Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].S(C1C=CC(C)=CC=1)(O[CH3:37])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[C:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH:27][CH3:37])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:10]2=[S:28])=[CH:5][C:4]=1[C:29]([F:32])([F:30])[F:31])#[N:2]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(S(N)(=O)=O)cc3)C2=S)cc1C(F)(F)F
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CNS(=O)(=O)c1ccc(N2C(=S)N(c3cnc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 50 °C
Yield: 30.3 %

Procedure:
A mixture of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro-[3.4]octan-5-yl)benzenesulfonamide (Compound 81, 97 mg, 0.20 mmol), methyl tosylate (37 mg, 0.20 mmol), and Cs2CO3 (65 mg, 0.20 mmol) in acetonitrile (1 mL) was heated at 50° C. for 20 h in a sealed tube. After being cooled room temperature, the reaction mixture was diluted with water and extracted with EtOAc (3×). The organic layer was dried over magnesium sulfate and concentrated to give a residue that was purified by column chromatography on silica gel (hexanes:DCM:acetone=5:9:1) to afford 30 mg of 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]-octan-5-yl)-N-methylbenzenesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.37 (s, 1H), 8.10 (dd, 2H), 7.58-7.49 (m, 2H), 4.52 (d, 1H), 2.80 (m, 3H), 2.78-2.69 (m, 2H), 2.63-2.47 (m, 2H), 2.29 (m, 1H), 1.74 (m, 1H). LCMS [M+1+Na]+ 518.0.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: NCCc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CNCCc4cccnc4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 66.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 3-(2-aminoethyl)pyridine (0.235 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-{1-(tert-butoxycarbonyl)-5-[(2-(pyridin-3-yl)ethyl)aminomethyl]indol-2-yl}isoindolinone (80.5 mg, yield 66%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.C1OC1C.[C:16]([O:19][CH2:20][C:21]1[CH2:22][S:23][C@@H:24]2[C@H:35]([NH2:36])[C:34](=[O:37])[N:25]2[C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])[CH3:17]>C(OCC)(=O)C>[C:16]([O:19][CH2:20][C:21]1[CH2:22][S:23][C@@H:24]2[C@H:35]([NH:36][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=3)[C:34](=[O:37])[N:25]2[C:26]=1[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])(=[O:18])[CH3:17]
Reactant: O=C(Cl)Cc1ccncc1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC1CO1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccncc3)[C@H]2SC1

Procedure:
A suspension of pyrid-4-ylacetyl chloride hydrochloride (6.0 g.) in ethyl acetate (50 ml) containing propylene oxide (12 ml.) was stirred, cooled in ice and treated dropwise with a solution of t-butyl 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (5.0 g.) in ethyl acetate (50 ml.). The mixture was stirred at 20° for 20 hours and then washed with saturated sodium bicarbonate solution and extracted with 2N hydrochloric acid. The aqueous extract was washed with ethyl acetate, neutralised with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and evaporated to small bulk whereupon crystallisation began. The crystalline solid was washed well with petroleum spirit (bp. 40°-60°) and dried to give the title ester as a buff coloured powder (5.4 g., 80% based on amine). A portion (250 mg.) was recrystallised from ethyl acetate as white needles (170 mg.), [α]D + 94° (c 0.9, DMSO) λmax. (EtOH) 256.5 nm (ε 9,900), νmax. (CHBr3) 3412 (NH), 1784 (β-lactam), 1736 (OAc), 1722 (CO2R), 1690 and 1512 cm.-1 (CONH), τ (d6 -DMSO) 0.81 (d, J 8 Hz; NH), 1.47 and 2.68 (2d, J 5 Hz; aromatic protons), 4.27 (q, J 8 and 5 Hz; C- 7H), 4.85 (d, J 5 Hz; C-6 H), 5.01 and 5.36 (2d, J 13 Hz; C-3CH2), 6.38 (s; CH2CONH), 6.39 (s; C-2CH2), 7.96 (s; OCOCH3), and 8.50 (s; C(CH3)3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[C:6](=[O:10])[C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)c1c(OCC)cc[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (60 g, 0.284 mol), 4-fluoro phenylboronic acid (120 g, 0.853 mol), Cu(AcO)2 (113 g, 0.568 mol) and pyridine (88 g, 1.137 mol) in DCM (500 mL) was stirred at RT for 4 h open to air. The solids were removed via filtration, washed with water and the filtrate extracted with DCM (2×). The combined organics were dried over Na2SO4 and concentrated to afford ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. The product was carried forward without further purification. (77 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1OC([Si](C)(C)C)=[CH:4][C:3]=1C=O.C[Si](C)(C)C1OC=C(C=O)C=1.CI.[CH2:26]([Si:28]([CH2:38][CH3:39])([CH2:36][CH3:37])[C:29]1[O:30][CH:31]=[C:32]([CH:34]=[O:35])[CH:33]=1)[CH3:27].ICCCC>>[CH2:1]([C:31]1[O:30][C:29]([Si:28]([CH2:36][CH3:37])([CH2:26][CH3:27])[CH2:38][CH3:39])=[CH:33][C:32]=1[CH:34]=[O:35])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1oc([Si](C)(C)C)cc1C=O
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Agent: C[Si](C)(C)c1cc(C=O)co1
Solvent: CI
Solvent: CCCCI
Product: CCCCc1oc([Si](CC)(CC)CC)cc1C=O

Procedure:
Using the same procedure as for 5-methyl-2-trimethylsilyl-4-furaldehyde but substituting 2-trimethylsilyl-4-furaldehyde (Compound 30) and methyl iodide with 2-triethylsilyl-4-furaldehyde (Compound 31) and 1-iodobutane, respectively, gives 5-butyl-2-triethylsilyl-4-furaldehyde (Compound 41). IR (neat): 1690 cm-1; 'HNMR (CDCl3):0.73 (q, 6H, J=8.4 Hz), 0.95 (m, 12H), 1.36 (p, 2H, J=7.5 Hz), 1.69 (p, 2H, J=7.5 Hz), 2.94 (t, 2H, J=7.5 Hz), 6.89 (s, 1H) and 9.91 (s, 1H) 13CNMR (CDCl3): 3.03, 7.17, 13.6, 22.2, 26.8, 30.4, 118.6, 122.5 158.4, 170.2 and 184.8. LRMS m/e (% abundance):266 (M+, 20) 238 (20) 237 (100), 87 (10) and 75 (20); HRMS exact mass calculated for C15H26O2Si 266.1702, found 266.1690.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:15]S([O-])(=O)=O.C[S+](C)C.ClCCl>O>[O:3]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH2:15]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: CS(=O)(=O)[O-]
Agent: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC2(CC1)CO2
Yield: 72 %

Procedure:
A solution of 47% sodium hydroxide (15 ml), ethyl 4-oxopiperidine-1-carboxylate (4.53 ml, 30 mmol), trimethylsulphonium methanesulphonate (7.36 g, 39 mmol) (Syn. Comm., 1985, 15, 749) and dichloromethane (30 ml) was heated to 50° C. for 16 h, cooled, diluted with water (30 ml), and extracted with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica, eluting with 2% methanol/dichloromethane to give the product as a mobile yellow oil (4.0 g), MS (+EI)m /z 185; 1H NMR (360 MHz) (CDCl3) 4.15 (2H, q, J7.1 Hz), 3.78 (2H, brs), 3.46 (1H, ddd, J3.7, 9.6, 13.3 Hz), 2.71 (2H, s), 1.87-1.79 (2H, m), 1.49-1.43 (2H, m), 1.28 (3H, t, J7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([OH:16])=O.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]([N:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1)=[O:16]
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2F)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccccc2F)s1

Procedure:
prepared by reaction of 5-(2-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=1.I[CH2:21][CH2:22][CH2:23][CH3:24].Cl>CN(C=O)C>[CH2:21]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[CH2:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Brc1ccc(Cc2cc3ccccc3[nH]2)cc1
Reactant: CCCCI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(Cc2ccc(Br)cc2)cc2ccccc21
Reaction time: 0.17 h

Procedure:
A mixture of sodium hydride (0.32 g) in DMF (50 ml) was cooled in an ice bath. A solution of 2-(p-bromophenylmethyl)-indole (2.0 g), prepared, e.g., as described in Preparation 3, in DMF, was added, and the mixture stirred for 10 minutes. 1-Iodobutane (0.9 ml) in DMF was added dropwise, and the mixture stirred for 30 minutes. It was then poured into cold dilute HCl and extracted with ether. The extract was washed three times with cold water, dried over magnesium sulphate, and the solvent evaporated to afford an orange-red oil, 1-(n-butyl)-2-(p-bromophenylmethyl)indole (2.5 g), a compound of Formula (H).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.O>C1COCC1>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:9][C:10]#[N:11])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCCO3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.4 mL, 15.0 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 15.0 mL, 15.0 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-methoxy-phenyl)-methanone (2.02 g crude, 7.5 mmol) in THF (15 mL) and refluxed for 30 min. The reaction mixture was poured into water (50 if L), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(4-methoxy-phenyl)-acrylonitrile as a yellow solid (1.44 g, 66% yield): mp, 112-114° C.; 1H NMR (DMSO-d6) δ 3.79 and 3.83 (2s, 3H, OCH3), 4.25-4.33 (m, 4H, CH2CH2), 6.07 and 6.08 (2s, 1H, CH), 6.77-7.32 (m, 7H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.3, 64.0, 64.0, 64.2, 64.3, 92.7, 93.0, 113.9, 114.1, 117.0, 117.2, 118.0, 118.6, 118.7, 121.9, 122.5, 129.1, 130.0, 130.1, 130.4, 130.8, 131.4, 143.1, 143.2, 144.7, 145.5, 160.3, 160.7, 160.8, 161.1. Anal. Calcd for C18H15NO3+0.1H2O: C, 73.26; H, 5.19; N, 4.75. Found: C, 72.96; H, 5.22; N, 4.67.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16](Br)[S:17][C:13]=3[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCN(C(C)C)C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37]>CC(N(C)C)=O>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]3[N:15]=[C:16]([NH:30][C@@H:31]4[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]4[OH:37])[S:17][C:13]=3[CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: Brc1nc2ccc(Cn3cnc4ccccc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccccc43)cc2s1
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a suspension of 6-((1H-benzo[d]imidazol-1-yl)methyl)-2-bromobenzo[d]thiazole from Step 1 of Example 1 (34.4 mg, 0.1 mmol) in DMA (3 mL) were added DIEA (15 mg, 0.12 mmol) and (1R,2R)-2-aminocyclohexanol (13.8 mg, 0.12 mmol) at rt. The reaction mixture was stirred in a sealed tube at 120° C. overnight. After cooling to rt, the mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using a mixture of water (containing 5% CH3CN, 0.05% HCOOH) and CH3CN (containing 0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (22 mg, 58%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.60-7.72 (m, 2H), 7.55 (dd, J=2.6, 6.0 Hz, 1H), 7.26-7.34 (m, 1H), 7.12-7.25 (m, 3H), 5.47 (s, 2H), 4.76 (br s, 1H), 3.26-3.39 (m, 2H), 2.03 (d, J=10.0 Hz, 1H), 1.87 (d, J=9.4 Hz, 1H), 1.62 (d, J=4.7 Hz, 2H), 1.03-1.39 (m, 4H). LCMS (ESI) m/z 379 (M+H)+.
Reaction SMILES: [N:1]([C@H:4]1[C:34](=[O:35])[N:6]2[CH:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:8](OS(C)(=O)=O)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]>C1C=CC=CC=1.CCOC(C)=O>[N:1]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]
Reactant: CC(=O)OCC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](N=[N+]=[N-])[C@H]2SC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-acetoxymethyl-cepham-4-carboxylate (0.72 g.), EM silica gel 60 (7.20 g.), and 3:1 PhH-EtOAc (20 ml.) is stirred in a stoppered flask for 4 days at room temperature. The mixture is filtered through a sintered glass funnel to remove the silica gel, which is washed with several portions of EtOAc. Evaporation of the filtrate and washings leaves an oil. This material is chromatographed on Baker silica gel using 9:1 φH-EtOAc as an eluting solvent, to provide p-nitrobenzyl 7α-azido-3-acetoxymethyl-ceph-3-em-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[C:11]([O-:14])(=[O:13])[CH3:12].[K+].CN(C=O)C>O>[C:11]([O:14][CH2:9][C:3]1[C:4]([Br:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])(=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: BrCc1c(Br)cccc1Br
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 1,3-dibromo-2-(bromomethyl)benzene (3.28 g, 10.0 mmol), potassium acetate (3.93 g, 40.0 mmol) and DMF (100 mL). The solution was stirred at room temperature for 14 h. After that time, the reaction mixture was diluted with water (900 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford an 88% yield (2.70 g) of 2,6-dibromobenzyl acetate 104g as an off-white solid: mp 62-65° C.; 1H NMR (300 MHz, CDCl3) d 7.57 (d, 2H, J=8.0 Hz), 7.07 (t, 1H, J=7.9 Hz), 5.42 (s, 2H), 2.11 (s, 3H); MS (ESI+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][N:20]([Si](C)(C)C)[Si](C)(C)C>>[NH2:20][CH2:19][CH2:18][CH2:17][N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:13]
Reactant: O=C1NCCN1Cc1ccccc1
Reactant: C[Si](C)(C)N(CCCBr)[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Product: NCCCN1CCN(Cc2ccccc2)C1=O

Procedure:
As shown in FIG. 9B (Scheme 4), the synthesis of 1-(3-aminopropyl)-3-benzylimidazolidin-2-one (35) will be performed by treating the starting material N1-benzylethane-1,2-diamine with diethoxymethoxyethane to form 1-benzyl-4,5-dihydro-1H-imidazole. The imidazole intermediate will be treated with BuLi (forming a lithiate) followed by quenching with water to form the final intermediate 1-benzylimidazolidin-2-one. Treating the imidazolidinone with NaH followed by Br—(CH2)3—N(SiMe3)2 under reducing conditions will afford the intermediate 35.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11]C)=[O:10]>[OH-].[Na+].CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1ccccc1COc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1COc1cccc(Br)c1
Yield: 107.6 %

Procedure:
Methyl 2-(3-bromophenoxy)methylbenzoate (34 g) was refluxed in a mixture of 100 mL of 10% sodium hydroxide and 200 mL of methanol for 3 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was then acidified with concentrated hydrochloric acid. Extracting the acidic solution with ethyl acetate and then concentration of the organic layer gave the 2-(3-bromophenoxy)methylbenzoic acid (35 g) m.p. 158°-159° C. pmr (CDCL3) δ: 8.10 (m, 1H, H6), 6.84-7.74 (m, 7H, aromatic H), 6.16 (br s, 1H, CO2H), 5.49 (s, 2H, ArCH2O).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].[OH:11][C:12]1[C:21]([CH3:22])=[CH:20][C:15]([C:16]([NH:18]O)=[NH:17])=[CH:14][C:13]=1[CH3:23]>>[OH:11][C:12]1[C:13]([CH3:23])=[CH:14][C:15]([C:16]2[N:17]=[C:8]([C:6]3[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)[O:10][N:18]=2)=[CH:20][C:21]=1[CH3:22]
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: Cc1cc(C(=N)NO)cc(C)c1O
Product: Cc1cc(-c2noc(-c3ccc(C=O)s3)n2)cc(C)c1O
Yield: 15.5 %

Procedure:
The title compound (140 mg) is prepared from 5-formyl-2-thiophene carboxylic acid (468 mg, 3.0 mmol) and 4,N-dihydroxy-3,5-dimethyl-benzamidine (540 mg, 3.0 mmol) according to Method A; LC-MS: tR=1.01 min; [M+1]+=301.04; 1H NMR (D6-DMSO): δ2.24 (s, 6H), 7.64 (s, 2H), 8.17 (s, 2H), 8.99 (s, 1H), 10.06 (s, 1H).
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[CH:13]2)[N:4]=1.[C:29]1([CH3:55])[CH:34]=[CH:33][C:32]([C:35]([O:37][C@@H:38]2[C@@H:42]([CH2:43][O:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=3)=[O:46])[O:41][C@H:40](Cl)[CH2:39]2)=[O:36])=[CH:31][CH:30]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:40]2[O:41][C@H:42]([CH2:43][O:44][C:45]([C:47]3[CH:48]=[CH:49][C:50]([CH3:53])=[CH:51][CH:52]=3)=[O:46])[C@@H:38]([O:37][C:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:55])=[CH:34][CH:33]=3)=[O:36])[CH2:39]2)=[C:5]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:14]=[CH:13]2)[N:4]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: Clc1nc(-n2cnc(-c3ccccc3)c2-c2ccccc2)c2[nH]cnc2n1
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3cnc4c(-n5cnc(-c6ccccc6)c5-c5ccccc5)nc(Cl)nc43)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1

Procedure:
The sodium salt of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (94 mg, 0.25 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2. Sampling of the reaction mixture showed no α-nucleoside by 1H NMR (500 MHz). Volatiles were evaporated in vacuo, and the residue was chromatographed (25 g silica gel, EtOAc/hexanes, 3:7→1:1) to give the β-anomer (quantitative). Recrystallization (EtOAc/hexanes) gave 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(4,5-diphenylimidazol-1-yl)purine: UV (MeOH) max 240, 275 nm (∈ 53 400, 19 300), min 223, 270 nm (∈ 42 000, 19 100); 1H NMR (500 MHz, CDCl3) δ 8.97 (s, 1H), 8.25 (s, 1H), 7.97 (d, J=7.9 Hz, 2H), 7.86 (d, J=7.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.19-7.40 (m, 13H), 6.56 (t, J=7.0 Hz, 1H), 5.77-5.78 (m, 1H), 4.76-4.79 (m, 1H), 4.65-4.69 (m, 2H), 2.92-2.96 (m, 2H), 2.45 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.06, 165.94, 154.03, 153.17, 147.13, 144.71, 144.45, 142.81, 140.38, 139.24, 133.50, 131.02, 129.85, 129.55, 129.37, 129.34, 128.25, 128.17, 127.47, 127.17, 126.41, 126.18, 124.00, 85.11, 83.52, 74.85, 63.84, 38.57, 21.78, 21.71; HRMS m/z 747.2100 (MNa+[C41H33ClN6O5Na]=747.2099).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[CH3:29][C:30]1[C:31]([NH2:37])=[N:32][CH:33]=[C:34]([CH3:36])[N:35]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH3:36][C:34]1[N:35]=[C:30]([CH3:29])[C:31]2[N:32]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:37]=2)[CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1cnc(N)c(C)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(C)n1
Temperature: 130 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (770 mg, 1.61 mmol, 1.0 eq), 3,5-dimethylpyrazin-2-amine (CAS-Nr. 91678-81-8, 218 mg, 1.77 mmol, 1.1 eq) and diisopropylethylamine (0.28 mL, 1.61 mmol, 1.0 eq) in 10 mL isopropanol was added 3 Å molsieves. The reaction mixture was heated to reflux temperature for 2 h. No conversion was observed under these conditions (UPLC-MS). Therefore, the reaction mixture was heated to 130° C. for 1 h under microwave conditions (single mode microwave oven). The reaction mixture was filtered to remove the molsieve and the filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera, 25 g Snap cartridge, DCM→DCM/ethanol 95/5) to deliver 249 mg (31%) of the title compound.