Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:13])[CH:5]=[C:6]([NH:11][CH3:12])[C:7]([F:10])([F:9])[F:8])C.[CH2:14]([O:17][C:18]([C:20]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:31]=[C:32]=[O:33])[CH:28]=[CH:27][C:26]=1[Cl:34])([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH2:16]>CN(C)C=O>[CH2:14]([O:17][C:18]([C:20]([O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:31]2[C:4](=[O:13])[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:11]([CH3:12])[C:32]2=[O:33])[CH:28]=[CH:27][C:26]=1[Cl:34])([CH3:22])[CH3:21])=[O:19])[CH:15]=[CH2:16]
Reactant: CCOC(=O)C=C(NC)C(F)(F)F
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
0.347 g of potassium tert.butylate (content: 97%, 0.003 mols) are suspended in 30 g of anhydrous dimethylformamide (water content <0.01%), and heated to a temperature of 40° C. Subsequently, 1.97 g of 3-methylamino-4,4,4-trifluorobut-2-enoic acid ethyl ester (content: 99.5%, 0.01 mols) are added at a temperature of 40 to 45° C., and this temperature is maintained for a further 30 minutes, whereby a red-brown solution is produced. After cooling the reaction mixture to a temperature of 0° C., 3.51 g of 5-isocyanato-2-chloro-benzoic acid 1-allyloxycarbonyl-1-methyl-ethyl-ester (content: 97%, 0.0105 mols) are dispensed in over the course of 30 minutes, whereby the temperature is maintained at between 0 and 5° C. After removing the cooling bath, the resultant dark brown solution is stirred for a further 30 minutes, and the pH value of the now dark red solution is adjusted to pH 7 with 2.7 g of 1 M HCl [the content of 2-chloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1-(2H)pyrimidinyl)-benzoic acid 1-allyloxyoarbonyl-1-methyl-ethyl-ester in this solution is 11%, which corresponds to a yield of 89%]. The solvent is subsequently distilled off in a rotary evaporator, and the residue (5.6 g) is recrystallised in 12 g of isopropyl alcohol [the inorganic salts are removed by hot filtration]. After drying in a vacuum drying chamber (60° C. for 12 hours), 4.10 g (86.3% of theory) of 2-ohloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1-(2H)pyrimidinyl)-benzoic acid 1-allyloxycarbonyl-1-methyl-ethyl-ester are obtained in a content of 99%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:36](=[O:49])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:50][CH2:51][CH2:52][CH2:53][CH2:54][C:55](Cl)=[O:56]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:55](=[O:56])[CH2:54][CH2:53][CH2:52][CH2:51][Br:50])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:49])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[S:38]3(=[O:39])=[O:40])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N)cc4)cc3)cc2)S1(=O)=O
Reactant: O=C(Cl)CCCCBr
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(NC(=O)CCCCBr)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Amino-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (74 mg, 0.1 mmol) was treated as described in general procedure U using 5-bromovaleryl chloride (40 mg, 0.2 mmol) to give the intermediate 5-bromo-pentanoic acid [4′-(4-(2,4-dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-amide, which was treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (46 mg, 0.3 mmol) at 0° C. in 1 mL anhydrous DMF (stirring at room temperature under nitrogen over night), followed by regular ethyl acetate/water workup and silica gel column chromatography to give 1-[4′-(4-(2,4-dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thia-diazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperidin-2-one, which was finally treated as described in general procedure W to give the desired compound 1-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperidin-2-one.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[O:13])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)N(C)CCC1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:24])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([O:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1)=[O:13]
Reactant: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Br)c2cccnc2c1O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: O=C(NCc1cc(Cl)cc(Cl)c1)c1nc(Oc2ccccc2)c2cccnc2c1O

Procedure:
To a solution of 5-bromo-N-(3,5-dichlorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide from Example 50 (26 mg, 0.068 mmol), phenol (28 mg, 0.304 mmol) and cesium carbonate (198 mg, 0.608 mmol) in DMPU (0.25 ml) was heated at 140C for 8 hrs. The reaction was poured into sat aq. Na2CO3 and extracted with CHCl3. The organic phase was washed with water and dried (Na2SO4). The solvent was evaporated in vacuo and the residue dissolved in DMF (0.7 ml) and purified by preparative HPLC. (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=O)=[CH:32][C:31]=1[C:40]#[N:41])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[NH3:42]>[Ni].O.CO>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([NH2:42])=[O:38])=[CH:32][C:31]=1[C:40]#[N:41])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: N
Reactant: COC(=O)c1ccc(CN(Cc2nc3ccccc3n2C(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C#N)c1
Agent: [Ni]
Solvent: CO
Solvent: O
Product: N#Cc1cc(C(N)=O)ccc1CN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reaction time: 16 h
Yield: 36 %

Procedure:
To 0.5 mL of Raney Nickel in water was added a solution of 2-{[(2-cyano-4-methoxycarbonyl-benzyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.55 g, 1 mmol) in methanol (25 mL). The solution was then saturated with ammonia gas for 10 minutes. The reaction vessel was then shaken vigorously under an atmosphere of hydrogen (40 psi) for 16 hours. The mixture was filtered through a celite pad and the filtrate concentrated under reduced pressure. The crude residue was purified by column chromatography (88:12 CH2Cl2:MeOH) to afford to give the amide (0.20 g, 36%). 1H NMR (CDCl3) δ 1.73 (m, 1H), 2.01 (m, 2H), 2.35 (m, 1H), 2.85 (m, 2H), 3.88 (t, 2H, J=15.9 Hz), 4.16 (m, 1H), 4.21 (d, 1H, J=9.6 Hz), 4.26 (d, 1H, J=7.8 Hz), 5.71 (br, 1H, NH), 6.12 (br, 1H, NH), 7.19 (m, 3H), 7.46 (d, 1H, J=7.8 Hz), 7.55 (br, 2H), 7.80 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=8.1 Hz), 7.96 (s, 1H), 8.64 (dd, 1H, J=4.5 Hz). 13C NMR (CDCl3) δ 21.71, 24.65, 29.44, 49.92, 53.09, 61.84, 112.81, 117.49, 122.30 (4C), 122.97, 130.44 (2C), 131.98, 132.32, 133.56, 135.37, 138.05 (2C), 147.13, 147.29, 155.27, 156.87, 167.82. ES-MS m/z 437 (M+H). Anal. Calcd. for C26H24N6O.0.6CH2Cl2: C, 65.54; H, 5.21; N, 17.24. Found: C, 65.93; H, 5.51; N, 17.44.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.OC[C:12]1(N)[CH2:16][CH2:15][CH2:14][CH2:13]1.OCCN.C1(=O)CCCC1>>[CH2:3]1[C:2]2([CH2:7][O:9][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[NH:1]2)[CH2:6][CH2:5][CH2:4]1
Reactant: NC1(CO)CCCC1
Reactant: NC1(C(=O)O)CCCC1
Solvent: NCCO
Solvent: O=C1CCCC1
Product: C1CCC2(C1)COC1(CCCC1)N2

Procedure:
1-Aminocyclopentanecarboxylic acid was converted to the methyl ester according to Method B1c, Step 1. The ester reduced to 1-hydroxymethylcyclopentanamine according to Method B1c, Step 2. The hydroxyethylamine was reacted with cyclopentanone according to Method B4d, Step 1 to give 6-aza-12-oxadispiro[4.1.4.2]tridecane. The oxazolidine was reduced according to Method B4d, Step 2 to give 1-(cyclopentylamino)-1-(hydroxymethyl)cyclopentane. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to 1-(cyclopentylamino)-1-(chloromethyl)cyclopentane. The 2-chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford 1-cyclopentyl-2-(2-methyl-4-nitrophenylimino)-3-oxa-l-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=O)[C:5](=O)[NH:6]2.[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]([NH2:26])[C:22]([NH2:25])=[N:23][N:24]=2)=[CH:17][CH:16]=1>C(O)CO.O>[F:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C:20]2[N:21]3[C:22]([N:25]=[C:5]4[C:4](=[N:26]3)[C:3]3[C:7](=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=3[CH3:1])[NH:6]4)=[N:23][N:24]=2)=[CH:17][CH:16]=1
Reactant: Nc1nnc(Cc2ccc(F)cc2)n1N
Reactant: Cc1ccc(C)c2c1NC(=O)C2=O
Solvent: OCCO
Solvent: O
Product: Cc1ccc(C)c2c1[nH]c1nc3nnc(Cc4ccc(F)cc4)n3nc12
Temperature: 125 °C
Reaction time: 18 h

Procedure:
According to the general cyclization procedure (for Example 27), 0.60 mmol of 4,7-dimethyl-1H-indole-2,3-dione (105 mg) and 0.70 mmol of (4-fluoro-benzyl)-[1,2,4]triazole-3,4-diamine (145 mg) in 2 mL of ethylene glycol was stirred at 125° C. overnight (18 hr). The mixture was cooled to room temperature, diluted with water (10 mL), stirred for 15 min. The precipitated product was collected by filtration, washed with MeOH+water 1:1. Dried on high vacuum. The crude product (187 mg) was suspended in anhydrous ethanol (6 mL), heated to reflux, sonicated while hot, allowed to cool overnight, filtered, washed with ice-cold methanol, filtered and dried on high vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:44]1[CH2:56][CH2:55][N:47]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=3[CH:54]=[C:46]2[C:45]1=[O:57])(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:56][CH2:55][N:47]3[C:48]4[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=4[CH:54]=[C:46]3[C:45]2=[O:57])=[CH:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 130c (250 mg, 0.663 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (338 mg, 0.729 mmol), Pd(PPh3)4 (38.3 mg, 0.033 mmol), Na2CO3 aqueous solution (1.0 N, 2.19 mL, 2.19 mmol), DME (2 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 130d.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH3:23])[C:16]=2[C:17]2[NH:21][C:20]([CH3:22])=[N:19][N:18]=2)=[O:10])=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].COCCOC>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.O>[CH3:23][C:15]1[C:16]([C:17]2[NH:21][C:20]([CH3:22])=[N:19][N:18]=2)=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[S:13][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1nnc(-c2c(C)csc2NC(=O)Cc2ccc(I)cc2)[nH]1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2c(C)csc2NC(=O)Cc2ccc(-c3ccncc3)cc2)[nH]1
Temperature: 90 °C

Procedure:
A 30 mL reaction vial was charged with 2-(4-iodophenyl)-N-(4-methyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)thiophen-2-yl)acetamide (140 mg, 0.32 mmol), pyridin-4-ylboronic acid (60 mg, 0.48 mmol), sodium bicarbonate (100 mg, 1.2 mmol), DME (2 mL), and water (2 mL). The heterogeneous mixture was stirred vigorously under a stream of nitrogen for 5 minutes before Pd(PPh3)4 was added and the vial was sealed under its Teflon cap. The reaction mixture was heated to 90° C. for 3.25 h before being transferred to a microwave vial and being microwaved to 150° C. for 5 minutes. The reaction mix was concentrated under reduced pressure and the residue was partitioned between methylene chloride and a saturated aqueous solution of ammonium chloride. The organic solution was washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the crude product was purified by column chromatography (3.5% MeOH/methylene chloride) Yield: 10.0 mg (8%). Method [1]: rt=1.136 min; MH+ 390.2. 1H-NMR (300 MHz, CD3OD) δ 8.71 (d, J=6.3 Hz, 1H), 8.60 (dd, J=4.6, 1.6 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.77 (dd, J=4.6, 1.6 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 6.58 (s, 1H), 3.94 (s, 2H), 2.45 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C.O>[CH:14]1([S:19][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: SC1CCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CSC1CCCC1
Temperature: 65 °C

Procedure:
Solid K2CO3 (9.01 g, 65.2 mmol) was added to a stirring solution of ethyl bromoacetate (5.16 mL, 46.6 mmol) and cyclopentanethiol (4.97 mL, 46.6 mmol) in DMF (25 mL). The resulting suspension was warmed at 65° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with hexanes (3×50 mL). The combined extract was washed with saturated brine (30 mL) and concentrated under vacuum to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.29 (t, J=7.1 Hz, 3H), 1.43-1.65 (m, 4H), 1.66-1.81 (m, 2H), 1.93-2.10 (m, 2H), 3.13-3.30 (m, 1H), 3.25 (s, 2H), 4.19 (q, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([CH3:13])=[CH:5][C:4]=1[OH:14].O[CH2:16][CH:17]=[C:18]([CH3:27])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:26])[C:23]([OH:25])=[O:24]>C1C=CC=CC=1>[C:23]([C:22]([CH3:26])=[CH:21][CH2:20][CH2:19][C:18]([CH3:27])=[CH:17][CH2:16][C:5]1[C:4]([OH:14])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]=1[CH3:13])([OH:25])=[O:24]
Reactant: COc1c(C)cc(O)c(OC)c1OC
Reactant: CC(=CCO)CCC=C(C)C(=O)O
Solvent: c1ccccc1
Product: COc1c(C)c(CC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Yield: 36.5 %

Procedure:
5 g of 2,3,4-trimethoxy-5-methylphenol was dissolved in 10 ml of benzene and 10 g of silica alumina was added thereto. 1.8 g of 8-hydroxy-2,6-dimethyl-2,6-octadienoic acid dissolved in 4 ml of benzene was added to the above solution. The obtained solution was heated to 40° to 50° C. for two hours to allow reaction. The reaction mixture was then filtered and the precipitate was washed with ethyl ether while the filtrate was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography with the use of ether/n-hexane as the eluent to give 1.3 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:31][C:32]([O:34][CH2:35]I)=[O:33])[CH2:28][CH2:29][CH3:30]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:35][O:34][C:32]([O:31][CH2:27][CH2:28][CH2:29][CH3:30])=[O:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCCOC(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCCCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 100.5 %

Procedure:
In the same manner as in Example 81, 223 mg of the title compound was prepared from 175 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 164 mg of (butan-1-yl)oxycarbonyloxymethyl iodide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8]1)([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[N:22]([C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28])=[N+:23]=[N-:24]>C1COCC1>[C:1]([O:5][C:6]([C@@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[N:22]=[N+:23]=[N-:24])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCC(=O)N1C(=O)c1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
A stirred solution of (2S)-5-oxo-proline tert-butyl ester (T. Kolasa and M. J. Miller, J. Org. Chem., 1990, 55, 1711-1721) (1.13 g, 6.13 mmol) in anhydrous THF (15 mL) was treated at −78° C. with LDA (9.19 mmol) and the reaction was stirred for 15min. A solution of 2-azidobenzoyl chloride (T. Okawa, T. Sugimori, S. Eguchi and A. Kakehi, Heterocycles, 1998, 47, 1, 375-382) (6.13 mmol) in anhydrous THF (5 mL) was then added dropwise and the reaction mixture was stirred at −78° C. for 1 h before being quenched with saturated aq.NH4Cl. The reaction was allowed to warm to room temperature and the organic layer was washed with saturated aq.NH4Cl, dried (MgSO4), filtered and evaporated to give an oil which was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound as a pale yellow oil (1.67 g, 82%): 1H NMR (400 MHz, CDCl3) δ 1.53 (9H, s), 2.14 (1H, m), 2.43 (1H, m), 2.55 (1H, m), 2.69 (1H, m), 4.79 (1H, dd, J 9.2, 3.2 Hz), 7.19-7.22 (2H, m), 7.36 (1H, m), 7.49 (1H, m). 13C NMR (100 MHz, CDCl3) δ 22.1 (CH2), 28.3 (CH3), 31.9 (CH2), 59.3 (CH), 83.0 (C), 118.7 (CH), 125.0 (CH), 127.9 (C), 129.1 (CH), 131.9 (CH), 137.9 (C), 167.5 (C), 170.2 (C), 173.6 (C).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,5-dichlorophenylboronic acid according to the coupling protocol of example 1. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.16 (dd, J=8.7, 2.3 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.84 (m, 1H), 6.82 (m, 2H), 3.28 (s, 3H), 2.00 (m, 2H), 1.92 (m, 2H), 0.82 (t, J=7.4 Hz, 6H); MS (ESI) m/z 379/381/383 ([M+H]+); MS (ESI) m/z 377/379/381 ([M−H]−); Anal. calcd for C19H20C12N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 60.10; H, 5.26; N, 7.26.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]1=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c([N+](=O)[O-])cc(Br)cn1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A solution of 5-bromo-3-nitro-pyridin-2-ol (5.0 g, 22.8 mmol) and K2CO3 (9.5 g, 3 equiv., 69 mmol) in DMF (25 mL) was treated with benzyl bromide (4.3 g, 1.1 equiv., 25 mmol) and heated to 50° C. After stirring overnight, the solution was poured into water (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (30-40% ethyl acetate in heptane) afforded 1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one as a yellow solid (5.56 g, 79%).
Reaction SMILES: [CH2:1]([C@H:16]([NH2:20])[C:17]([OH:19])=[O:18])[CH2:2][C:3]([NH:5][C@H:6]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:7][SH:8])=[O:4].[N:21]([O-])=[O:22].[Na+].CC(C)=O>O.Cl>[N:21]([S:8][CH2:7][C@@H:6]([C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[NH:5][C:3](=[O:4])[CH2:2][CH2:1][C@@H:16]([C:17]([OH:19])=[O:18])[NH2:20])=[O:22]
Reactant: O=N[O-]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 76 %

Procedure:
1.53 g (5 mmol) L-glutathione (GSH) was dissolved in a mixture of 5.5 ml water and 2.5 ml (2 N) aqueous HCl solution cooled in ice bath, then 0.345 g (mmol) sodium nitrite was added. The mixture was stirred for 40 min at 5° C., then 10 ml acetone was added and the solution was stirred for further 10 min. The precipitated brown deposit was filtered and subsequently washed with ice-cold water (5×1 ml), acetone (3×10 ml) and ether (3×10 ml). Thus 1.29 g (3.8 mmol) of S-nitrosoglutathione was obtained (76% yield).