Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li].Br[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:13]1[CH2:16][C:15](=[O:17])[CH2:14]1>CCOCC.C1COCC1>[C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][C:15]2([OH:17])[CH2:16][O:13][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1COC1
Reactant: BrCCCCc1ccccc1
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC1(CCCCc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
Under argon atmosphere at −45° C., to a stirred mixture of Lithium in pellets (0.129 g, 18.7 mmol) suspended in dry Et2O (15 mL), 4-bromo-butylbenzene (1.5 g, 7.03 mmol) in dry Et2O (10 mL), was added dropwise. The reaction was left to stir at 0° C. for 3 h, then the mixture was transferred via a cannula to a solution of 3-oxetanone (0.4 g, 5.55 mmol) in dry THF (10 mL), previously cooled to −78° C. After 3 h at −78° C., the reaction mixture was quenched with a saturated NH4Cl solution, the organic solvents removed under reduced pressure. The crude mixture was then dissolved in CH2Cl2, dried over Na2SO4, concentrated to dryness and subjected to column chromatography using a Teledyne ISCO apparatus, eluting with Cy/TBME (from 100:0 to 70:30) to afford a pure compound (0.4 g, 35%) as colorless oil. 1H NMR (CDCl3): δ 1.41-1.55 (m, 2H), 1.65-1.78 (m, 2H), 1.84-1.94 (m, 2H), 2.62-2.73 (m, 2H), 4.52 (d, J=7.2 Hz, 2H), 4.58 (d, J=7.0 Hz, 2H), 7.21 (dd, J=5.4, 7.2 Hz, 3H), 7.27-7.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[BH4-].[Na+].[CH2:33](O)C>>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH2:27][O:28][CH3:33])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCO
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1COC
Reaction time: 8 h

Procedure:
A solution of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde in dry ethanol was treated with 2 equivalents of sodium borohydride at 0° C., allowed to come to room temperature, quenched with water and evaporated to dryness under reduced pressure. The resultant residue is dispersed in water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was dissolved in 0.5M methanolic HCl, stirred overnight and evaporated to dryness under reduced pressure. This residue was dissolved in chloroform, washed with dilute sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified using flash chromatography and was crystallized from ethylacetate/hexane to give the title compound as a solid, mp 154-157° C., identified by NMR and mass spectral analyses.
Reaction SMILES: Cl[CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4].C[Si]([N-:29][Si](C)(C)C)(C)C.[Li+].FC(F)(F)C(O)=O>O1CCCC1>[NH2:29][CH:2]([B:5]1[O:9][C:8]([CH2:11][CH2:12][CH:13]([CH3:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:10])[C:7]([CH3:24])([CH3:23])[O:6]1)[CH2:3][CH3:4]
Reactant: CCC(Cl)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(N)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Temperature: -78 °C
Reaction time: 8 h
Yield: 129.1 %

Procedure:
0.82 g (2.27 mmol) of tert-butyl 5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 10 ml of tetrahydrofuran and then cooled to −78° C. under a nitrogen atmosphere. 2.3 ml (2.3 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise. The solution was then stirred overnight while slowly warming to room temperature. The solvent was removed by evaporation and the residue was taken up in diethyl ether. Insoluble material was removed by filtration and the filtrate was cooled to 0° C. 0.52 ml (6.8 mmol) of trifluoroacetic acid was added and the solution was stirred at 0° C. for 30 minutes. The solution was evaporated and the residue was co-evaporated with toluene to give 1 g of tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS), 5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in the next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][CH2:17]O)([O-:3])=[O:2].S(Cl)([Cl:21])=O>ClC(Cl)Cl>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCCl
Reaction time: 8 h

Procedure:
To a stirred mixture of 26 parts of 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol and 150 parts of trichloromethane are added dropwise 40 parts of sulfinyl chloride. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding N-(3-chloropropyl)-2-nitro-4-(trifluoromethyl)benzenamine as a residue.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([O:13]CC)=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].CO.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cn(C)c(=O)c(C)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cl)c(C(=O)O)cn(C)c1=O
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To a solution of ethyl 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (172 mg, 0.75 mmol) dissolved in a 4:1 mixture of THF:MeOH (5 mL) (v:v), was added a aqueous solution of LiOH (1.52 mmol, 1M). After stirring for 40 min, the reaction mixture was acidified to pH ˜1 with HCl (1N, aq) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated under the reduced pressure to give an off-white solid as the title compound. (163 mg, 100% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:17](OC)=[O:18])(=O)[CH3:14]>C1(C)C(C)=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:13]1[NH:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:17](=[O:18])[C:16]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)[nH]c2cc(-c3ccccc3)nn2c1=O
Yield: 85.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5-amine (4 g, 25.1 mmol) and dimethyl 2-acetylsuccinate (12 mL, 74.0 mmol) in xylene (120 mL) was added p-toluenesulfonic acid monohydrate (50 mg, 0.263 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 20 h. The solid was filtered and washed with hexanes to afford the title compound (6.4 g, 86%). 1H-NMR (400 MHz, MeOD) δ ppm 2.37 (3H, s), 3.66 (2H, s), 3.72 (3H, s), 6.46 (1H, s), 7.34-7.53 (3H, m), 7.87-8.06 (2H, m).
Reaction SMILES: N#N.CC1C=CC(S(N[C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.C(N(CC)CC)C.[C:36]([C@H:39]1[CH2:43][N:42]([C@@H:44]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH3:45])[C:41](=[O:54])[CH2:40]1)(=[O:38])[CH3:37].C(O)=O.Cl>CC#N.[Cl-].[Na+].O.CCOC(C)=O>[OH:38][C@H:36]([C@H:39]1[CH2:43][N:42]([C@@H:44]([C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)[CH3:45])[C:41](=[O:54])[CH2:40]1)[CH3:37]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(C)=O)CC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In a vial under N2, [Rh(C5Me5)Cl2]2 (62 mg, 0.10 mmol) and (1R,2R)-(−)-N-p-Tosyl-1,2-diphenylethylenediamine (87 mg, 0.24 mmol) were taken up in MeCN (1 mL). Triethylamine (0.1 mL, 0.7 mmol) was added and the resulting mixture was stirred 40 min prior to use. Meanwhile, a solution of (R)-4-acetyl-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.03 (1.06 g, 4.06 mmol) and triethylamine (3 mL, 21.3 mmol) in MeCN (20 mL) was cooled to an internal temperature of −10° C. under Ar in a jacketed 3-neck flask equipped with a thermocouple. Formic acid (0.525 mL, 13.9 mmol) was added during the cooling ramp once the internal temperature reached 0° C. Once the internal temperature reached −10° C., the aforementioned catalyst mixture was added in one portion, washing with additional MeCN (3×1 mL). The resulting orange solution was stirred for 48 h at −10° C. and was then warmed to r.t. Hydrochloric acid (3 M, 7.5 mL, 22.5 mmol) was added followed by dilution with EtOAc (50 mL) and brine (30 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated onto 10 g silica gel. The product was purified by silica gel chromatography (35% to 50% acetone in hexanes) to afford (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.05.
Reaction SMILES: C([O:8][C:9](=[O:18])[NH:10][C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1.[H-].[Na+].Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][N:14]([CH3:15])[C:12](=[O:13])[C@@H:11]([N:10]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:9](=[O:18])[OH:8])[CH3:17]
Reactant: BrCc1ccccn1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N(C)C)N(Cc1ccccn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.00 g of benzyl[(1S)-2-(dimethylamino)-1-methyl-2-oxo ethyl]carbamate in DMF was added 0.33 g of NaH under ice cooling and the reaction mixture was stirred at room temperature for 10 minutes. Therein, a solution of 3.25 g of 2-(bromo methyl)pyridine in DMF (15 ml) was added, and the solution was stirred at room temperature for 3 hours. A saturated aqueous solution of NaHCO3 was added to the reaction solution, and the resulting mixture was extracted with EtOAc. The combined organic layer was washed with water and with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N, moving bed: CHCl3/EtOAc=1/1; v/v) to obtain 1.04 g of the title compound (colorless oil).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:19]([O:21][CH3:22])=[O:20])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)c1ccc(C)c(N)c1C
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Cl)nc3ccccc23)c1C
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
To a solution of 2-chloroquinoline-4-carboxylic acid (0.40 g, 0.0019 mol) in CH2Cl2 (8 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (0.31 g, 0.0017 mol, see preparation 10) and triethylamine (0.80 ml, 0.0058 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.45 ml, 0.0038 mol) is added via syringe and stirred at room temperature. After 16 hours, the reaction is diluted with water and extracted twice with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is triturated with 20% diethyl ether in pentane and filtered to give the title compound as an off-white solid (0.55 g, 77%). Mass spectrum (m/z): 369.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)=[N:23][NH:24][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: COc1cccc(C(=O)c2ccc(OC)cc2C(=O)O)c1
Reactant: NN
Solvent: O
Product: COc1cccc(-c2n[nH]c(=O)c3cc(OC)ccc23)c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(3-methoxybenzoyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29].O>CS(C)=O>[CH2:30]([N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Oc1ccc(Sc2ccncc2)cc1
Reactant: CCCCN(CCCC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccc(Sc2ccncc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 0.014 mol of 4-(4-hydroxy-phenylthio) pyridine and 3 g of finely crushed anhydrous potassium carbonate in 50 ml of dimethylsulphoxide was placed under stirring for 30 min. To this medium 0.016 mol of 1-chloro-3-(di-n-butylamino) propane was added and the stirring was maintained at room-temperature for 24 hours. The reaction medium was poured into water and extracted with ethyl ether. The organic phase was washed with water, dried no sodium sulphate and filtered. After the solvent was evaporated off, an oil was provided which was purified by chromatography on a silica column (eluent: methanol). The required compound in free base form so obtained was then transformed into an oxalate by adding an ethereal solution of oxalic acid.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[CH3:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[C:23]([CH3:22])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:5]=2[C:6]=1[CH3:19])=[O:10]
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Reactant: Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 85 °C
Yield: 69.3 %

Procedure:
A solution of (6-Bromo-3-methyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone (50 mg, 0.13 mmol) in toluene (1.5 mL) and ethanol (1.5 mL) was degassed with argon for 15 min. At this time, 3-methyl benzene boronic acid (21.2 mg, 0.16 mmol, 1.2 eq) was added followed by [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II), complex with dichloromethane (1:1) (10.6 mg, 0.01 mmol, 0.1 eq) and 2M aqueous Na2CO3 (0.21 mL, 3 eq). The reaction was bubbled with argon for another 5 min and then heated to 85° C. for 4 h. The reaction was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. The solvent was removed at reduced pressure and purified on the pre-HPLC to afford 35.6 mg (69%) of a yellow solid as the product. 1H-NMR (CDCl3): δ 7.72 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.57 (dd, J=1.6, 8.0 Hz, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.58 to 7.53 (m, 4H), 7.33 (t, 1H), 7.18 (d, J=7.2 Hz, 1H), 2.56 (s, 3H), 2.42 (s, 3H); LC-MS (MH+=395/397).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:27])([CH3:26])[C:19]([O:21]C(C)(C)C)=[O:20])[CH2:11]1)(C(C)(C)C)(C)C.[SiH](CC)(CC)CC.[CH3:35][C:36]1[O:40][C:39]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)=[N:38][C:37]=1[CH:48]=O>C(#N)C>[CH3:35][C:36]1[O:40][C:39]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)=[N:38][C:37]=1[CH2:48][O:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([CH2:16][O:17][C:18]([CH3:26])([CH3:27])[C:19]([OH:21])=[O:20])[CH2:11]1
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@H]1CCC[C@@H](CO[Si](C)(C)C(C)(C)C)C1
Reactant: Cc1ccc(-c2nc(C=O)c(C)o2)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: Cc1ccc(-c2nc(COC[C@@H]3CCC[C@H](COC(C)(C)C(=O)O)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of tert-butyl 2-[cis-3-(tert-butyldimethylsilanyloxymethyl)cyclohexyl-methoxy]-2-methylpropionate are added to a mixture of 20 mg of BiBr3 and 30 mg of HSiEt3 in 0.5 ml of acetonitrile. 38 mg of 5-methyl-2-p-tolyloxazole-4-carbaldehyde in 0.2 ml of acetonitrile are added dropwise, and the mixture is stirred at room temperature overnight. The resulting black solid is filtered and the filtrate is concentrated and taken up in 1 ml of trifluoroacetic acid. The solution is stirred at room temperature overnight. The solvent is distilled off under reduced pressure and the residue is purified by HPLC. This gives 3.4 mg of 2-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxymethyl)cyclohexylmethoxy]-2-methylpropionic acid as a colorless oil. C24H33NO5 (415.24); MS (ES−): 414.25 (M−H+).
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=1.O1CCCC1.O.[OH-].[Li+]>O>[F:13][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(C(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(F)F)n1
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of methyl 6-(difluoromethyl)pyridine-2-carboxylate (0.58 g, 3.1 mmol, from Step 1) in Water (22 mL) and Tetrahydrofuran (20 mL, 250 mmol) was added Lithium hydroxide, monohydrate (0.65 g, 15 mmol). The reaction was stirred for 2 hours. The basic mixture was extracted with ether, which was discarded. The mixture was then acidified by the addition of 1N HCl and the volume of solvent reduced in vacuo. The product was purified via preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.1% TFA). The eluent containing the desired mass was evaporated by rotary evaporation to afford a solid product (0.35 g, 65%). 1H NMR (400 MHz, CD3OD): δ 8.27 (ddd, 1H), 8.17 (dd, 1H), 7.92 (dd, 1H), 6.78 (t, 1H); 1H NMR (400 MHz, CD3OD): δ−117.52 (d, 2F); LCMS (M+H)+: 173.9.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:8][N:9]([CH3:19])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CC(O)c1ccccc1)S(=O)(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CC(OS(C)(=O)=O)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Methanesulfonyl chloride (0.028 mL, 41 mg, 0.36 mmol) was added dropwise over 5 min to a 0° C. solution of N-(2-hydroxy-2-phenylethyl)-N-methylbenzenesulfonamide (100 mg, 0.357 mmol) and triethylamine (0.075 mL, 54 mg, 0.054 mmol) in 1.0 mL of ethyl acetate. After 15 min., the resulting suspension was poured into 40 mL of ice cold ethyl acetate and washed succesively with 20 mL of ice water, 20 mL of ice cold 2.0 N HCl, 20 mL of ice water and 20 mL of brine. The ethyl acetate layer was dried over sodium sulfate and evaporated to give 128 mg of crude N-(2-methanesulfonyloxy-2-phenylethyl)-N-methylbenzenesulfonamide.
Reaction SMILES: C([S:4][C:5]([S:26]C(=O)C)=[C:6]([N:20]1[CH:23](Cl)[CH2:22][C:21]1=[O:25])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])(=O)C.CO.CN>C(Cl)Cl.C(N(CC)CC)C>[S:4]=[C:5]1[CH:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[N:20]2[C:21](=[O:25])[CH2:22][C@H:23]2[S:26]1
Reactant: CC(=O)SC(SC(C)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Agent: CN
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1C(=S)S[C@@H]2CC(=O)N12
Reaction time: 0.25 h

Procedure:
Following the procedure of Example 1(b), a carbon tetrachloride solution containing an equimolar amount of chlorine was added to a solution of p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4-methylthio-2-azetidinon-1-yl)acetate (144 mg, 0.306 mmole) in methylene chloride (2 ml) to give p-nitrobenzyl 2-[bis(acetylthio)methylidene]-2-(4chloro-2-azetidinon-1-yl)acetate. This crude 4-chloroazetidinone derivative was dissolved in methylene chloride (3 ml) and triethylamine (43 μl), and then 135 μl of a 30% methanol solution of methylamine were added thereto, after which the mixture was stirred for 15 minutes. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent:ethyl acetate) to afford 60 mg of the desired compound.
Reaction SMILES: [Mg].CI.Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:16])[O:15]CCO2)=[C:7]([O:17][Si](C)(C)C)[CH:6]=1.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CC(C)=O.O>[OH:17][C:7]1[CH:6]=[C:5]([Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:10]=[CH:9][C:8]=1[C:11](=[O:15])[CH3:16]
Reactant: C[Si](C)(C)Cl
Reactant: CC1(c2ccc(Br)cc2O[Si](C)(C)C)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Mg]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc([Si](C)(C)C)cc1O
Yield: 42.9 %

Procedure:
A mixture of 321 mg (13.2 mmol) of magnesium and 0.07 ml of methyl iodide in 1.32 ml of dry tetrahydrofuran was refluxed. After cooling, the mixture was diluted with 3.96 ml of dry tetrahydrofuran. To the mixture was added a solution of 4.0 g of crude 2-(4-bromo-2-trimethylsilyloxyphenyl)-2-methyl-1,3-dioxolane obtained above in 9.6 ml of dry tetrahydrofuran dropwise under refluxing and the mixture was refluxed for additional 2 hours. After cooling, 1.68 ml (13.2 mmol) of trimethylsilyl chloride was added to the reaction mixture and the mixture was refluxed for 2 hours. After cooling, water was added to the reaction mixture. The mixture was extracted with ether. The organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and evaporated. To the residue were added 72 ml of acetone, 10.8 ml (600 mmol) of water and 0.46 g (1.8 mmol) of pyridinium p-toluenesulfonate (PPTS). The mixture was refluxed for 4 hours, neutralized with aqueous sodium bicarbonate solution, and evaporated. The residue was dissolved in ether. The solution was washed with water, sodium bicarbonate and brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel [eluent: n-hexane-AcOEt (15:1)] to give 1.08 g of pale yellow liquid (yield 43%). MS spectrum m/z: 208 (M+), 198 (M+ -15).