Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([CH2:15][OH:16])[N:9]=2)([CH2:3][CH3:4])[CH3:2]>C1COCC1.O=[Mn]=O>[CH:1]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([CH:15]=[O:16])[N:9]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1nc2ccc(CO)nc2s1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCC(C)Nc1nc2ccc(C=O)nc2s1
Reaction time: 1 h

Procedure:
To a solution of (2-(sec-butylamino)thiazolo[5,4-b]pyridin-5-yl)methanol (0.1155 g, 0.487 mmol, 1.0 eq.) in THF (3.5 mL) under nitrogen was added MnO2 (0.6357 g, 7.3 mmol, 15.0 eq.). After 1 hr, the reaction solution was filtered through Celite and rinsed with THF. The filtrate was concentrated in vacuo to give crude 2-(sec-butylamino)thiazolo[5,4-b]pyridine-5-carbaldehyde as a colorless oil which was carried to the next step without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1.CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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.[Pd]>[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[CH2:2]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CN(c2ccc(C(F)(F)F)cn2)CCO1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
tert-Butyl morpholin-2-ylmethylcarbamate (1.0 g, 4.62 mmol), 2-chloro-5-(trifluoromethyl)pyridine (839 mg, 4.62 mmol), Pd(dba)2 (133 mg, 0.23 mmol), sodium tert-butoxide (533 mg, 5.55 mmol) and X-Phos (220 mg, 0.46 mmol) were combined in toluene (10 mL). The mixture was degassed with nitrogen for 5 minutes and sealed. The resulting mixture was stirred at 100° C. for 12 h. The mixture was filtered and rinsed with THF. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (0% to 35% ethyl acetate in hexanes) to give the desired compound as a light brown waxy material (350 mg, 21%). [MH]+=362.1.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].Cl>CCO.O>[O:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCBr
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 75.7 %

Procedure:
Phenol (1.88 g, 20 mmol) was mixed with NaOH (0.80 g, 20 mmol) in EtOH (50 mL). 8-Bromooctanoic acid (2.23 g, 10 mmol) was then added to the mixture and refluxed for 12 h. After cooling to room temperature, water (100 mL) was added and the mixture was acidified with 2N HCl (pH=2). The solid was filtered and washed with water (2×50 mL), and recrystallized from hexane-ethyl acetate (5:1) to give the product as white brick-like crystals (1.79 g, 76%), mp 67°-68° C.; 1H-NMR: 1.42 (m, 6H), 1.65 (m, 2H), 1.80 (m, 2H), 2.37 (t, 2H), 3.97 (t, 2H), 6.93 (m, 3H), 7.30 (t, 2H), 10.05 (bs, 1H). Anal. Calcd. for C14H20O3 : C, 71.16, H, 8.53%; Found: C, 71.09, H, 8.54%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:25].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[CH3:25][C:6]1[CH:7]=[C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1cccc2nc(-c3cc(C)c(OCCBr)c(C)c3)[nH]c(=O)c12
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cccc2nc(-c3cc(C)c(OCCN4CCCC4)c(C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5-methoxy3H-quinazolin-4-one (0.50 g, 1.20 mmol) in N,N-dimethylformamide (10 mL) was added pyrrolidine (0.53 g, 7.40 mmol) and the reaction mixture was stirred at room temperature for 15 hours. DMF was removed under reduced pressure, the residue was purified by column chromatography (silica gel 230-400 mesh; 5% methanol in dichloromethane as eluent) to give the title compound as a white solid. Yield: 0.25 g (52%). MP 157-158° C. 1H NMR (400 MHz, DMSO-d6): 11.95 (s, 1H), 7.89 (s, 2H), 7.70 (t, J=8.19 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 3.91-3.89 (m, 2H), 3.87 (s, 3H), 2.82 (t, J=6.2 Hz 2H), 2.53-2.50 (m, 4H), 2.30 (s, 6H), 1.69 (m, 4H). MS (ES+) m/z: 394.61 (M+1).
Reaction SMILES: [Br-].[CH:2]1([CH2:8][Zn+])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1COCC1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32](Br)[N:31]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH2:8][CH:2]5[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]5)[N:31]=4)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: [Zn+]CC1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(CC2CCCCC2)n1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a 0.5 M solution of (cyclohexylmethyl)zinc(II) bromide in THF (0.8 mL, 0.4 mmol) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol) and the reaction was stirred under nitrogen for 20 minutes. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide (36 mg, 0.1 mmol) was added and the reaction was irradiated in the microwave for 10 minutes at 150° C. The reaction was quenched with a saturated ammonium chloride solution (2 mL) and a saturated ethylenediamine tetraacetic acid disodium salt solution (2 mL). The mixture was stirred for 30 minutes before it was extracted with dichloromethane (3×4 mL). The organics were dried over Na2SO4 and evaporated. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product (20 mg, 0.05 mmol, 50%). ESI-MS m/z calc. 378.19. found 379.1 (M+1)+; retention time 3.55 minutes.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6](I)[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2].[CH3:17][C:18]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([CH:17]=[CH2:18])[C:5]=1[O:14][CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1c(C#N)c(Cl)cc(C(C)=O)c1OCC
Temperature: 80 °C

Procedure:
A mixture of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (1.3 g, 3.6 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (740 μL, 4.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (100 mg, 0.20 mmol) and potassium carbonate (1.5 g, 11 mmol) in 1,4-dioxane (20 mL) and water (10 mL) was heated at 80° C. overnight. The mixture was cooled to room temperature and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification on silica gel using ethyl acetate in hexanes (0-20%) gave the desired compound, 780 mg, 87%. LCMS calculated for C13H13ClNO2 (M+H)+: m/z=250.1; found: 250.1. 1H NMR (400 MHz, DMSO-d6): δ 7.78 (s, 1 H), 6.83 (m, 1 H), 6.10 (m, 1 H), 5.83 (m, 1 H), 3.84 (m, 2 H), 2.58 (s, 3 H), 1.22 (m, 3 H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([O:18][C:19]([C@:21]1([N:34]=[N+:35]=[N-:36])[C@@H:26](O)[CH2:25][C@@H:24]2[C@H:22]1[C@@:23]2([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:20])[CH3:17].N1C=CC=CC=1.C(OCC)C>ClCCl>[CH2:16]([O:18][C:19]([C@:21]1([N:34]=[N+:35]=[N-:36])[C@@H:26]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH2:25][C@@H:24]2[C@H:22]1[C@@:23]2([F:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](O)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](N=[N+]=[N-])(C(=O)OCC)[C@@H]21
Temperature: -77 °C
Reaction time: 0.5 h

Procedure:
0.36 mL of trifluoromethane sulfonic acid anhydride dissolved in 1.2 mL of dichloromethane was added dropwise to 364 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 6.1 mL of dichloromethane and 0.21 mL of pyridine at −77° C. to −69° C., under a nitrogen atmosphere. The mixture was stirred for 30 minutes at −77° C., and further stirred for 30 minutes at ice-cooling. 30 mL of diethyl ether was added thereto, and after the solids were filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 487 mg of (1R,2R,3S,5R,6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]1[CH2:15][C@@H:14]([CH2:16][O:17][Si](C(C)C)(C(C)C)C(C)C)[C@H:13]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=O)=[CH:30][CH:29]=2)[C@@H:12]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]3[O:48][CH2:47][C:46](=O)[N:45]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:44]=3[CH:55]=2)[CH2:11]1)=O)(C)(C)C.[CH2:56]1[CH2:60][O:59][CH2:58][CH2:57]1>O>[CH2:60]([O:59][C@H:58]([CH3:57])[CH2:37][O:36][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:13]2[C@@H:12]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]4[O:48][CH2:47][CH2:46][N:45]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:44]=4[CH:55]=3)[CH2:11][NH:10][CH2:15][C@H:14]2[CH2:16][OH:17])=[CH:29][CH:30]=1)[CH3:56]
Reactant: C1CCOC1
Reactant: COCCCN1C(=O)COc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H]3c3ccc(C(=O)OC)cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4.30 mmol of NaOH are added to a solution of 1.05 mmol of (3R,4R,5S)-4-(4-methoxycarbonyl-phenyl)-3-[4-(3-methoxy-propyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-5-triisopropylsilanyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester in 10 ml of THF and 10 ml of H2O. The resulting reaction mixture is stirred at 90° C. for 16 h and then cooled to RT. After dilution with H2O and acidification (pH 3) with 4N aqueous HCl, the mixture is extracted with TBME (2×)—the combined organic phases are washed with brine, dried over Na2SO4 and concentrated by evaporation. The crude title compound is obtained as a viscous brown oil. Rf=0.24 (EtOAc/heptane 2:1+a drop of formic acid); Rt=6.71 (gradient I).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl.Cl.[N:15]1([C:21]2[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=2)[CH2:20][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CCOC(=O)COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccc(OCC(=O)OCC)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 2-[4-(1-piperazinyl)phenoxy]acetate dihydrochloride as starting raw materials, to produce ethyl 2-[4-[4-((E)-2-decenoyl)piperazin-1-yl]phenoxy]acetate (ethyl ester of Compound 47).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C:3]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]=2[Si](CC)(CC)CC)([OH:9])[CH2:5][CH2:4]1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][N:2]([CH3:1])[C:3]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(c2ccccc2)(N(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(O)(CCCc2c[nH]c3ccccc23)CC1
Reaction time: 6 h
Yield: 11.8 %

Procedure:
A solution of 4-dimethylamino-4-phenyl-1-[3-(2-triethylsilanyl-1H-indol-3-yl)propyl]cyclohexanol (852 mg, 1.8 mmol) in absolute tetrahydrofuran (50 mL) was mixed with tetra-n-butyl ammonium fluoride trihydrate (1.66 g, 5.3 mmol), stirred 6 h with reflux, then stirred over the weekend at 50° C. and then concentrated to low volume in a vacuum. The residue was purified by means of flash chromatography (38 g, 20×2.5 cm) with ethyl acetate/methanol (9:1). 80 mg of the title compound were obtained that were stirred overnight with cyclohexane (20 mL). 406 mg of the target compound were also obtained, which contained still larger amounts of impurity. This mixture was purified once again by flash chromatography (38 g, 20×2.5 cm), in which case cyclohexane/ethyl acetate (4:1) was firstly used as mobile solvent. All fractions that contained the target compound were treated with cyclohexane as above.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]3[O:19][N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])[N:25]=3)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(-c3c(C)noc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (132 μL; 1.56 mmol; 3 eq.), Intermediate 30 (120 mg; 0.52 mmol; 1 eq.), Intermediate 1 (86 mg; 0.52 mmol, 1 eq.) and DIEA (268 μL; 1.56 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) afforded the title compound as an orange foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.C(N(CC)CC)C.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C1C=CC=CC=1.[Cu]I>[CH3:11][S:8]([C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cccc(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(S(C)(=O)=O)c1
Temperature: 70 °C
Yield: 95 %

Procedure:
To a solution of 0.23 g (1 mmol) of 1-bromo-3-methanesulfonyl-benzene in benzene (2 mL) was added 40 mg (0.1 mmol) of PdCl2(Ph3P)2, 30 mg (0.1 mmol) CuI, triethylamine (1 mL) and 0.3 mL of ethynyl-trimethyl-silane. The reaction mixture was heated at 70° C. for 3 h After removal of solvent, the residue was purified by column chromatography elution with hexanes/ethyl acetate (v/v=7:1 then 5:1) to give 0.24 g (95%) of (3-methanesulfonyl-phenylethynyl)-trimethylsilane. 1H NMR (CDCl3, 400 MHz): δ 8.4 (s, 1H), 7.88 (d, 1H), 7.70 (d, 1H), 7.52 (dd, 1H), 3.05 (s, 3H), 0.27 (s, 9H) ppm.
Reaction SMILES: [OH:1][C:2]1[C@@H:3]([C@@H:9]([OH:12])[CH2:10][OH:11])[O:4]C(=O)C=1O.[OH:13]O>>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:9]([CH2:10][OH:11])[OH:12])[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: OO
Product: O=C(O)[C@H](O)[C@@H](O)CO

Procedure:
Under pH 6-10, preferably at pH 7-9, vitamin C was oxidized by oxidant, for example, by hydrogen peroxide solution to get a solution of L-threonic acid,
Reaction SMILES: [CH:1]1([CH:4]([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH3:5])[CH2:3][CH2:2]1.O[C:12]([CH3:27])([CH2:25][CH3:26])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]>>[CH3:27][C@@:12]([O:9][C:8](=[O:10])[CH2:7][O:6][CH:4]([CH:1]1[CH2:3][CH2:2]1)[CH3:5])([CH2:25][CH3:26])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]
Reactant: CC(OCC(=O)O)C1CC1
Reactant: CCC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Product: CC[C@@](C)(OC(=O)COC(C)C1CC1)C(=O)c1ccc(S(C)(=O)=O)cc1

Procedure:
The title compound was prepared as described in Example 134 Step 2 using (1-cyclopropylethoxy)acetic acid and 2(R) 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)butan-1-one from Example 117, Step 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:35]([CH3:37])[CH3:36])[CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:20][CH:19]=1.[ClH:38]>CCOCC>[ClH:38].[CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:35]([CH3:37])[CH3:36])[CH2:25][NH:26][CH3:27])=[CH:20][CH:19]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CN(C)C(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: CNCC(c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1)C(C)C
Yield: 47 %

Procedure:
Following General Procedure D1, tert-butyl 2-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)-3-methylbutyl(methyl)carbamate (100 mg, 0.2 mmol) was reacted with HCl in ether (8 mL) to afford the desired product (40 mg, 47%) as an off-white solid: ESI MS m/z 421 [C25H28N2O2S+H]+
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[S:10][C:9]=12)=[O:2].[CH3:38]I>CN(C=O)C.C1COCC1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Pd]>[CH:1]([NH:3][CH2:4][C:5]1[N:6]([CH3:38])[CH:7]=[N+:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:2]
Reactant: CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3c[n+]4cn(C)c(CNC=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 134 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-formylaminomethyl imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 2 ml of DMF was added 1.6 ml of methyl iodide, and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure. The residue thus obtained was dissolved in 5 ml of THF and 5 ml of 0.1 M sodium phosphate buffer (pH 6.8), and 150 mg of 10% Pd-C. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 1 hour. The catalyst was collected by filtration, and washed with a mixed solution of 2 ml of 0.1 M sodium phosphate buffer (pH 6.8) and 2 ml of THF. The filtrate was washed with 10 ml of ethyl acetate, and the aqueous layer obtained was purified by column chromatography on COSMOSEAL 40C18-PREP (water:methanol=20:1). The fraction containing the aimed product was concentrated under reduced pressure, and then lyophilized to give 58 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43]N=1)C.O>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)CCCCCCCCCCCCC>[C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:25][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:23][O:24][CH2:41][CH2:46][CH2:45][CH2:44][CH2:43][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:6][CH2:7][CH2:28][CH3:29])=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1ccccn1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(O)CO)cc1)C(=O)OC(C)(C)C
Agent: CCCCCCCCCCCCCCCl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of (4-(6,7-dihydroxy-4-thiaheptanoylamino)benzoyl)glutamic acid di-t-butyl ester as obtained in Reference Example 6 (50 mg) in chloroform (1 ml), triethylarnine (0.258 ml), myristyl chloride (0.196 ml) and dimethylaminopyridine (1 mg) were added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (76 mg, yield 85%) as a wax-like substance.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.[CH3:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([NH2:54])(=[O:53])=[O:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[CH:16][N:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH:54][S:51]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[CH3:44])(=[O:53])=[O:52])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cn1ccc2ccc(CC(=O)NCC3CCCC3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cn1ccc2ccc(CC(=O)NCC3CCCC3)cc21
Yield: 75.7 %

Procedure:
A solution of 4-[6-(cyclopentylmethylcarbamoyl)methylindol-1-ylmethyl]-3-methoxybenzoic acid (0.60 g), 4-dimethylaminopyridine (0.18 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.33 g), and 2-methylbenzenesulfonamide (0.25 g) in methylene chloride (70 ml) was stirred under a nitrogen atmosphere for 80 hr. The mixture was diluted with methylene chloride, washed with 10% v/v hydrochloric acid and water, and evaporated. The resulting white solid was precipitated from methylene chloride with hexane to give the title compound (0.62 g, 76%) as a white solid: mp 187°-188°.