Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]=[C:23]4[N:27]([CH:28]=3)[C:26]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:32][C:25]=3[S:24]4)=[CH:17][CH:16]=2)=[O:13])[CH:7]=1)([CH3:5])[CH3:4].[NH4+].F[C@H:44]1[O:52][C@H:51]([C:53]([O-:55])=[O:54])[C@@H:49]([OH:50])[C@H:47]([OH:48])[C@H:45]1[OH:46]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[OH:50][CH:49]1[CH:47]([OH:48])[CH:45]([OH:46])[CH:44]([O:1][CH2:2][C:3]([CH3:4])([C:6]2[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[N:22]=[C:23]5[N:27]([CH:28]=4)[C:26]4[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH2:35][N:36]6[CH2:41][CH2:40][O:39][CH2:38][CH2:37]6)=[CH:32][C:25]=4[S:24]5)=[CH:17][CH:16]=3)=[O:13])[CH:7]=2)[CH3:5])[O:52][CH:51]1[C:53]([OH:55])=[O:54]
Reactant: O=C([O-])[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(C)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)(COC1OC(C(=O)O)C(O)C(O)C1O)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
3,4,5-Trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6) is prepared by following a general procedure given in Org. Lett. 2008, 10, 1585. To a stirred mixture of 1-[5-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1) (1 equivalent), 1-deoxy-1-fluoro-α-D-glucopyranuronic acid ammonium salt, prepared as described in Org. Lett. 2008, 10, 1585 (1.2 equivalents) in 50 mM sodium phosphate buffer (pH=7.5) at rt, is added E. coli. E504G β-glucuronylsynthase (final concentration 0.1-0.2 mg/mL) or E. coli. E504A β-glucuronylsynthase (final concentration 0.1-0.2 mg/mL) and the mixture is stirred at rt for 4 days. Lyophilization of the mixture and purification of the residue by preparative reverse-phase HPLC or silica gel flash chromatography affords 3,4,5-trihydroxy-6-{2-methyl-2-[3-(3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureido)-isoxazol-5-yl]-propoxy}-tetrahydro-pyran-2-carboxylic acid (I-6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.FC1C=C(B(O)O)C=C([CH:26]=[O:27])C=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH2:18][C:15]1[C:16]2[N:17]=[C:8]([C:4]3[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[CH:3]=3)[CH:26]=[O:27])[CH:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=Cc1cc(F)cc(B(O)O)c1
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2ccc(-c3cc(F)cc(C=O)c3)nc12
Temperature: 100 °C
Yield: 89.5 %

Procedure:
A suspension of 6-chloropyrido[3,2-d]pyrimidin-4-amine (1) (3.61 g, 20 mmol), 3-fluoro-5-formylphenylboronic acid (CAS 328956-60-1) (4.03 g, 24 mmol, 1.2 eq), Pd(PPh3)4 (1.16 g, 1.0 mmol, 0.05 eq), and K2CO3 (5.53 g, 40 mmol, 2.0 eq) in a mixture of dioxane (100 mL) and H2O (10 mL) was heated at 100° C. for 3 h. After it was cooled to r.t., the reaction was extracted with EtOAc (100 mL) and water (60 mL). The organic layer were washed with water and concentrated. The yellow solid was recrystallized in MeCN to give the titled product (4.8 g, yield: 90%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([OH:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCC(C)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of the product of Example 7A (505 mg, 2.447 mmol) in THF (19 mL) at 0° C. was added a 1M solution (in THF) of lithium aluminum hydride (12.2 mL, 12.237 mmol) dropwise. After completion of addition the ice bath was removed and the reaction was stirred at room temperature for 1 hour under nitrogen atmosphere. Then, in succession, was added water (183 μL), 15% NaOH solution (183 μL), and water (548 μL). The reaction stirred for an additional 15 minutes before it was filtered and washed with THF. The filtrate was then concentrated under reduced pressure to obtain 4-(4-hydroxymethyl-phenyl)butan-2-ol as a brown oil (314 mg, 71% yield). Then to a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (234 mg, 1.155 mmol) in THF (45 mL) was added 4-(4-hydroxymethylphenyl)butan-2-ol (312 mg, 1.732 mmol), triphenylphosphine (454 mg, 1.732 mmol), and then diisopropyl azodicarboxylate (DIAD, 335 μL, 1.732 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Thin layer chromatography (100% ethyl acetate) indicated consumption of the pyridazinone starting material and the reaction was concentrated. The crude material was purified by flash column chromatography (4:1 hexane:ethyl acetate to 100% ethyl acetate) to obtain a clear oil (200 mg, 48% yield). 1H NMR (600 MHz, CDCl3): δ 7.73 (s, 1H), 7.32 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 5.30 (s, 1H), 5.27 (s, 2H), 3.83 (m, 1H), 2.80-2.76 (m, 1H), 2.71-2.66 (m, 1H), 1.63 (s, 9H), 1.23 (d, 3H, J=6.2); 13C (CDCl3 159.3, 153.9, 143.2, 132.5, 129.2, 127.6, 125.4, 150 MHz): δ HRMS calcd for C, 118.5, 73.4, 67.6, 66.6, 40.9, 32.0, 28.1, 23.9.19H25ClN2O3: 365.162647, found 365.1624.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[N:13]([CH2:27][CH2:28][CH3:29])[CH2:12]1>C(Cl)Cl.C(N(CC)CC)C>[C:1]([NH:10][C@H:11]1[CH2:25][C@H:24]2[C@@H:14]([CH2:15][C:16]3[C:26]4[C:19](=[CH:20][CH:21]=[CH:22][C:23]2=4)[NH:18][CH:17]=3)[N:13]([CH2:27][CH2:28][CH3:29])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN1C[C@@H](N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1C[C@@H](NC(=O)c2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 20 °C
Reaction time: 17.5 h

Procedure:
1.4 ml benzoylchloride in 5 ml CH2Cl2 are added drop-wise with stirring at 5°-10° C. to a suspension of 3.0 g 8α-amino-6-n-propylergoline in 100 ml CH2Cl2 and 2.0 ml triethylamine. The obtained reaction mixture is stirred for 15 to 20 hours at 20° C. and then washed thoroughly 2× with 25 ml 2N NaOH and H2O. The organic phase is dried over MgSO4, filtered and evaporated. The residue (pale brown foam) is dissolved in ethanol, and crystallised as the hydrobromide by addition of equivalent amounts of HBr in acetic acid. M.P. on recrystallisation from C2H5OH/H2O (80:2)=290° with decomposition.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].Cl[CH2:23][CH:24]1[O:28][C:27](=[O:29])[NH:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:29]=[C:27]1[NH:26][CH2:25][CH:24]([CH2:23][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4=[CH:14][C:15]5[O:19][CH2:18][O:17][C:16]=5[CH:20]=[C:12]4[O:11][CH2:10]3)[C:2]2=[O:21])[O:28]1
Reactant: O=C1NCC(CCl)O1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCC(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)O1
Temperature: 25 °C
Reaction time: 11 h
Yield: 30.1 %

Procedure:
A mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (1.37 g, 4.89 mmol), 5-(chloromethyl)-1,3-oxazolidin-2-one (1.34 g, 5.38 mmol) and cesium carbonate (2.39 g, 7.34 mmol) in N,N-dimethylformamide (8.0 mL) was stirred at ambient temperature for 11 h and filtered. The solid was washed with ethyl acetate and the filtrate was washed with water (3×15 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography to afford 1′-[(2-oxo-1,3-oxazolidin-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1H)-one (0.56 g, 25%): mp 195-202° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.30 (m, 1H), 7.17-7.04 (m, 3H), 6.50 (s, 1H), 6.12 (s, 1H), 5.84 (s, 2H), 5.27 (br, 1H), 5.02-4.96 (m, 1H), 4.91-4.87 (m, 1H), 4.68-4.64 (m, 1H), 4.14-3.96 (m, 2H), 3.75-3.68 (m, 1H), 3.55-3.44 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.9, 158.5, 155.9, 149.0, 142.4, 142.2, 131.7, 129.4, 124.0, 123.9, 119.2, 109.6, 102.8, 101.6, 93.7, 80.3, 74.9, 58.1, 43.5, 43.1; MS (ES+) m/z 403.2 (M+23), 381.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[C:9]2=[O:16])=[CH:4][CH:3]=1.CO.[CH2:19]1COCC1.[N+](=C[Si](C)(C)C)=[N-]>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:19])=[O:14])[C:9]2=[O:16])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CCN(c2ccc(F)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.20 g, 0.90 mmol) in a mixture of Et2O (6 mL), MeOH (2 mL), and THF (2 mL) was added (diazomethyl)trimethylsilane (1.1 mL, 2.0 M) at 0° C. The resulting mixture was stirred for 30 minutes at room temperature, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, NaHCO3 solution (2×), and brine, dried over MgSO4, and concentrated under reduced pressure to give the desired product (0.206 g, 98%). LRMS (ESI pos) m/e 238.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[NH2-].[Na+].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([NH:21][C:7]1[CH:2]=[C:3]([O:10][CH3:11])[C:4]([CH3:9])=[C:5]([F:8])[CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COc1c(Cl)ccc(F)c1C
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(NCc2ccccc2)cc(F)c1C
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
To a −78° C. cooled solution of 1-chloro-4-fluoro-2-methoxy-3-methylbenzene (470 mg, 2.69 mmol) in THF (5.5 mL) was added sodium amide (95%, 276 mg, 6.72 mmol). After 30 minutes, the solution was warmed to −20 to −30° C. and then benzylamine (441 μL, 4.05 mmol) was added dropwise over 1 minute. The reaction was stirred overnight, and LCMS showed no starting material. The reaction was quenched by cooling in an ice bath followed by dropwise addition of saturated NH4Cl and water. After stirring for 1 hour, the reaction mix was extracted twice with ethyl acetate, and the combined organic phases dried over MgSO4 and concentrated via rotary evaporation. The crude product was purified by silica gel chromatography (0-30% ethyl acetate/hexanes) to yield a 223 mg (34%) of N-benzyl-3-fluoro-5-methoxy-4-methylaniline as an orange oil. 1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 6.06-6.00 (m, 1H), 6.00 (s, 1H), 4.29 (s, 2H), 3.74 (s, 3H), 2.00 (s, 3H); LCMS (m/z): 246 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.C([Li])CCC.[Br:16]C(Br)(Br)Br.[Cl-].[NH4+]>O1CCCC1>[Br:16][C:7]1[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][N:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: COCCCn1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCn1ccnc1Br
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The solution of 1.05 g of 1-(3-methoxypropyl)-1H-imidazole in 14 ml of tetrahydrofuran is cooled to −70° C. and admixed slowly with 4.6 ml of n-butyllithium (1.6M in hexane). The mixture is stirred at −70° C. over 1 hour and subsequently admixed slowly with the solution of 2.54 g of tetrabromomethane in 14 ml of tetrahydrofuran. After a further 30 minutes, the reaction mixture is admixed with 25 ml of saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine, (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.51 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=1.78.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH:8][C:10](=[O:12])[CH3:11])=[N:6][CH:7]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C)c(Br)cn1
Temperature: 110 °C

Procedure:
5-bromo-4-methylpyridin-2-amine (0.578 mmol) was dissolved in acetic anhydride (5.78 mmol) and heated at 110° C. for 30 minutes. The reaction was quenched with ice. The aqueous reaction mixture neutralized with sodium hydroxide solution was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over sodium sulfate. The organic layer was evaporated to dryness. The crude material was purified (silica column, MeOH/CHCl3). 1HNMR (300 MHz, DMSO-d6): 10.53 (s, 1H), 8.34 (s, 1H), 8.06 (s, 1H), 2.30 (s, 3H), 2.05 (s, 3H); MS (m/z): 231 (M+2)+.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O-].[Na+].[CH:36]([C:38]1[CH:47]=[CH:46][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:39]=1)=O>O1CCCC1>[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1/[CH:5]=[CH:36]\[C:38]1[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[CH:46][CH:47]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C\c2ccc(C(=O)OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 52.6 g of (2-chloro-4-methoxycarbonylbenzyl)-triphenylphosphonium bromide in 500 ml of tetrahydrofuran was treated at 0° C. with 115 ml of 2% methanolic sodium methylate solution. Then, a solution of 16.4 g of methyl 4-formylbenzoate was added dropwise within 10 minutes and the mixture was stirred at room temperature for 1 hour. The suspension was filtered over Dicalite and the filtrate was evaporated. The residue was chromatographed using ethyl acetate/hexane/methylene chloride and gave dimethyl (Z)-2-chlorostilbene-4,4'-dicarboxylate, MS: m/z 330 (M+), and dimethyl (E)-2-chlorostilbene-4,4'-dicarboxylate as colourless crystals, m.p. 134°-135° C., MS: m/z 330 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].CO>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1c(C2=CCOCC2)sc(C(=O)O)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a round bottom flask containing ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (43.0 mg, 0.111 mmol) were added tetrahydrofuran (1.23 mL, 15.2 mmol), sodium hydroxide (1.0N in water, 0.925 mL, 0.925 mmol), and methanol (0.617 mL, 15.2 mmol). The mixture was stirred at room temperature overnight. Reaction was quenched via addition of 1N HCl in water (2 mL), then diluted with EtOAc and transferred to separatory funnel. The layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organics were washed with brine, dried over Na2SO4, and filtered, at adsorbed to Celite (10 mL). Column chromatography (40 g ISCO column, gradient elution 0-8% MeOH/DCM afforded 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylic acid (95) (25 mg, 63%) as a white solid. LC/MS: (FA) ES− 358, 360; 1H NMR (400 MHz, DMSO) δ 14.04 (br s, 1H), 7.33 (d, J=8.5, 2H), 7.26 (d, J=8.5, 2H), 6.64 (s, 1H), 4.43 (s, 2H), 4.24 (d, J=2.9, 2H), 3.79 (dd, J=5.4, 5.4, 2H), 3.32 (br s, 2H).
Reaction SMILES: Cl[CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[O-].[K+]>O1CCCC1>[O:30]([CH:2]([C:15]1[CH:19]=[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCC(Cl)c1coc([Si](C)(C)C)c1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(Oc1ccccc1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(1-chlorotridecyl)-5-trimethylsilylfuran, phenol and potassium methoxide in tetrahydrofuran is stirred at room temperature to give 3-(1-phenoxytridecyl)-5-trimethylsilylfuran. A mixture of this intermediate and Rose Bengal in tetrahydrofuran is exposed to oxygen by the procedure of Example 1 to give 4-(1-phenoxytridecyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Cl:27][CH2:28][C:29]([C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[S:36][C:35]=12)=[O:30]>>[Cl:27][CH2:28][C:29]([C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[S:36][C:35]=12)=[O:30]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)CCl)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)CCl)c4s3)[C@H](C)[C@H]12
Yield: 54.7 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-(7-chloroacetylimidazo-[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (1.01 g) was prepared in the same manner as in step a) of Example 1, except that 2.85 g of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.66 g of 7-chloroacetyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23]C)=[C:17]([CH2:25][CH3:26])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH2:25][CH3:26])[C:18]([OH:23])=[C:19]([CH2:21][CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1O
Yield: 38.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-methoxy-phenyl)-methanone (19.3 g, 51.2 mmol) and 1M boron tribromide/CH2Cl2 (36.8 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2 & 5% EtOAc/hexane step gradient gave 7.07 g (37%) of the title compound. 1H NMR (DMSO-d6) δ1.08 (t, 6H), 1.79 (s, 3H), 2.17 (s, 3H), 2.57 (q, 4H), 3.81 (s, 2H), 7.06 (dd, 2H), 7.16-7.18 (m, 1H), 7.22-7.26 (m, 2H), 7.37 (s, 2H), 9.10 (s, 1H). mass spectrum (EI), m/z 362 (M+).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[N:5]([CH2:25][CH3:26])[C:6]([O:9][C:10]2[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)=[N:7][N:8]=1)[CH3:3].Cl.C(N(CC)CC)C.[Cl:35][C:36]1[CH:37]=[C:38]([S:43](Cl)(=[O:45])=[O:44])[CH:39]=[CH:40][C:41]=1[Cl:42].C([O-])([O-])=O.[K+].[K+]>O>[C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=2)[O:9][C:6]2[N:5]([CH2:25][CH3:26])[C:4]([C@H:2]([NH:1][S:43]([C:38]3[CH:39]=[CH:40][C:41]([Cl:42])=[C:36]([Cl:35])[CH:37]=3)(=[O:45])=[O:44])[CH3:3])=[N:8][N:7]=2)[CH2:21][CH2:20]1)(=[O:24])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCn1c(Oc2cccc(N3CCN(C(C)=O)CC3)c2)nnc1[C@@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1c(Oc2cccc(N3CCN(C(C)=O)CC3)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Water was added to a mixture (307 mg) of 1-(4-[3-[5-((R)-1-aminoethyl)-4-ethyl-4H-[1,2,4]triazol-3-yloxy]-phenyl]-piperazin-1-yl)-ethanone obtained in Example 27-(2) and triethylamine hydrochloride, 3,4-dichlorobenzenesulfonyl chloride (0.13 ml), and K2CO3 (355 mg). The mixture was stirred at room temperature for 15 hours. The precipitated solid was filtered and purified by column chromatography (NH SiO2, MeOH/CHCl3=1/50) to give the titled compound (Compound 697) (117 mg, colorless syrup).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CS(C)=O>[CH3:18][O:11][C:2]([CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(O)(C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(C)(C(=O)c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
5.7 g (2.5 . 10-2 mol) α-methyl-benzoin are reacted in 50 ml DMSO at room temperature with 5 g (2.8 . 10-2 mol) p-toluene-sulphonic acid methyl ester in the presence of 11 ml of a 10% by weight sodium hydroxide solution. The crude product is filtered through silica gel/petroleum ether and yields, besides 0.95 g (17% of theory) of educt, 4.8 g (80% of theory) α-methyl-benzoin methyl ether of m.p. 36° - 38°C (petroleum ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CCCC([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:42])=[O:41])=[C:36]([C:47]#[N:48])[CH:35]=2)=O)=CC=1>>[C:43]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:11]2[CH:10]=[CH:9][C:8]([B:5]3[O:4][CH2:3][C:2]([CH3:1])([CH3:20])[CH2:7][O:6]3)=[CH:13][CH:12]=2)=[CH:35][C:36]=1[C:47]#[N:48])(=[O:42])=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Reactant: CC(C)(C)S(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1C#N
Product: CC1(C)COB(c2ccc(CCCC(=O)Nc3ccc(S(=O)(=O)C(C)(C)C)c(C#N)c3)cc2)OC1
Yield: 93 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 10C (430 mg, 0.930 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 10D (431 mg, 93%) as a brown foam. This crude material was taken on to the next step.