1[CH2:20][CH2:21][C:22](=[O:38])[CH2:23][C@@H:24]([OH:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CCC(=O)C[C@H](CC(=O)OC)O[Si](C)(C)C(C)(C)C)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(=O)OC)[C@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
The silyl ether from Step C (230 mg, 0.00024 mol) was dissolved in 5 ml of tetrahydrofuran (THF) and treated with 54 μl, (0.057 g, 0.00095 mol) of acetic acid and 710 μl (1M in THF, 0.00071 mol) of tetrabutylammonium fluoride (Bu4N F) and the mixture was stirred overnight at room temperature. Another 57 μl of acetic acid and 710 μl of Bu4N F were added and stirring was continued an additional 24 hours. The mixture was poured into 100 ml of ether and washed with 1×5 ml of 1N hydrochloric acid, 1×10 ml of saturated aqueous sodium bicarbonate and 2×10 ml of brine and dried (MgS04) Concentration to dryness gave 120 mg of an oil. The oil was chromatographed on a "Still" column of silica gel (1.5×17.7 cm, 230-400 mesh) by elution with 5% acetone in methylene chloride (v/v) collecting 5 ml fractions. Fractions 12-20 containing the product were combined and concentrated to dryness to give 53 mg of solid (m.p. 64°-66° C.). Recrystallization of a sample from hexane gave material with m.p. 67°-68° C.
Reaction SMILES: O[C:2]1([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)[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.C(NC(C)C)(C)C.CS(Cl)(=O)=O>CN(C=O)C.O.[OH-].[Na+]>[NH:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ncc[nH]2)CC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-(1H-imidazol-2-yl)piperidine-1-carboxylate (10.5 g) and diisopropylamine (13.8 mL, 2.5 equiv.) in anhydrous DMF under N2 at 0° C. was added in one portion of methanesulfonyl chloride (6.19 mL, 2 equiv.). The reaction was stirred at 0° C. for 2 hours when a further 2 equivalents of methanesulfonyl chloride and 2.5 equivalents of diisopropylamine was added and the resulting mixture stirred at room temperature overnight. The mixture was diluted with water (200 mL) and adjusted pH 9 with 1 N NaOH and then extracted with ethyl acetate (3×). The combined ethyl acetate layers was dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 5% methanol in dichloromethane with 0.5% ammonium hydroxide to give tert-butyl 4-(1H-imidazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (7.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C-:19]#[N:20].[K+]>CN(C)C=O>[C:19]([C:11]1[N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][N:12]=1)#[N:20]
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nccc(-c2cccc(C#N)c2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccnc(C#N)n2)c1
Reaction time: 4 h

Procedure:
A mixture of 4-(3-cyanophenyl)-2-methylsulfonylpyrimidine and potassium cyanide in N,N-dimethylformamide is stirred for 4 hours at 100° . The reaction mixture is concentrated by evaporation, distilled water is added thereto and the whole is extracted with methylene chloride. The organic phase is dried and concentrated by evaporation to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C@H:12]([NH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].Cl.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:11])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To a solution of 2-fluoronitrobenzene (1.0 g, 7.09 mmol) in DMF (5 mL) were added H-ALA-OTBU HCl (2.6 g, 14.2 mmol) and DIPEA (2.5 mL, 14.2 mmol). The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated to afford 1.8 g (95%) of the desired product as orange oil. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH3:19][S:20][CH3:21].[F:22][C:23]([F:29])([F:28])[S:24]([OH:27])(=[O:26])=[O:25].C(OCC)(=O)C>C(#N)C>[F:22][C:23]([F:29])([F:28])[S:24]([O-:27])(=[O:26])=[O:25].[F:22][C:23]([F:29])([F:28])[S:24]([OH:27])(=[O:26])=[O:25].[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S+:20]([CH3:21])[CH3:19])[CH2:15][S:14][C@H:9]12
Reactant: CSC
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[S+](C)CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a mixture of 7-aminocephalosporanic acid (6.0 g) and dimethyl sulfide (1.36 g) in acetonitrile (30 ml) was added trifluoromethanesulfonic acid (9.0 g) below 18° C. under cooling in an ice-bath and stirring, which was continued for 30 minutes at 15° to 18° C. To the reaction mixture was added ethyl acetate (80 ml), and the mixture was seeded and stirred for one hour at ambient temperature. A resulting precipitate was filtered, washed with ethyl acetate and dried to give 7-amino-3-dimethylsulfoniomethyl-3-cephem-4-carboxylate bis(trifluoromethanesulfonate) (8.55 g), mp. 190° to 195° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[Cl:13][CH2:14][O:15][C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[C:18]([Br:23])[CH:17]=1>>[Cl-:13].[NH2:1][C:2]1[N:3]([CH2:14][O:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[C:18]([Br:23])[CH:17]=2)[C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N+:6]=1[CH2:14][O:15][C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[C:18]([Br:23])[CH:17]=1
Reactant: ClCOc1cc(Br)cc(Br)c1
Reactant: Cc1cc2nc(N)[nH]c2cc1C
Product: Cc1cc2c(cc1C)[n+](COc1cc(Br)cc(Br)c1)c(N)n2COc1cc(Br)cc(Br)c1
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5,6-dimethylbenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3,5-dibromophenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: C1(N2C(=O)C3=CNC4C=[CH:15][C:16]([N:19]5[CH2:24]CN[CH2:21][CH2:20]5)=CC=4C3=N2)C=CC=CC=1.[NH2:27][C:28]1[CH:37]=[CH:36][C:35]2[NH:34][CH:33]=[C:32]3[C:38](=[O:48])[N:39]([C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[N:40]=[C:31]3[C:30]=2[CH:29]=1.CN1CCNCC1>>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([N:39]2[C:38](=[O:48])[C:32]3=[CH:33][NH:34][C:35]4[CH:36]=[CH:37][C:28]([N:27]5[CH2:21][CH2:20][N:19]([CH3:24])[CH2:16][CH2:15]5)=[CH:29][C:30]=4[C:31]3=[N:40]2)=[CH:46][CH:45]=1
Reactant: Nc1ccc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2c1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Agent: CN1CCNCC1
Product: CN1CCN(c2ccc3[nH]cc4c(=O)n(-c5ccc(Cl)cc5)nc-4c3c2)CC1

Procedure:
The title compound was prepared following the procedure described for 7a using 6b and 1-methyl-piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.50 (7H, br), 3.75 (3H, s), 7.00 (1H, d, J=9.06 Hz), 7.40 (1H, m), 7.48 (1H, br), 7.68 (1H, d, J=9.06 Hz), 7.92 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=8.79 Hz), 8.56 (1H, br), 9.12 (1H, br). m/z 394.9 (MH+).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:23][CH:24]=[N:25][N:26]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:23][CH:24]=[N:25][N:26]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nncs2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1N(O)[C@@H]2CC[C@@H](c3nncs3)N1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
BCl3 (1 M in CH2Cl2, 9.0 mL, 9.0 mmol) was added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (560 mg, 1.8 mmol) in dry CH2Cl2 (20 mL) at −78° C. The mixture was stirred under a N2 atmosphere at 0° C. for 6 hrs., then, MeOH (9 mL) was slowly added dropwise at −78° C. The solvents were evaporated under vacuum at 0° C. to give (2S,5R)-6-hydroxy-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (329 mg, 81%) as a yellow solid, which was used directly in the next step. ESI-MS (EI+, m/z): 227.1 [M+H]−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:12]=[C:13]([CH3:24])[C:14]=2[CH2:15][CH2:16][CH2:17][CH2:18]C(OCC)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[BH4-].[Li+].[O:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:28]([C:25]1[N:11]2[N:12]=[C:13]([CH3:24])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:34][CH2:33][OH:32])=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:10]2=[CH:27][CH:26]=1)[CH3:29].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=3)[N:12]=[C:13]([CH3:24])[C:14]=2[CH2:15][CH2:16][CH2:36][CH2:35][CH2:34][CH2:33][OH:32])[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CCCCc1c(C)nn2c(CC)ccc2c1-c1cccc(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(CCCCCCO)c(C)nn12
Product: CCc1ccc2c(-c3cccc(CN)c3)c(CCCCCCO)c(C)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %
Yield: 31.9 %

Procedure:
To a solution of ethyl 5-[4-(3-cyanophenyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl]pentanoate (45 mg) in tetrahydrofuran (1 mL) was added lithium borohydride (5 mg) in an ice-water bath. Then the reaction mixture was stirred at ambient temperature. After 2 hours, another lithium borohydride (5 mg) was added therein and was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and was evaporated in vacuo. The residue was purified by p-TLC (hexane-ethyl acetate=1-1) to give 3-[7-ethyl-3-(6-hydroxyhexyl)-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzonitrile (26 mg, 64.5%) as an yellow oil and 6-{4-[3-(aminomethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-3-yl}-1-hexanol (13 mg, 31.9%) as a yello solid.
Reaction SMILES: O[C:2]([C:4](F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[CH3:39].C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[CH2:30]([C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:31][N:11]2[CH2:12][CH2:13][N:8]([CH2:14][C:15]3[N:16]=[N:17][C:18]4[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=4)[N:20]=3)[CH2:9][CH2:10]2)=[C:2]([CH3:4])[CH:28]=1)[CH3:39]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCc1cc(C)c(CN2CCN(Cc3nnc4nc(N)nc(N)c4n3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added 1-Chloromethyl-2-methyl-Naphthalene (34 mg; 0.18 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 23 mg of yellow colored 3-[4-(4-Ethyl-2-methyl-naphthalen-1-ylmethyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.