Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O=[CH:14][C:15]([Cl:18])([Cl:17])[Cl:16]>O>[Cl:16][C:15]([Cl:18])([Cl:17])[CH:14]([C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1)[C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ccc(C(c2ccc(O)cc2)C(Cl)(Cl)Cl)cc1
Yield: 98.2 %

Procedure:
A 4-necked 3-L flask, equipped with a mechanical stirrer, a nitrogen inlet, and thermometer, is charged with 83% sulfuric acid (640 g). To this sulfuric acid, phenol (354 g) is added at 20° C. Chloral (200 g) in an additional funnel is added dropwise to the phenolic stirring mixture. The reaction temperature is maintained below 30° C. After the addition, the mixture is allowed to stir at room temperature for 18 hours, before water (640 g) is added. The resulting mixture is filtered and washed with more water to afford 1,1,1-trichloro-2,2-bis(4-hydroxyphenyl)ethane (423 g) as white solids.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O)=[C:4]([CH3:15])[CH:3]=1.CN(C=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[C:13]=2[CH:14]=1
Reactant: Cc1cc(F)ccc1OC(C)(C)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(F)cc2c1OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluoro-2-methylphenoxy)-2-methylpropanoic acid (658) (5 g, 23.6 mmol) in tetrahydrofuran (50 mL) at 0° C. was added cat. DMF and oxayl chloride (2.5 mL, 28.3 mmol). The reaction was warmed to room temperature, stirred for 1 hour, and concentrated in vacuo. The oil was dissolved in dichloromethane (50 mL), cooled to −78° C. and AlCl3 (7.6 g, 56.6 mmol) was added. The reaction was allowed to warm to room temperature overnight. Ice water was added and the dichloromethane was removed in vacuo. The aqueous phase was extracted with ethyl acetate (3×50 mL) and washed with saturated sodium bicarbonate dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to provide 5-fluoro-2,2,7-trimethylbenzofuran-3(2H)-one (659).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([O:17]C)[CH:3]=1.Cl.N1C=CC=CC=1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([OH:17])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1ccc(Br)cc1O
Temperature: 170 °C

Procedure:
A mixture of (4-bromo-2-methoxyphenyl)(4-fluorophenyl)methanone (1.60 g, 5.18 mmol) and pyridine hydrochloride (15.0 g, 130 mmol) was heated at 170° C. for 4.5 h and allowed to cool to rt. The resulting mixture was diluted with Et2O and washed with a 2N HCl solution. The ether layer was extracted twice with a 1N NaOH solution. The combined aqueous layers were acidified and extracted with Et2O, and the combined organics dried (MgSO4), filtered and concentrated. The title compound was obtained as a yellow solid, slightly contaminated with an impurity. It was used as such in the following step.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:12]([C:18]2[CH:23]=[C:22]([C:24](=[O:34])[NH:25][CH2:26][C:27]3[CH:32]=[N:31][C:30]([CH3:33])=[CH:29][N:28]=3)[CH:21]=[CH:20][C:19]=2[CH2:35][C:36]2[C:44]3[C:39](=[CH:40][C:41]([C:45]#[N:46])=[CH:42][CH:43]=3)[N:38]([CH2:47][CH3:48])[CH:37]=2)=[CH:13][CH:14]=[C:15]([CH3:17])[CH:16]=1)=[O:10])C1C=CC=CC=1.C(C1C=C2C(C(CC3C=CC(C(=O)NCC4C=NC=CC=4)=CC=3C3C(C(O)=O)=CC(C)=CC=3)=CN2CC)=CC=1)(=N)[NH2:50].NCC1C=NC(C)=CN=1>>[C:45]([C:41]1[CH:40]=[C:39]2[C:44]([C:36]([CH2:35][C:19]3[CH:20]=[CH:21][C:22]([C:24](=[O:34])[NH:25][CH2:26][C:27]4[CH:32]=[N:31][C:30]([CH3:33])=[CH:29][N:28]=4)=[CH:23][C:18]=3[C:12]3[C:11]([C:9]([OH:8])=[O:10])=[CH:16][C:15]([CH3:17])=[CH:14][CH:13]=3)=[CH:37][N:38]2[CH2:47][CH3:48])=[CH:43][CH:42]=1)(=[NH:50])[NH2:46]
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3cnc(C)cn3)cc2-c2ccc(C)cc2C(=O)OCc2ccccc2)c2ccc(C#N)cc21
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3cccnc3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Agent: Cc1cnc(CN)cn1
Product: CCn1cc(Cc2ccc(C(=O)NCc3cnc(C)cn3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Yield: 84 %

Procedure:
Part A. 2′-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-4-methyl-5′-[(5-methylpyrazin-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid benzyl ester: The compound of Example 37, Part D was coupled with 2-aminomethyl-5-methylpyrazine using the procedure described for Example 15, Part G to provide the amide in 84% yield. 1H NMR (500 MHz, CDCl3) δ ppm 1.37 (t, J=7.42 Hz, 4H) 2.41 (s, 3H) 2.55 (s, 3H) 3.78 (s, 2H) 4.03 (q, J=7.51 Hz, 2H) 4.71 (dd, J=11.00, 4.95 Hz, 2H) 4.95 (m, 2H) 6.66 (s, 1H) 7.01 (m, 4H) 7.17 (dd, J=14.30, 8.25 Hz, 2H) 7.24 (m, 4H) 7.51 (s, 1H) 7.55 (s, 1H) 7.67 (d, J=8.25 Hz, 1H) 7.83 (s, 1H) 8.36 (s, 1H) 8.52 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH:13]([CH3:17])[C:14]([OH:16])=O)/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.O>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:13]([CH3:17])=[C:14]2[OH:16]
Reactant: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: Cc1c(C(=O)O)cc2ccc(F)cc2c1O
Yield: 107.8 %

Procedure:
A solution of 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid (28 g, 118 mmol) in trifluoromethanesulfonic acid (140 mL) was stirred at room temperature for 16 h. The resulting mixture was carefully poured into ice cooled water with continuous stirring to obtain a solid precipitate, which was filtered, washed with water and dried in vacuo to yield 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (28 g, >100% crude) as yellow solid. This crude product was used in the next step without further purification. MS cald. for C12H8FO3 [(M−H)−] 219, obsd. 218.9.
Reaction SMILES: Cl(O)(=O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=NC)[C:14]2[N:18]([CH3:19])[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=2[CH3:25])=[CH:9][CH:8]=1.C(=O)(O)[O-:29].[Na+].S(OC)(OC)(=O)=O.C([O-])(=O)C.[Na+]>CO.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]2[N:18]([CH3:19])[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=2[CH3:25])=[O:29])=[CH:9][CH:8]=1
Reactant: CN=C(c1ccc(Cl)cc1)c1c(C)cc(CC(=O)OC)n1C
Reactant: O=C([O-])O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Yield: 65 %

Procedure:
Methyl 5-[(4-chlorophenyl)(methylimino)methyl]-1,4-dimethyl-1H-pyrrole-2-acetate perchlorate (1.5 g, 3.6 mmole) was treated with saturated aqueous sodium bicarbonate and extracted with chloroform (50 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was treated with dimethyl sulfate (0.62 g, 4.9 mmole) and heated at ~40° C. for one hour. The viscous reaction mixture was dissolved in methanol (10 ml) and treated with sodium acetate (2 g, 24 mmole) and water (2 ml) and heated at reflux overnight. The reaction was cooled and diluted with water (5 ml). The crystalline solid was isolated by filtration, washed with water, air dried, and recrystallized from methanol (10 ml) to yield 0.71 g (65%) of the title compound as a tan solid, m.p. 125°-131° C.
Reaction SMILES: C(=O)=O.[Na+].[Cl-].OP([O-])(O)=O.[K+].[Cl-].[K+].[Cl-].[Cl-].[Ca+2].[O-]S([O-])(=O)=O.[Mg+2].[CH2:23]1[N:28]([CH2:29][CH2:30]O)[CH2:27][CH2:26]N(CCS(O)(=O)=O)C1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C[N:51]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=CC=1)CC#C.Cl.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N[C@H](C([O-])=O)CCC([O-])=O>C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>[N:51]1[CH:55]=[C:56]([C@@H:27]2[CH2:26][CH2:30][CH2:29][N:28]2[CH3:23])[CH:57]=[CH:58][CH:59]=1
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: C#CCN(C)Cc1ccccc1
Agent: Cl
Agent: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: CN1CCC[C@H]1c1cccnc1
Reaction time: 0.17 h

Procedure:
Rat brain synaptosomes were prepared as follows: Female Sprague Dawley rats (100-200 g) were killed by decapitation after anesthesia with 70% CO2. Brains are dissected, and hippocampus, striatum, and thalamus isolated, and homogenized in 0.32 M sucrose containing 5 mM HEPES pH 7.4 using a glass/glass homogenizer. The tissue was then centrifuged for 1000×g for 10 minutes and the pellet discarded. The supernatant was centrifuged at 12000×g for 20 minutes. The resultant pellet was re-suspended in perfusion buffer (128 mM NaCl, 1.2 mM KH2PO4, 2.4 mM KCl, 3.2 mM CaCl2, 1.2 mM MgSO4, 25 mM HEPES, 1 mM Ascorbic acid, 0.01 mM pargyline HCl and 10 mM glucose pH 7.4) and centrifuged for 15 minutes at 25000×g. The final pellet was resuspended in perfusion buffer and placed in a water bath (37° C.) for 10 minutes. Radiolabeled neurotransmitter is added (30 uL 3H DA, 20 L3H NE, 10 uL 3H glutamate) to achieve a final concentration of 100 nM, vortexed and placed in a water bath for additional 10 minutes. Tissue-loaded filters are placed onto 11-mm diameter Gelman A/E filters on an open-air support. After a 10-minute wash period, fractions are collected to establish the basal release and agonist applied in the perfusion stream. Further fractions were collected after agonist application to re-establish the baseline. The perfusate was collected directly into scintillation vials and released radioactivity was quantified using conventional liquid scintillation techniques. Release of neurotransmitter was determined in the presence of 10 uM of various ligands and was expressed as a percentage of release obtained with a concentration of 10 uM (S)-(−)-nicotine or 300 uM TMA resulting in maximal effects. The compound of Example 1 exhibits an Emax of 15 percent.
Reaction SMILES: [CH:1]1([C:4]2[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:3][CH2:2]1.Br[C:25]1[CH:26]=[C:27]([CH2:31][OH:32])[CH:28]=[N:29][CH:30]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH:1]1([C:4]2[C:12]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([CH2:31][OH:32])[CH:26]=3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:2][CH2:3]1
Reactant: OCc1cncc(Br)c1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cncc(CO)c1)c2C1CC1
Temperature: 130 °C

Procedure:
To 4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, (50 mg, 0.160 mmol) was added (5-bromo-pyridin-3-yl)-methanol (CAS#37669-64-0, 36 mg, 0.192 mmol), 1,2-dimethoxyethane (1.0 mL), and 2 M aqueous sodium carbonate (0.200 mL, 0.40 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (73 mg, 0.008 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 130° C. for 1 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was partially purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 10%). Further purification was accomplished via reverse phase HPLC (10 to 40% acetonitrile/water w/0.1% NH4OH) to furnish 4-Cyclopropyl-5-(5-hydroxymethyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 295.14485 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.17-0.25 (m, 2H), 0.72-0.80 (m, 2H), 1.87-1.98 (m, 1H), 3.25 (s, 3H), 3.64 (s, 2H), 4.83 (s, 2H), 6.80 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.80 (t, J=2.0 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([NH:9]CC#C)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CCCCCC.C(OCC)(=O)C>[C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCNC(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A solution of N-(1-Phenylethyl)propargylamine (500 mg, 3.1 mmol) in THF (5 ml) was added to the LVT reagent prepared as described in Example 2.1 above, and the resulting mixture stirred for 2 hours at room temperature. The reaction mixture was diluted with hexane-ethyl acetate mixture (70:30) and filtered through celite. The filtrate washed with brine, dried (Na2SO4), and concentrated under vacuum. The crude product was purified using chromatography (SiO2) to yield 1-phenylethylamine (290 mg, 77%). The rotation (αD) of the de-protected 1-phenylethylamine was used to determine the ee of the products in Example 1.11.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=2)[N:9]=1.[CH:19]1([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[CH:19]1([C:26]([NH:3][CH2:4][C:5]2[S:6][CH:7]=[C:8]([C:10]3[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=3)[N:9]=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: O=C(O)C1CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(N)=Nc1nc(-c2csc(CNC(=O)C3CCCCCC3)n2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (2.0 g), cycloheptanecarboxylic acid (1.02 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.50 g), 1-hydroxybenzotriazole hydrate (1.07 g) and triethylamine (1.24 g) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was suspended in water (200 ml). The mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution and then extracted with a mixture of ethyl acetate (250 ml) and tetrahydrofuran (50 ml). The extract was dried over magnesium sulfate and then was evaporated. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol =10:1. Recrystallization from a mixture of methanol, tetrahydrofuran and diisopropyl ether afforded 4-(2-cycloheptanecarbonylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (0.72 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][N:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[CH2:21]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29](Cl)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1.[OH-].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)C>[C:9]1([C:8](=[N:7][CH:6]([CH:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=3)[C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClC1c2ccccc2CCc2ccccc21
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
Ethyl N- (diphenylmethylene) glycinate (12 g, 45 mmol) and 5-chlorodibenzosuberane (12.32 g, 54 mmol) are dissolved in 250 mL of dichloromethane, tetrabutylammonium bromide (17.6 g, 55 mmol) and 47 mL of 50% sodium hydroxide solution are added and the mixture is mechanically stirred at room temperature for 4 hours. Then it is diluted with 75 mL of dichloromethane and water and the layers are separated. The organic layer is washed with water, dried over magnesium sulfate, filtered, and stripped under vacuum to give a brown-orange oil. The oil is taken up in 250 mL of diethyl ether and 100 mL of water. The diethyl ether solution is additionally washed with water, dried (magnesium sulfate), and stripped to give a clear red-orange sticky oil residue (~21 g) which is used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=S(Cl)Cl.O.C([O-])([O-])=O.[Na+].[Na+].[CH3:26][CH2:27]O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]([O:14][CH2:26][CH3:27])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2cc(O)ccc2c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Yield: 64 %

Procedure:
To a solution of the compound obtained in stage A (15 g, 79 mmol) in EtOH (500 ml) was added dropwise SOCl2 (40 mL). The resulting mixture was stirred under reflux during 12 hours. After adding water (200 mL), the pH was adjusted to 7.0 with 20% aqueous Na2CO3. The aqueous solution was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to afford 11 g (yield: 64%) of the product of molecular formula C12H11NO3. Aspect: pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:6]([C:8]2[NH:9][C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([O:19]CC)=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1.[OH-].[Li+].Cl>O1CCCC1.CO.O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[C:6]([C:8]2[NH:9][C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(Cl)ccc3Oc3ccc(F)cc3F)[nH]c(C)c2c(=O)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1[nH]c(-c2cc(Cl)ccc2Oc2ccc(F)cc2F)c2cc(C(=O)O)[nH]c(=O)c12

Procedure:
A mixture of Example 24b (0.14 g, 0.305 mmol) and lithium hydroxide (0.073 g, 3.05 mmol) in tetrahydrofuran/methanol/water (2 mL each) was stirred at 80° C. for 2 hours. The mixture was cooled, diluted with water and brought to pH 4 with 1M HCl producing a yellow solid that was collected by filtration, washed with water and dried to constant mass (0.10 g, 76%).
Reaction SMILES: C([C:4]1([F:23])[CH:21]=[CH:20][C:7]([C:8]([CH2:10][C:11]([NH:13]C2C=CC=CC=2)=O)=[O:9])=[C:6]([F:22])[CH2:5]1)(=O)C.Cl>C(O)C>[C:8]([C:7]1[CH:6]=[CH:5][C:11]([NH2:13])=[C:10]([CH:20]=1)[C:8]([C:7]1[CH:20]=[CH:21][C:4]([F:23])=[CH:5][C:6]=1[F:22])=[O:9])(=[O:9])[CH3:10]
Reactant: CC(=O)C1(F)C=CC(C(=O)CC(=O)Nc2ccccc2)=C(F)C1
Agent: Cl
Solvent: CCO
Product: CC(=O)c1ccc(N)c(C(=O)c2ccc(F)cc2F)c1
Yield: 198.9 %

Procedure:
A mixture of 4-acetyl-2-(2,4-difluorobenzoyl)acetanilide (4.2 g) and concentrated hydrochloric acid (10 ml) in ethanol (30 ml) was refluxed for 5 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (100 ml). The solution obtained was washed with an aqueous solution of sodium bicarbonate, dried and evaporated to give crystals of 5-acetyl-2-amino-2',4'-difluorobenzophenone (3.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]([C:17]1[C:18](=[O:28])[O:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22](O)[CH:21]=2)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1[C:18](=[O:28])[O:19][C:20]2[CH:21]=[C:22]([O:12][CH2:11][CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])[CH:23]=[CH:24][C:25]=2[CH:26]=1)=[O:16]
Reactant: COC(=O)c1cc2ccc(O)cc2oc1=O
Reactant: CN(CCO)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2ccc(OCCN(C)C(=O)OC(C)(C)C)cc2oc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
2-(N-tert-butoxycarbonyl-N-methylamino)ethanol (0.5 g, 3 mmol) and 7-hydroxyl-3-coumarin carboxylic acid methyl ester (0.6 g, 3 mmol) are dissolved in 60 mL of anhydrous tetrahydrofuran. Triphenylphosphine (1.2 g, 4.5 mmol) is added, and diethyl azodicarboxylate (720 μL, 0.45 mmol) is added dropwise and slowly at 0° C. The resulting solution is stirred at room temperature for 24 hours. After the solvent was removed under reduced pressure at 30° C., the residue is mixed with methanol at room temperature. A solid is produced by filtrating under reduced pressure and 0.83 g of the captioned compound is obtained, yield: 72.6%. m.p. 128-129° C. 1H NMR(DMCO-d6): δ=1.40(s, 9H), 2.96(s, 3H), 3.65(s, 2H), 3.81(s, 3H), 4.32(s, 2H), 6.94(d, J=2.2 Hz, 1H), 7.00(dd, J=2.2 Hz, 8.4 Hz, 1H), 7.80(d, J=8.8 Hz, 1H), 8.60 (s,1H); EI-MS(m/z): 377(1, M+), 102(100).
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].[S:27]1[C:31]([C:32]([C:34]2[N:35]=[CH:36][N:37]3[CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[S:39][C:38]=23)=[O:33])=[CH:30][N:29]=[CH:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C: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]([C:40]3[S:39][C:38]4=[C:34]([C:32]([C:31]5[S:27][CH:28]=[N:29][CH:30]=5)=[O:33])[N:35]=[CH:36][N:37]4[CH:41]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
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)c3cncs3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncs5)c4s3)[C@H](C)[C@H]12
Yield: 85.2 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(thiazol-5-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (244 mg) was prepared in the same manner as in step a) of Example 1, except that 179 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 260 mg of 7-(thiazol-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[C:7]=1[CH3:8].[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:8][C:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][C:3]=1[CH2:2][O:27][C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:28])([CH3:13])[O:15]2)=[CH:26][CH:25]=1
Reactant: Cc1c(CCl)oc2ccccc12
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)oc2ccccc12
Reaction time: 12 h
Yield: 44 %

Procedure:
A mixture of 2-Chloromethyl-3-methyl-benzofuran (675.9 mg, 3.75 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (825 mg, 3.75 mmol, 1 eq), K2CO3 (2.1 g, 15.2 mmol, 4 eq) in 20 mL of CH3CN was heat to reflux under nitrogen atmosphere. Reaction was complete after 12 hrs. Regular work-up and column purification (5% EtOAc/hexane) to give 3-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran in 44% yield (601 mg). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.3 (s, 12 H) 2.3 (s, 3 H) 5.2 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.3 (m, 2 H) 7.5 (dd, J=21.6, 7.7 Hz, 2 H) 7.8 (d, J=8.8 Hz, 2 H).