Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[CH3:19][NH:20][C@H:21]([C:24]([OH:26])=[O:25])[CH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.CCCCCC.C(OCC)C>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([N:20]([CH3:19])[C@@H:21]([CH2:22][OH:23])[C:24]([OH:26])=[O:25])=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CN[C@@H](CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](CO)C(=O)O
Reaction time: 0.33 h

Procedure:
A solution of FmocCl (1.35 g, 5.21 mmol) in tetrahydrofuran (5 mL) was added to a solution of N-methyl-L-serine (Compound SP822) (621 mg, 5.21 mmol) and sodium carbonate (580 mg, 5.47 mmol) in tetrahydrofuran (15 mL)-water (20 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 20 minutes, followed by addition of diethyl ether (10 mL) and hexane (5 mL). The resulting mixture was extracted with water, and the aqueous layer was washed with ether (15 mL), followed by addition of concentrated hydrochloric acid (1 mL). The resulting mixture was extracted with ethyl acetate three times, and the organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (Compound SP823) (1.49 g, 84%).
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].[CH2:21](Cl)[CH:22]=[CH:23][CH3:24]>CN(C=O)C>[CH2:21]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)/[CH:22]=[CH:23]/[CH3:24]
Reactant: CC=CCCl
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/COC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Yield: 80.1 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (5.2 g, 20 mmol), sodium hydride (55% content, 1.31 g, 30 mmol), crotyl chloride (3.63 g, 40 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 5.05 g of the title compound as a colorless oily substance (80%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:15]1[N:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1cccc(CO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)c1cccc(C=O)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of DMSO (0.90 mL, 12.7 mmol) in dichloromethane (10 mL) at −78° C. was treated with oxalyl chloride (3.1 mL, 2 M in dichloromethane) dropwise, stirred for an additional 15 minutes at −78° C., treated with a solution of the product from Example 115E (0.88 g, 5.3 mmol) in dichloromethane (14 mL) over 10 minutes, stirred for 20 minutes, treated dropwise with triethylamine (3.6 mL, 26.1 mmol) at −78° C., stirred for 10 minutes, warmed to 0° C., stirred for an additional 10 minutes, quenched with water and partitioned between dichloromethane and water. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 5% ethyl acetate in chloroform to give the title compound (0.77 g, 88% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([C:16]([OH:18])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:32][NH2:33].O>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([C:16]([NH:32][NH2:33])=[O:18])=[CH:5][N:4]=1
Reactant: NN
Reactant: CSc1ncc(C(=O)O)c(OCC[Si](C)(C)C)n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(C(=O)NN)c(OCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carboxylic acid (9.73 g) obtained in Step 2 was dissolved in THF (100 mL), carbonyldiimidazole (5.5 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Then, hydrazine monohydrate (4.70 mL) was added dropwise to the reaction mixture, and the resulting mixture was stirred at room temperature for 2.5 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the mixture was dried under reduced pressure to give crude 2-methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carbohydrazide [Compound (E) in which R1 is 2-trimethylsilylethoxy].
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@H:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:32])[CH:3]=1.[N:33]1[NH:34][N:35]=[N:36][C:37]=1[CH2:38][NH2:39].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(#N)C>[Br:1][C:2]1[C:10]2[S:9][CH:8]=[C:7]([CH:11]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@H:12]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:39][CH2:38][C:37]4[N:33]=[N:34][NH:35][N:36]=4)=[O:21])=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH3:15])[C:6]=2[CH:5]=[C:4]([CH3:32])[CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(C)cc12
Reactant: NCc1nn[nH]n1
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@H](c1ccc(C(=O)NCc2nn[nH]n2)cc1)C(c1ccc(Cl)cc1)c1csc2c(Br)cc(C)cc12
Temperature: 65 °C

Procedure:
A mixture of 4-{(1S)-1-[(7-bromo-5-methyl-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoic acid (EXAMPLE 3, Step A, 20.0 mg, 0.038 mmol), 1-(2H-tetrazol-5-yl)methanamine (10.9 mg, 0.110 mmol), EDC (22.0 mg, 0.110 mmol), HOBt (17.0 mg, 0.110 mmol) and DIEA (0.050 mL, 0.29 mmol) in DMF (1 mL) was heated at 65° C. for 12 hours. The mixture was allowed to cool to RT, diluted with acetonitrile, then purified by preparative reverse-phase HPLC eluting with 38-100% acetonitrile/water+0.1% TFA. Following lyophilization, this afforded the title compound as a white solid. 1H NMR (500 MHz, d6-DMSO) δ 9.04 (br, 1H); 7.96 (s, 1H); 7.84 (s, 1H); 7.67 (d, J=8 Hz, 2H); 7.64 (d, J=8 Hz, 2H); 7.52 (d, J=8 Hz, 2H); 7.39 (d, J=8.5 Hz, 2H); 7.35 (br, 1H); 4.84 (d, J=11.5 Hz, 1H); 4.67 (d, J=5.5 Hz, 2H); 3.74 (t, J=12 Hz, 1H); 2.40 (s, 3H); 1.44-1.52 (m, 1H); 1.24-1.32 (m, 1H); 0.91 (q, J=7.5 Hz, 2H); 0.67 (t, J=7 Hz, 3H). LC2: 2.63 min. (M+H)+ 608.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[OH:8].[H-].[Na+].Cl[C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][C:21]=2[N:22]=1.O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[O:8][C:12]1[CH:13]=[CH:14][C:15]2[CH2:16][N:17]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:19][O:20][C:21]=2[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC1CCCCC1O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1CCCCC1Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
To a solution of 2-methylcyclohexanol (0.20 g) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-[(2-methylcyclohexyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.55 g, 86%) as a yellow oil.
Reaction SMILES: C([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[C:11]2[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31]C)[CH:26]=2)=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[OH:31][C:27]1[CH:26]=[C:25]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[N:15][C:16]=3[NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[NH:8][N:9]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(Nc4cccc(Cl)c4)c23)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Oc1cccc(-c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 0 °C

Procedure:
With the exclusion of air and moisture, a mixture of 44.2 mg (0.1 mmol) of 1-benzyl-4-(3-chloro-phenylamino)-3-(3-methoxy-phenyl)-pyrazolo[3,4-d]pyrimidine, 80 mg (0.6 mmol) of anhydrous aluminum chloride and 2 ml of toluene is heated under reflux for 2 hours. The reaction mixture is then poured into ice-water and extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium hydrogen carbonate in water and with brine, dried over sodium sulfate and concentrated by evaporation in vacuo. Purification of the residue by flash chromatography on silica gel (230-400 mesh) using methylene chloride and methylene chloride/methanol mixtures (19:1 and 17:3, respectively) yields the title compound; m.p. >220° C.; FAB-MS: (M+H)+ =338.
Reaction SMILES: [CH:1]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CBr.C([Li])CCC.[Si:27]([O:44][CH2:45][C@H:46]([CH3:49])[CH:47]=O)([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[Si:27]([O:44][CH2:45][C@@H:46]([CH3:49])[CH:47]=[CH2:1])([C:40]([CH3:42])([CH3:43])[CH3:41])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@H](C=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H](C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
Under argon atmosphere, Ph3P+CH3Br (2.2 g, 7.4 mmol) was suspended in 15 ml of THF, butyllithium (5.2 ml, 9.3 mmol) was added to the resultant solution at 0° C., and the mixture was stirred for 20 min. The treated mixture was added to a 15-ml THF solution of (S)-3-(t-butyldiphenylsilyloxy)-2-methylpropanal (49) (1.2 g, 3.7 mmol) at 0° C. The resultant mixture was stirred for 15 min and further for 45 min after the temperature was returned to room temperature. Then, the reaction mixture was extracted with ethyl acetate after the addition of a saturated ammonium chloride aqueous solution. The ethyl acetate layer was washed with brine, dried over magnesium sulfate, and evaporated. The crude product was purified by column chromatography (12 g, 2% AcOEt-hexane) to obtain a colorless oily product (50) (1.1 g, 92%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH2:24])[CH2:17][CH2:16][CH2:15][C:14]2=1>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]1[CH:18]([NH:24][C:7]([C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[O:9])[CH2:17][CH2:16][CH2:15][C:14]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: Cn1ccc(C(=O)O)n1
Product: Cn1ccc(C(=O)NC2CCCc3c2[nH]c2ccc(Cl)cc32)n1

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-1-methyl-1H-pyrazole-3-carboxamide was prepared from 1-methyl-1H-pyrazole-3-carboxylic acid and 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine in a similar manner as described above to give an off-white solid (20% yield). 1H-NMR (CDCl3): δ 8.95 (s, 1H), 7.43 (m, 1H), 7.37 (m, 1H), 7.22 (d, 1H), 7.07 (dd, 1H), 6.80 (m, 1H), 5.30 (m, 1H), 3.88 (s, 3H), 2.71 (m, 2H), 2.27 (m, 1H), 1.97 (m, 3H); MS m/z 327 (M−1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O.Br[CH2:43][CH2:44][CH2:45][CH2:46]Br>C(Cl)Cl>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([N:1]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cc(F)cc(F)c4)n3)c(Cl)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Fc1cc(F)cc(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N5CCCC5)CC4)ncc3Cl)n2)c1
Temperature: 60 °C

Procedure:
To a scintillation vial containing N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3,5-difluorobenzyl)-2,4′-bipyridine-2′,6-diamine (12.3 mg, 0.028 mmol) (obtained following example 2) and K2CO3 (15.32 mg, 0.111 mmol) was added DMSO (0.5 ml) and 1,4-dibromobutane (5.98 mg, 0.028 mmol). The reaction mixture was capped and heated at 60° C. for 7 hr. The reaction mixture was diluted with DCM and washed with H2O, sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC to yield 5′-chloro-N6-(3,5-difluorobenzyl)-N2′-(trans-4-(pyrrolidin-1-yl)cyclohexyl)-2,4′-bipyridine-2′,6-diamine (7.8 mg, 46.0%), LCMS (m/z): 498.3 (MH+), retention time=0.65 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.26-1.40 (m, 2H) 1.48-1.62 (m, 2H) 1.85-1.98 (m, 2H)1.99-2.24 (m, 7H) 2.99-3.14 (m, 4H) 3.51-3.68 (m, 3H) 4.54 (s, 2H) 6.69-6.80 (m, 3H) 6.81-6.90 (m, 3H) 7.60-7.69 (m, 1H) 7.94 (s, 1H).
Reaction SMILES: P(I)(I)P(I)I.[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:63][O:64][CH3:65])[C:33]([NH:35][CH:36]2[C:43](=[O:44])[N:42]3[CH:37]2[CH2:38][S:39][CH:40]([S:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([N+:60]([O-:62])=[O:61])[CH:55]=2)[C:41]3(O)[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:63][O:64][CH3:65])[C:33]([NH:35][CH:36]2[C:43](=[O:44])[N:42]3[CH:37]2[CH2:38][S:39][C:40]([S:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([N+:60]([O-:62])=[O:61])[CH:55]=2)=[C:41]3[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:34])[N:31]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C1CSC(Sc1cccc([N+](=O)[O-])c1)C2(O)C(=O)OC(C)(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: IP(I)P(I)I
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3cccc([N+](=O)[O-])c3)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
A suspension of 677 mg of diphosphorus tetraiodide in 7 ml of pyridine was stirred under an inert atmosphere for 5 minutes and then 780 mg of the product of Step A were added. The mixture was stirred for 2 hours and then a further 363 mg of diphosphorus tetraiodide were added. The stirring was maintained for 1 hour and the reaction mixture was poured into 50 ml of ethyl acetate and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was dissolved in methylene chloride. The organic phase was washed with 0.1N hydrochloric acid, then with water, dried and concentrated to dryness. The residue was chromatographed on silica and eluted with a mixture of chloroform and acetone (10-0.5) to obtain 348 mg of racemic 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(3-nitrophenylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate which crystallized from ether.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[C:11]([CH2:21][CH2:22][N+:23]([O-])=O)=[CH:12][C@H:13]2[C:18]([NH2:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](O)(=[O:28])[CH3:27].CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C>C(O)C.C(Cl)Cl.[Zn]>[C:26]([NH:23][CH2:22][CH2:21][C:11]1[C@@H:10]2[CH2:17][N:14]([C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:13]([C:18]([NH2:20])=[O:19])[CH:12]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)O
Reactant: NC(=O)[C@@H]1C=C(CC[N+](=O)[O-])[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-4-(2-nitroethyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 226, 0.300 g, 0.87 mmol) in ethanol (10 mL) was added zinc dust (1.416 g, 21.66 mmol) and acetic acid (1.984 mL, 34.65 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Then DIPEA (2.118 mL, 12.13 mmol) was added to reaction mixture followed by acetic anhydride (0.245 mL, 2.60 mmol). The reaction mixture was stirred for an additional 2 hours, then diluted with DCM, washed with saturated bicarbonate and concentrated to dryness. Flash chromatography, 0%-10% MeOH/DCM, afforded the title compound as a clear oil (0.31 g, 61%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]5)=[CH:35][CH:34]=4)[N:26]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][C:30]1[C:25]([NH:24][C:20]2[CH:19]=[C:18]([S:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:17])=[O:16])[CH:23]=[CH:22][CH:21]=2)=[N:26][C:27]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:40][CH2:41][N:42]([CH3:45])[CH2:43][CH2:44]3)=[CH:35][CH:34]=2)=[N:28][CH:29]=1
Reactant: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(S(=O)(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1Nc1cccc(S(=O)(=O)NC2CCNCC2)c1
Reaction time: 3 h

Procedure:
Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 mL) and treated with TFA (0.3 mL). After 3 h, reaction solvents removed and resulting residue was purified by HPLC (0.01 g, 6%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36])=[O:27]>CN(C)C=O.C(OCC)(=O)C>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[NH:28][C:26](=[O:27])[N:25]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][S:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Reactant: Sc1nc2ncccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCCCCSc1nc2cccnc2[nH]1)C(=O)Nc1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Part B. A 100 mL flask was charged with 2-mercaptoimidazo[4,5-b]-pyridine (0.65 g, 0.0043 mol), sodium iodide (0.129 g, 0.00086 mol), and potassium carbonate (0.789 g, 0.00571 mol) in N,N-dimethylformamide (15 mL). A solution of N-(5-bromopentyl)-N-heptyl-N'-(2,4-difluorophenyl)urea (2.34 g, 0.00558 mol) in N,N-dimethylformamide (20 mL) was added and the mixture was heated to 60° C. under nitrogen atmosphere for 18 hours, then cooled and poured into ethyl acetate (100 mL). The ethyl acetate solution was washed with water (3×100 mL), dried over magnesium sulfate and concentrated. Purification by flash chromatography of the resulting residue afforded the product, which solidified upon standing overnight. The residue was recrystallized to afford the title compound (2.13 g, 0.0043 mol) as a viscous oil. 1H NMR (CDCl3) δ8.27 (dd,1H,J=5.2, 1.4 Hz), 8.06-7.98 (m,1H), 7.91 (dd,1H,J=7.9, 1.3 Hz), 7.18 (dd,1H,J=7.9, 4.9 Hz), 6.84-6.76 (m,1H), 6.49 (d,1H,J=3.3 Hz), 3.41-3.24 (m,6H), 1.94-1.84 (m,2H), 1.74-1.51 (m,6H), 1.35-1.23 (m,8H), 0.88 (t,3H,J=6.6 Hz).
Reaction SMILES: [CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([OH:14])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>CN(C)C=O>[CH2:1]([C:5]1([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][C:12]2[C:7](=[C:8]([Cl:16])[C:9]([Cl:15])=[C:10]([O:14][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])[CH:11]=2)[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O

Procedure:
The starting material, 2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-1H-inden-1-one, dissolved in dimethylformamide was treated with potassium carbonate and trifluoromethanesulfonyl chloride to form (2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate (Step 1). This material was subjected to triflate displacement by reaction with diethyl malonate to form diethyl-5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)malonate (Step 2). The malonate of Step 2 was then alkylated with ethyl 4-bromobutyrate to form diethyl 2-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)-2-(ethoxycarbonyl)-1,6-hexanedioate (Step 3). Upon hydrolysis the hexanedioic acid is formed (Step 4) which undergoes monodecarboxylation by treatment with copper in quinoline to form a compound of the present invention such as 5-(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)pentanoic acid (Step 5). The starting materials used in these examples is obtained as shown in the Journal of Medicinal Chemistry, 20, 1400 (1977); and 21, 437 (1978). This synthetic route is illustrated below: ##STR3##