Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[ClH:17].[N:18]1(C(=N)N)[CH:22]=[N:21]C=N1.CCOCC>CN(C)C=O>[ClH:17].[N:1]1([C:22](=[NH:18])[NH2:21])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)n1cncn1
Reactant: C1CCCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N=C(N)N1CCCCCC1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of hexahydro-1H-azepine (5.63 ml, 50.0 mmol), diisopropylethylamine (8.73 ml, 50.0 mmol) and 1H-1,2,4-triazole-1-carboximidamide hydrochloride (6.11 g, 55 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature over the weekend. Ether (100 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 10 minutes. The ether was decanted from the solid residue. The residue was stirred with ether (50 ml) at 5° C. (ice water bath) for 10 minutes and the ether layer was separated from the residue. Ether (50 ml) was added to the residue and the mixture was stirred at 5° C. The resulting solid was collected, washed with ether and dried to give the title compound as a colourless solid (6.8 g, 77%). LC/MS [M+H]+=142.
Reaction SMILES: [C:1]1([CH3:47])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:16][CH2:17][N:18]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:19][CH2:20][N:21]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH2:22][C:23]([O:25]C)=[O:24])[CH2:11][C:12]([O:14]C)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[C:33]1([CH3:36])[CH:34]=[CH:35][C:30]([S:27]([N:21]([CH2:20][CH2:19][N:18]([S:37]([C:40]2[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=2)(=[O:38])=[O:39])[CH2:17][CH2:16][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:47])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:11][C:12]([OH:14])=[O:13])[CH2:22][C:23]([OH:25])=[O:24])(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: COC(=O)CN(CCN(CCN(CC(=O)OC)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(CCN(CC(=O)O)S(=O)(=O)c2ccc(C)cc2)CCN(CC(=O)O)S(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 72 h
Yield: 93 %

Procedure:
Dimethyl 3,6,9-tris(p-toluenesulfonyl)-3,6,9-triazaundecanedioate prepared as in Example 28E (16 g, 22.5 mmol) was slurried in tetrahydrofuran (100 ml). Sodium hydroxide (2N, 160 ml) was added dropwise over a 1 h period. After 72 h, the solvent was evaporated under reduced pressure, and hydrochloric acid (1N) was added to lower the pH to 4. This aqueous phase was extracted several times with ethyl acetate. The combined ethyl acetate layers were washed twice with brine, dried (MgSO4), filtered, and evaporated to give a white solid, 14.22 g (93% yield): mp 177°-80° C.; 1H NMR (DMSO-d6) δ 2.38 and 2.40 (2 s, 9 H), 3.10 (m, 4 H), 3.29 (m, 4 H), 3.73 (s, 4 H), 7.37 and 7.41 (2 d, J=7.9, 8.2 Hz, 6 H), 7.61 and 7.66 (2 d, J=8.2 , 8.0 Hz, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:14][C:13](=O)[CH2:12][N:11]3[C:7](=[N:8][CH:9]=[N:10]3)[C:6]=2[CH:16]=1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:29])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:29][C:13]1[CH2:12][N:11]2[C:7](=[N:8][CH:9]=[N:10]2)[C:6]2[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:14]=1
Reactant: O=C1Cn2ncnc2-c2cc(F)ccc2N1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccc(N(C)C)cc1
Solvent: ClC(Cl)Cl
Product: Fc1ccc2c(c1)-c1ncnn1CC(Cl)=N2
Temperature: 65 °C
Reaction time: 20 h
Yield: 81.3 %

Procedure:
To a suspension of 9-fluoro-6H-1,3,3a,6-tetraaza-benzo[e]azulen-5-one (4.40 g, 20 mmol) in chloroform (250 mL) were added N,N-dimethyl-p-toluidine (12 mL) and phosphorus oxychloride (5.7 mL, 60 mmol), and the resulting mixture was stirred for 20 h at 65° C. Further N,N-dimethyl-p-toluidine (1.2 mL) and phosphorus oxychloride (0.6 mL, 6.3 mmol) were added, and stirring was continued for 1 h at 65° C. After cooling to ambient temperature the reaction mixture was poured onto aqueous sodium hydrogencarbonate (sat., 1 L), and the resulting mixture was stirred vigorously for 45 min. The layers were separated and the aqueous layers was extracted with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated. Purification by chromatography (SiO2, hexane:ethyl acetate=100:0 to 40:60) and recrystallisation from diisopropyl ether afforded 5-chloro-9-fluoro-4H-1,3,3a,6-tetraaza-benzo[e]azulene (3.85 g) as a brown solid which was dissolved in DMF (65 mL) and cooled to −55° C. 1-Chloro-3-isocyanomethyl-benzene (4.00 g, 26.4 mmol), and a solution of potassium tert-butylate (3.15 g, 27.3 mmol) in DMF (15 mL) were added at −50° C. to −55° C. The reaction mixture was stirred for 1 h at −40° C. to −50° C. before allowing to warm to ambient temperature. Acetic acid (1.1 mL) was added, and the mixture was poured onto aqueous sodium hydrogencarbonate (sat., 2 L) and extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium hydrogencarbonate (sat.) and dried over sodium sulfate. Purification by chromatography (SiO2, dichloromethane:ethanol=100:0 to 98.5:1.5) afforded the title compound (1.25 g, 18%) as a white crystalline solid. MS: m/e=352.2 [M+H]+.
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Ni].CO>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccccc1OCc1ccccc1

Procedure:
Hydrazine hydrate (5 ml) was added dropwise over 20 minutes to a stirred suspension of Raney nickel in a solution of 2-(benzyloxy)nitrobenzene in methanol (200 ml) causing gentle reflux. The stirred mixture was heated under reflux for a further 30 minutes, cooled, filtered and evaporated. The residue was distilled under vacuum to give a pale oil, b.p. 146°-150°/0.5 mm.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[CH:4]=1
Reactant: Cc1cc(C=O)ccc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CO)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To 4-formyl-2-methylbenzoic acid (75 mg, 0.46 mmol), in methanol (5 ml), was added sodium borohydride (26 mg, 0.69 mmol). The solution was stirred at 25° C. for 1 h. The reaction was quenched with saturated aqueous ammonium chloride and the pH adjusted to 2 with 2 N aqueous hydrochloric acid, then extracted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude 4-(hydroxymethyl)-2-methylbenzoic acid (37 mg, 76%) was obtained and was used without further purification. 1H NMR (400 MHz, DMSO): 12.73-12.68 (s, 1H), 7.82-7.77 (d, 1H), 7.24-7.19 (m, 2H), 5.32-5.27 (m, 1H), 4.53-4.48 (d, 2H), 2.53-2.49 (s, 3H). MS (EI) for C9H10O3: 167 (MH+).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:12]1[C:13](Cl)=[C:14]([Cl:24])[C:15]2[O:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17][C:16]=2[CH:23]=1)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:24][C:14]1[C:13]2[O:3][N:2]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:12]=2[CH:23]=[C:16]2[CH2:17][CH:18]([C:20]([OH:22])=[O:21])[O:19][C:15]=12
Reactant: O=C(c1ccccc1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2cc3c(-c4ccccc4)noc3c(Cl)c2O1
Reaction time: 48 h
Yield: 32.3 %

Procedure:
Hydroxylamine hydrochloride (15.19 g. 0.2186 mol.) and (3a) (10.84 g., 0.0322 mol.) were heated at reflux in 75 ml. of dry pyridine for 5 hours. On cooling, the pyridine was removed on a rotary evaporator and chased with ethanol. The residue, a yellow gum, was taken up in ethyl acetate and washed with dilute aqueous hydrochloric acid and brine, then dried over anhydrous magnesium sulfate and evaporated to a gum containing both E and Z isomers of the oxime. Without further purification, the gum was taken up in 20 ml. of absolute ethanol and treated with 120 ml. of 1M alcoholic potassium hydroxide at reflux on a steam bath for 3 hours then refrigerated at 0°-5° C. for 48 hours. The resulting precipitate was collected by filtration, washed with hexane, dried, and dissolved in 300 ml. warm distilled water. Acidification to pH 2.0 by addition of 4.0M aqueous hydrochloric acid gave a gelatinous precipitate which was extracted into ethyl acetate, dried with anhydrous magnesium sulfate, decolorized with Darco, and evaporated. Recrystallization from ethyl acetate with hexane afforded the furobenzisoxazole (4a) in 32.3% yield, m.p. 214°-215° C. Analysis (C16H10ClNO4) C,H,N,Cl.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[ClH:25].[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccnc3cc(Cl)ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc2c(NC3CCNCC3)ccnc2c1

Procedure:
A solution of 4-(7-chloro-quinolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.09 g, 5.78 mmol) in dioxane (30 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 262.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([OH:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[O-:29][C:30]#[N:31].[K+]>O>[C:30]([NH:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]([OH:18])[C:15]([C:19]([OH:21])=[O:20])=[CH:14][N:13]=2)=[CH:10][CH:11]=1)=[O:4])(=[O:29])[NH2:31]
Reactant: NCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)NCC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of 0.928 g (3.2 mmol ) of 2-[4-(N-glycylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid and 25 ml of water is treated with 1 ml (7.2 mmol) of triethylamine followed by 1.3 g (16 mmol) of potassium cyanate. After standing at room temperature overnight a 0.5 g (6.2 mmol) portion of potassium cyanate is added and the reaction mixture is allowed to stand at room temperature for another 18 hrs. The solution is concentrated in vacuo to 1/3 its volume and acidified to pH 2.5 with hydrochloric acid. The product is filtered, washed with water, ethanol, and ether to give 1.0 g of 2-[4-(N-carbamoylglycylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid.
Reaction SMILES: [C:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:25]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=[N:23][N:22]=2)=[CH:11][CH:10]=1)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:25]([C:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:24]=[N:23][N:22]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 99.9 %

Procedure:
N-Pentanoyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (1.61 g) was dissolved in tetrahydrofuran (40 mL) and at room temperature, lithium aluminum hydride (340.1 mg) was added, and then the mixture was heated under reflux. Ninety minutes later, water (5 mL), a 10% aqueous solution of sodium hydroxide (5 mL) and water (5 mL) were added successively under ice bath cooling. The organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. As water remained to the residue, ethyl acetate was added to conduct extraction twice from the remaining water. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to afford N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl] amine (1.57 g). Yield: 100%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:33][OH:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH:33]=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
((1S,2S,4R)-2-[tert-butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methanol (257.0 mg, 0.0005369 mol) was dissolved in methylene chloride (10.0 mL) under argon. N-Methylmorpholine N-oxide (126 mg, 0.00107 mol), and 4 Å molecular sieves (250 mg, freshly flame dried) were then added and the mixture was stirred for 10 minutes at room temperature. Tetrapropylammonium perruthenateVII (18.9 mg, 0.0000537 mol) was then added, and the resulting dark green solution was stirred for 1 h at room temperature. The reaction mixture was filtered through a silica gel plug, eluting with DCM (20 mL), followed by 50% ethyl acetate in DCM (150 mL). The eluate was evaporated to provide the product as a clear light green oil. The residue was carried on to the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([CH3:21])[CH3:20])[O:15][C:14]2=[O:22])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:32][CH:33]=[CH:34][CH3:35]>CN(C)C=O.O>[F:1][C:2]1[C:12]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([CH3:20])[CH3:21])[O:15][C:14]2=[O:22])=[CH:11][C:5]2[N:6]([CH2:32][CH:33]=[CH:34][CH3:35])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC(C)=C1OC(=O)N(c2cc3c(cc2F)OCC(=O)N3)C1=O
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCN1C(=O)COc2cc(F)c(N3C(=O)OC(=C(C)C)C3=O)cc21
Temperature: 70 °C

Procedure:
To a solution of 3-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.1 g), potassium carbonate (0.3 g) and potassium iodide (0.1 g) in N,N-dimethylformamide (50 ml), 1-bromo-2-butene (0.5 g) was added, followed by heating at 70° C. for 4 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography to give Compound No. 8 (1.0 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1>CC(O)C.Br.CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2COCCc2cccc(Br)n2)CC1
Agent: Br
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Brc1cccc(CCOCn2c(NC3CCNCC3)nc3ccccc32)n1
Yield: 19.7 %

Procedure:
A mixture of (±)-1,1-dimethylethyl 4-[[1-[(6-bromo-2-pyridinyl)ethoxymethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (0.0026 mol) in 2-propanol (30 ml) and HBr/CH3COOH (2 ml) was stirred and refluxed for 2 hours and then cooled. The solvent was evaporated. The residue was taken up in H2O and CH2Cl2. The mixture was alkalized with a NaOH solution. The organic layer was separated, washed with H2O, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/NH3 90/10). The pure fractions were collected and the solvent was evaporated. The residue was suspended in petroleum ether. The precipitate was filtered off and dried. This fraction was recrystallized from a small amount of CH3CN. The precipitate was filtered off and dried, yielding 0.22 g of (±)-1-[(6-bromo-2-pyridinyl)ethoxymethyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine (19.6%) (compound 4).
Reaction SMILES: [N+](C1C=CC(COC(C2N3[C@H](SC=2)C(C(OC(=O)C)[C:21]2[N:22]=[C:23]4[CH2:28][N:27]([CH3:29])[C:26](=[O:30])[CH2:25][N:24]4[CH:31]=2)(Br)C3=O)=O)=CC=1)([O-])=O.P([O-])([O-])([O-])=O.[C:44](OCC)(=[O:46])C>C1COCC1.C(#N)C.[Zn]>[CH3:29][N:27]1[C:26](=[O:30])[CH2:25][N:24]2[C:31]([CH:44]=[O:46])=[CH:21][N:22]=[C:23]2[CH2:28]1
Reactant: CC(=O)OC(c1cn2c(n1)CN(C)C(=O)C2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Reactant: CCOC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: CC#N
Solvent: C1CCOC1
Product: CN1Cc2ncc(C=O)n2CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R,6RS)-6-[Acetoxy-(7-methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (481 mg) was dissolved in THF (6.7 mL) and acetonitrile (3.1 mL). Freshly activated Zn dust (1.92 g) and 0.5 M phosphate buffer (pH 6.5, 9.9 mL) were added to the mixture. The reaction vessel was covered with foil to exclude light. The reaction mixture was vigorously stirred for 2 h at room temperature. The reaction solution was mixed with ethyl acetate and filtered through a pad of Celite. The pad was washed with water and the aqueous layer was separated. The aqueous layer was cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0. The mixture was concentrated under high vacuum at 35° C. and lyophilized. The residue was separated by the preparative HPLC (Inertsil ODS-2, GL Science Inc., 10×250 mm, 0.05 mol/L phosphate buffer (pH 7.1): CH3CN=93:7, 4.0 mL/min.). The separated fractions of (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt and (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt were cooled to 3° C. and 1 M NaOH was added to adjust pH to 8.0 respectively. Each solution was concentrated under high vacuum at 35° C. Each concentrate was applied to Diaion HP-21 (60 mL, Mitsubishi Kasei Co. Ltd.) resin column chromatography. After adsorbing, the column was eluted with water and then with 5% acetonitrile-water. The combined fractions were concentrated under high vacuum at 35° C. and lyophilized to give the title compound (5R),(6Z)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as a yellow amorphous solid (125 mg, 44.4%, Mp 115-117° C. (dec)) and compound (5R),(6E)-6-(7-Methyl-6-oxo-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazin-2-ylmethylene)-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt as yellow amorphous solid (19 mg, 6.7%) respectively.
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:3].[CH3:13][C:14]1([CH3:20])[C:18](=[O:19])[CH:17]=[CH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.C(O)(C)C.O1CCCC1>[CH3:13][C:14]1([CH3:20])[C:18](=[O:19])[CH2:17][CH:16]([C:7]2[CH:8]=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[CH2:15]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1(C)CC=CC1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccc(C#N)cc2)CC1=O
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Bis(1,5-cyclooctadienerhodium chloride) (1.09 g, 2.18 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3.05 g, 4.90 mmol) are added to tetrahydrofuran (72 mL) and the mixture is stirred under a nitrogen atmosphere for 30 minutes. This solution is added to a mixture of 4-cyanophenylboronic acid (80.04 g, 544.68 mmol), 5,5-dimethylcyclopent-2-en-1-one (24 g, 217.87 mmol), potassium carbonate (40.65 g, 294.13 mmol), tetrahydrofuran (144 mL), and isopropyl alcohol (16.7 mL) at 60° C. The mixture is stirred at 60° C. for 16 hours and then concentrated to dryness. The crude mixture is poured into water (500 mL) and is extracted with ethyl acetate (2×500 mL). The organic extracts are dried over MgSO4, filtered through silica gel, and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with 6:1 hexane:ethyl acetate to give the title compound (41 g, 88%, 192.24 mmol). 1H NMR (300.13 MHz, CDCl3) δ 7.65-7.62 (m, 2H), 7.37 (d, J=8.1 Hz, 2H), 3.56-3.43 (m, 1H), 2.86-2.76 (m, 1H), 2.42-2.32 (m, 1H), 2.32-2.24 (m, 1H), 1.86 (t, J=12.4 Hz, 1H), 1.17 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:52]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: N#Cc1ccc(Br)cn1
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: N#Cc1ccc(N2CCCCC2)cn1
Temperature: 80 °C

Procedure:
A solution of 500 mg (2.73 mmol) 5-bromopicolinonitrile, 63 mg (0.07 mmol) Pd2 dba3 and 130 mg (0.27 mmol) 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl in 20 ml DME was stirred and degassed with N2 for 10 min. 1.45 g (6.83 mmol) K3PO4 and 297 μl (3.0 mmol) piperidine were added. The mixture was heated at 80° C. under N2 over night. The mixture was cooled to r.t. and filtered through a plug of SiO2 with CH2Cl2/MeOH 9:1. The filtrate was concentrated and purified by flash chromatography (SiO2, Pet. ether/EtOAc 4:1→1:1) to afford 323 mg (63%, yellow oil).
Reaction SMILES: S[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N+]([O-])([O-])=O.[K+].[S:18]([Cl:22])(Cl)(=[O:20])=[O:19].C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C>[Cl:22][S:18]([C:6]1[CH:5]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:3]=[CH:2][CH:7]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)Cc1cccc(S)c1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Methyl 2-(3-mercaptophenyl)acetate (0.55 g, 3.0 mmol) was dissolved in 10 mL acetonitrile and potassium nitrate (0.76 g, 7.5 mmol) was added and the reaction mixture cooled to 0° C. To this suspension sulfuryl chloride was added (0.6 mL, 7.5 mmol) at 0° C. and the reaction mixture was let warm to room temperature and stirred overnight. A solution of saturated sodium bicarbonate was added followed by ethyl acetate (100 mL each). The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford methyl 2-(3-chlorosulfonylphenyl)acetate as an oil (0.59 g, 2.4 mmol, 79% yield). 1H NMR (CDCl3) 7.91 ppm, 2H, m; 7.60 ppm, 1H, d; 7.53 ppm, 1H, t; 3.73 ppm, 2H, s; 3.72 ppm, 3H, s.