Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C1(N=C=NC2CCCCC2)CCCCC1.[C:23](O)(=[O:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:23](=[O:35])[CH2:24][C:25]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[C:27]([O:28][CH3:29])[CH:26]=1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: COC(CN)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)NCC(OC)OC)cc1OC

Procedure:
To a cooled solution of aminoacetaldehyde dimethylacetal (21 g., 0.2 mole) and dicyclohexylcarbodimide (42.5 g., 0.205 mole) in 500 ml. of methylene chloride was added homoveratric acid (39.2 g., 0.2 mole) portionwise with cooling and stirring. After the addition was completed, the reaction mixture was stirred at room temperature for 1/2 hour, kept in refrigerator overnight and filtered. The filtrate was evaporated to dryness to give an oil which was chilled to form the solid N-(2,2-dimethoxyethyl)-3,4-dimethoxyphenylacetamide, m.p. 60°-63° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH3:34])([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=1)[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:18])[CH3:19])[O:11][C:10]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)([CH3:34])[CH2:9][C:8]2=[O:35])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)CC(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2=O

Procedure:
12.3 g of 6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chroman-4-one (prepared as described in Preparation 19) were dissolved in a mixture of 200 ml of methanol and 20 ml of benzene, and then catalytically reduced for 6 hours at room temperature, in the presence of 2.4 g of 10% w/w palladium-on-carbon, under 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, eluted with a 4:1 by volume mixture of benzene and ethyl acetate, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]([CH2:14][CH3:15])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]([CH2:14][CH3:15])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CCC(C)Nc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)Nc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
6-Amino-9-benzyl-2-(sec-butylamino)purine (58 mg, 0.20 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (57 mg, yield 78%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]([CH3:24])[N:6]=1>O1CCCC1.O>[CH3:24][C:7]1[N:6]=[C:5]([S:2][CH3:1])[CH:10]=[C:9]([Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(Cl)nc(C)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.8 %

Procedure:
Sodium thiomethoxide (140 mg, 2 mmol) was added to 4-chloro-2-methyl-6-(tributylstannyl)pyrimidine (835 mg, 2 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange oil. The crude product was purified by silica gel chromatography, eluting with 5% EtOAc/hexanes to give 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (256 mg, 30% yield). 1H NMR (300 MHz, CDCl3) δ 7.07 (s, 1H); 2.62 (s, 3H); 2.51 (s, 3H); 1.44-1.70 (m, 6H); 1.21-1.42 (m, 6H); 0.98-1.21 (m, 6H); 0.91 (t, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16](=[N:24]O)[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C.O1CCCC1>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH:16]([NH2:24])[C:15]=4[CH:14]=[CH:13][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc12
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc12
Yield: 70.5 %

Procedure:
The procedure used in Example 6 is followed, but starting from 4 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, and 0.7 g of Raney nickel in 100 ml of ethanol and 100 ml of tetrahydrofuran for 10 hours at 60° C. under an initial hydrogen pressure of one bar. After filtration of the catalyst, and then purification by formation of a paste in diisopropyl ether, in this way we obtain 2.7 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder which is used as it is in the following stage.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=[O:14])[CH2:4][C:5]([NH:7]C1C=CC=CC=1)=[O:6].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.O>C1(C)C(C)=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[C:4]([C:3](=[O:14])[CH:2]([CH3:15])[CH3:1])[C:5]([NH2:7])=[O:6])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)C(=O)C(=Cc1ccc(OCc2ccccc2)cc1)C(N)=O

Procedure:
Step A—A solution of 4-methyl-N-phenyl-3-oxopentanamide, 12, (5 mmol), 4-benzyloxybenzaldehyde (5 mmol) and pyridine (1 mL) in xylene (100 mL) is heated at reflux, with azeotropic removal of water. The progress of the reaction is monitored by tlc. When the reaction is complete, the solvent is removed under reduced pressure, and the residue is chromatographed to afford 2-(4-benzyloxyphenylmethylene)-4-methyl-3-oxopentanamide, 13, (R=4-benzyloxy).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[C:13]([CH3:25])[C:12]([CH:26]=[CH2:27])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[Pd+2].[OH-].CO>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:25])[C:12]([CH2:26][CH3:27])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)OCc2ccccc2)c1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(NC(=O)OC(C)(C)C)c(C(=O)O)c1C

Procedure:
A mixture of Example 145A (450 mg, 1.2 mmol), palladium hydroxide (540 mg), and methanol (150 mL) was heated to 50° C. in a Paar shaker under 65 psi hydrogen pressure for 72 hours. The mixture was filtered, concentrated, and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40 mL/min to provide the desired product. MS (ESI(+)) m/e 280 (M+H)+, 297 (M+NH4)+, 302 (M+Na)+; (ESI(−)) m/e 278 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.28 (br s, 1H), 8.35 (s, 1H), 7.32 (d, 1H), 7.17 (d, 1H), 2.58 (q, 2H), 2.24 (s, 3H), 1.43 (s, 9H), 1.12 (t, 3H).
Reaction SMILES: [Si](O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC=C2[C@H](O)C)C[C@@H](O[Si](C(C)(C)C)(C)C)C1)(C(C)(C)C)(C)C.CC(C)([O-])C.[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.O1[C@H](C(C)C)C1.[Si]([O:84][C@@H:85]1[C@@:110]2([CH3:111])[C:89](=[CH:90][CH:91]=[C:92]3[C@@H:109]2[CH2:108][CH2:107][C@@:106]2([CH3:112])[C@H:93]3[CH2:94][CH:95]=[C:96]2[C@H:97]([O:99][CH2:100][C@H:101]([OH:105])[CH:102]([CH3:104])[CH3:103])[CH3:98])[CH2:88][C@@H:87]([O:113][Si](C(C)(C)C)(C)C)[CH2:86]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C1(C)C=CC=CC=1>[OH:84][C@@H:85]1[C@@:110]2([CH3:111])[C:89](=[CH:90][CH:91]=[C:92]3[C@@H:109]2[CH2:108][CH2:107][C@@:106]2([CH3:112])[C@H:93]3[CH2:94][CH:95]=[C:96]2[C@H:97]([O:99][CH2:100][C@H:101]([OH:105])[CH:102]([CH3:104])[CH3:103])[CH3:98])[CH2:88][C@@H:87]([OH:113])[CH2:86]1
Reactant: CC(C)[C@@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)[O-]
Agent: CC(C)[C@@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[C@@H](O)CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 61.7 %

Procedure:
Using 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (69.7 mg, 0.125 mmol), potassium t-butoxide (170 mg, 1.52 mmol), dibenzo-18-crown-6(22.0 mg, 0.0610 mmol), toluene (4 ml) and (R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1.24 mmol), alkylation reaction (109° C., 1 hour) and work up were performed by the same procedure as in Example 119, and then the residue was separated by preparative thin layer chromatography (0.5 mm×3, hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) to give a fraction containing 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene (23.6 mg). An aliquot of 21.1 mg was deprotected with tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.2 ml) (reaction temperature 76° C., reaction period 13 hours) and worked up by the same procedure as in Example 119, and then the residue was purified by preparative thin layer chromatography (0.25 mm×1, dichloromethane:ethanol =15:1, developed twice) to give the title compound as a colorless oil (9.4 mg, 20%).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[CH:8][N:7]=1)[CH3:5])=[O:2].[OH-].[Na+].Cl.[O-]C#[N:19].[Na+]>C(Cl)(Cl)Cl.CO>[NH:3]([C@@H:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[CH:8][N:7]=1)[CH3:5])[C:1]([NH2:19])=[O:2]
Reactant: C[C@@H](NC=O)c1ncc2sccn12
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@@H](NC(N)=O)c1ncc2sccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
To 0.234 g of 5-[(R)-1-(formylamino)ethyl]imidazo[5,1-b]thiazole (Preparation 18) was added 3 ml of an aqueous solution of 2N sodium hydroxide, and the mixture was stirred at room temperature for 16 hours. After the reaction mixture was adjusted to pH 5 with 5N hydrochloric acid and heated to a temperature of 70° C., 0.160 g of sodium cyanate was added and the resulting mixture was stirred at 70° C. for 1 hour and at room temperature for further 16 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with 50 ml of methylene chloride and 50 ml of methanol to stir well the mixture before removal of insolubles by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified on Sephadex LH20 (eluent: chloroform-methanol=1:1) to give 0.221 g of the title compound (yield 87%). NMR (DMSOd-6) δ: 1.45 (3H, d, J=6.9 Hz), 5.13 (1H, dq, J8.7 Hz, 6.9 Hz), 5.52 (2H, br), 6.45 (1H, d, J=8.7 Hz), 6.92 (1H, s), 7.20 (1H, d, J=4.2 Hz), 7.80 (1H, d; J=4.2 Hz).
Reaction SMILES: C([O:4][C:5]1[CH:20]=[CH:19][C:8]([CH:9]=[CH:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:7][CH:6]=1)(=O)C.Cl>CO.O1CCOCC1>[F:18][C:13]1[CH:12]=[C:11]([CH:10]=[CH:9][C:8]2[CH:19]=[CH:20][C:5]([OH:4])=[CH:6][CH:7]=2)[CH:16]=[C:15]([OH:17])[CH:14]=1
Reactant: CC(=O)Oc1ccc(C=Cc2cc(O)cc(F)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Oc1ccc(C=Cc2cc(O)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A 1 M solution of BBr3 (9 ml, 9 mmol) in CH2Cl2 was added to a well-stirred solution of 5-benzyloxy-3-fluoro-4′-acetoxystilbene (1.09 g, 3 mmol) in dry CH2Cl2 (120 mL) at −78° C. The mixture was warmed to −20° C. and stirred for 10 minutes. Then MeOH was added at −78° C. The mixture was washed with saturated NaHCO3, and water, dried over Na2SO4, filtered and evaporated. The 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 61%) was obtained as white solid. To a solution of the crude 4′-acetoxy-3-fluoro-5-hydroxystilbene (0.50 g, 1.8 mmol) in MeOH (7.5 ml) was added 3.7 ml 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3-fluoro-5,4′-dihydroxystilbene (0.33 g, 780%) was obtained. Data are: 1H NMR (Aceton-d6, 300 MHz) δ 8.624 (s, 2H), 7.46 (m, 2H), 7.06 (q, 2H), 6.84 (m, 4H), 6.66 (dt, 1H); 13C NMR (Aceton-d6, 75 MHz) δ 164.90 (d), 159.96 (d), 158.57, 142.02 (d), 130.84, 129.63, 129.10, 125.55 (d), 116.53, 110.28 (d), 104.44 (d), 102.00 (d); 19F NMR (Aceton-d6, 282 MHz) δ-32429.72 (t); HRMS (EI+) found 230.0738, calcd 230.0743 for C14H, FO2.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10].[H-].[Na+].Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH:24]1([N:7]2[CH2:8][CH2:9][CH:5]([CH2:4][C:3]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=3[Cl:1])[C:6]2=[O:10])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1
Reactant: O=C1NCCC1Cc1ccc(Cl)cc1Cl
Reactant: BrC1C=CCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1C1C=CCCC1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
Charge a flask with 3-(2,4-dichloro-benzyl)-pyrrolidin-2-one (Preparation 19) (100 mg, 0.41 mmol), dissolve in THF (4 mL) and cool to 0° C. under nitrogen. Add NaH (15 mg, 0.61 mmol) and stir at 0° C. for 20 minutes. Add 3-bromo-cyclohexene (198 mg, 1.23 mmol) and stir at room temperature overnight. Pour into saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify residue over silica gel (5:1 hexanes:ethyl acetate) to afford 68 mg (51%) of the title compound as a white solid. Mass spectrum (apci) m/z=324.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:27][O:28][C:29]([NH:31][C:32](=NC(OC)=O)SC)=[O:30]>C(O)(=O)C.CO>[CH3:27][O:28][C:29]([NH:31][C:32]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[CH:3][C:2]=2[N:1]=1)=[O:30]
Reactant: Nc1ccc(OS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OCc4ccccc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-benzyloxy-benzenesulfonic acid 3,4-diamino-phenyl ester (134 mg) in acetic acid (0.83 ml) and methanol (2.5 ml) at 80° C. was added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (89 mg). The reaction mixture was refluxed for 2 hours then allowed to cool to ambient temperature and stirred at this temperature for 14 hours. The resultant precipitate was filtered, washed with diethyl ether and dried under vacuum to afford 4-benzyloxy-benzenesulfonic acid 2-methoxycarbonylamino-1H-benzoimidazol-5-yl ester as a beige solid. Mass spectrum: 454 [M+H]+; retention time=11.46 minutes.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12][C:13]1[C@H:14]([CH3:37])[C@@H:15]2[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])=[O:5])[CH3:2].C(=O)([O-])[OH:41].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:38]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:13]1[C@H:14]([CH3:37])[C@@H:15]2[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]2[C:17]=1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19])=[O:41])=[O:5])[CH3:39]
Reactant: CCN(CC)C(=O)c1ccccc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
10 ml of a methylene cloride solution containing 554 mg (1.00 mmol) of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 37) were cooled in an ice bath, and then 1.5 ml (1.5 mmol) of a 1M aqueous solution of sodium hydrogencarbonate and then 215 mg (1.00 mmol) of m-chloroperbenzoic acid (80% purity) were added, and the reaction solution was stirred for 90 minutes at the same temperature. An the end of this time, an aqueous solution of sodium sulfite was added to the reaction solution, and the mixture was stirred for 10 minutes to complete the reaction. The reaction solution was then diluted with methylene chloride, ice-cooled, washed with an aqueous solution of sodium hydrogencarbonate and condensed by evaporation under reduced pressure. The resulting residue was purified by column chromatography through 50 g of silica gel. Elution with ethyl acetate afforded 145 mg (yield 25%) of an isomer of the title compound of lower polarity (the isomer is a result of the configuration of the S-oxide), followed by 96 mg (yield 17%) of a higher polarity isomer of the title compound, both as foam-like solids.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16](=[O:31])[N:17]2[CH:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[CH2:20][CH:19]=[N:18]2)[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:6][C@@H:7]([C:16](=[O:31])[N:17]2[CH:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])[CH2:20][CH:19]=[N:18]2)[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccccc1
Reaction time: 4 h
Yield: 100.5 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(phenylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (386 mg, 0.90 mmol) in 1,4-dioxane (5.0 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (11.3 mL, 45.2 mmol) at room temperature. The reaction mixture was stirred for 4 hours. LCMS showed the reaction was complete. The solvent was removed by reduced pressure to afford (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(phenylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoic acid (336 mg, 100%), which was used directly in the next step.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:17](OCCC(C)C)=[O:18].CCOC(C)=O>C1COCC1.C1CCCCC1>[C:1]([C:5]1[NH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[C:8]([N:17]=[O:18])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cnc(C(C)(C)C)[nH]2)cc1
Reactant: CC(C)CCON=O
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2[nH]c(C(C)(C)C)nc2N=O)cc1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A yellow solution of Intermediate 51a (390 mg, 1.82 mmol) and isopentyl nitrite (0.294 mL, 2.18 mmol) in THF (10 mL) was stirred at 50° C. for 8 h, then cooled to RT and concentrated in vacuo to leave a dark green oil. FCC, using 0-25% EtOAc in cyclohexane, gave the title compound as a green solid (154 mg, 35%). LCMS (Method 3): Rt 3.82 min, m/z 244 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:21]4[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=4)=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)cc1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and p-tolyl isocyanate (32 μL, 0.25 mmol) in CH2Cl2 (5 mL) are reacted according to method C yielding the title product as a colorless solid.
Reaction SMILES: C([N:3](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:25]=[C:26]1[N:34]([C@@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:36])[CH2:33][C@@:32]2(C(O)=O)[C@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2>C1(C)C=CC=CC=1>[NH2:3][C@:32]12[CH2:33][N:34]([C@@H:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH3:36])[C:26](=[O:25])[C@@H:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2
Reactant: CCN(CC)CC
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)O)CC=CC[C@H]2C1=O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@]2(N)CC=CC[C@H]2C1=O
Yield: 83.7 %

Procedure:
Triethylamine (1.61 mL, 11.5 mmol) and diphenylphosphoryl azide (1.62 mL, 7.52 mmol) were added to a solution of [(1S,6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-en-1-yl]carboxylic acid (1.65 g, 5.78 mmol) in toluene (28.9 mL) in a nitrogen atmosphere with stirring under ice-cooling, and the mixture was stirred at 100° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and triethylamine was azeotropically distilled with toluene (×3). 1,4-Dioxane (14.4 mL) and 4 mol/L hydrochloric acid (14.4 mL) were added to the resulting residue, and the mixture was stirred at 50° C. for six hours. The reaction solution was diluted with water (30.0 mL) and washed with ethyl acetate (50 mL×2). A 1 mol/L sodium hydroxide solution (55.0 mL) was added to the aqueous layer, followed by extraction with chloroform (100 mL×1, 80 mL×1). The organic layer was washed with brine (150 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 1.24 g of the title compound as an amorphous.