Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[H-].[Na+].I[CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCc1ccccc1Br)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl [2-(2-bromophenyl)ethyl]carbamate (810 mg, 2.7 mmol) in dry THF (2.0 mL) was transferred to a flask with a suspension of sodium hydride (65 mg, 2.7 mmol) in dry THF (2.0 mL) under an atmosphere of argon. The mixture was stirred for 15 min at room temperature and 10 min at 60° C. Iodomethane (0.19 mL, 2.97 mmol) was added with a syringe. After 4 h the reaction mixture was poured into water and extracted with EtOAc (×3). The organic phases were combined and washed with brine and dried with MgSO4. The crude product was purified by chromatography eluting with petroleum ether/EtOAc 10:1 to afford the title compound as a colourless oil.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15](=O)[CH2:16][CH3:17])=[N:3]1.OS(O)(=O)=O.O.[NH2:26]N.C([O-])(O)=O.[Na+]>C(O)(=O)C.O.C(O)C>[CH2:16]([C:15]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([O:13][CH3:14])[CH:9]=2)[C:4](=[O:5])[NH:3][N:26]=1)[CH3:17]
Reactant: CCC(=O)c1cc(OC)ccc1C1=NC(C)(C)CO1
Reactant: NN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCc1n[nH]c(=O)c2ccc(OC)cc12
Temperature: 80 °C
Yield: 41.3 %

Procedure:
A solution of 1-[2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-propan-1-one (6.4 g, 15.9 mmoles), prepared as described in example 8, in 110 ml of a mixture of water (10 ml), ethanol (100 ml) and concentrated H2SO4 (8 ml) up to 200 ml with ethanol, was stirred under N2 and reflux for 20 hours, then concentrated, taken up in water and extracted more times with ethyl ether. The organic phases were washed with water, anhydrified and brought to dryness to give an oil which was dissolved in acetic acid and added, at 15° C., with hydrazine monohydrate (1.56 g, 31.2 mmoles) in acetic acid (10 ml). At the end of the addition, the mixture was heated to 80° C. and, after 20 hours, brought to small volume, taken up in water, neutralised with NaHCO3 and extracted more times with CHCl3. The organic phases were anhydrified and brought to dryness to give a residue, which was flash chromatographed (eluent: hexane/ethyl acetate 9:1, then 7:3). There were thus obtained 1.34 g of the title compound (yield: 44%). m.p.: 230-235° C.
Reaction SMILES: [I-].N([CH:9]=[CH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]=1[CH2:21][CH3:22])C1C=CC=CC=1.[C:23]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[CH3:34])#[N:24].C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C=O>[C:23]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[CH:34]=[CH:9][CH:10]=[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH2:21][CH3:22])#[N:24]
Reactant: CC[n+]1c(C=CNc2ccccc2)ccc2ccccc21
Reactant: Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [I-]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN1C(=CC=Cc2ccc([N+](=O)[O-])cc2C#N)C=Cc2ccccc21
Yield: 47 %

Procedure:
The condensation of 4.02 g. (0.01 mole) of 2-(2-anilinovinyl)-1-ethylquinolinium iodide (prepared as described in British Pat. No. 344,409 m.p. 263°-5° C (dec.)) with 2-cyano-4-nitrotoluene (1.67 g., 0.01 mole) was effected in 15 ml. of dimethylformamide containing 2 ml. of acetic anhydride by heating the reaction mixture to reflux, adding 1.01 g. (0.01 mole) of triethylamine, heating at reflux for 1 to 2 minutes and cooling rapidly. The precipitate was collected, washed successively with dimethylformamide, water and ether and then dried to yield 47% of theory of blue dye base m.p. 250°-252° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:14]=[C:13]([O:25][CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[N:7][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C1COCC1.C(OCC)C>[Br:50][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:29])[C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)[CH:14]=[C:13]([O:25][CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[N:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(CO)cn2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(CBr)cn2)c1
Reaction time: 16 h
Yield: 100.8 %

Procedure:
N-(5-Hydroxymethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (0.79 g, 1.92 mmol) in THF (10 mL) was added to a solution of triphenylphosphine (1.03 g, 3.84 mmol) and carbon tetrabromide (1.27 g, 3.84 mmol) in diethyl ether (10 mL). After 16 hours, the reaction mixture was concentrated under reduced pressure and partitioned in EtOAc (30 mL) and water (30 mL). The organic layer was rinsed with water (20 mL), and then a saturated sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated to yellow oil. After chromatography on silica gel with a gradient from 5-100% ethyl acetate-hexanes, N-(5-bromomethyl-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (0.92 g, 101.3% yield) was obtained, including some impurity, but was used as-is. 1H NMR (300 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.45 (s, 1H), 8.15 (d, J=6.0 Hz, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.45 (d, J=3.0 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 7.10 (d, J=3.0 Hz, 1H), 6.65 (s, 1H), 4.75 (s, 2H), 4.70 (m, 1H), 4.25 (t, 2H), 3.05 (t, 2H), 1.25 (s, 6H); LCMS (m/z): 477.1 [C22H23BrN2O3S+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([O:11]CC=C)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=C(Cl)C=C(Cl)[CH:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:15]([CH2:25][CH:20]=[CH2:21])[CH:16]=2)=[CH:17][CH:18]=1
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: C=CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Product: C=CCc1cc(Oc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C

Procedure:
The crude allyl ether from step 3 (20.0 g) was dissolved in 2,4,6-trichlorobenzene (60 mL), and the solution was heated at reflux for 4 h. After being cooled to room temperature, the solution was directly loaded onto a column of silica gel and eluted sequentially with hexane and an 8:2 mixture of hexane and ethyl acetate to give 4-(4-chlorophenoxy)-2-(2-propenyl)phenol.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][CH:12]([CH3:14])[CH3:13])=[C:4]([C:8](O)=[O:9])[S:5][C:6]=1[CH3:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.Cl>C1COCC1>[Br:1][C:2]1[C:3]([S:11][CH:12]([CH3:14])[CH3:13])=[C:4]([C:8]([NH:27][C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: Nc1nnn[nH]1
Reactant: Cc1sc(C(=O)O)c(SC(C)C)c1Br
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1sc(C(=O)Nc2nnn[nH]2)c(SC(C)C)c1Br
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
A mixture of 4-bromo-5-methyl-3-[(1-methylethyl) thio]-2-thiophenecarboxylic acid (3.0 g, 10 mmoles) and 1,1'-carbonyldiimidazole (1.8 g, 11 mmoles) in THF (25 mL) is stirred under argon and heated under reflux. After 1.5 hours 5-aminotetrazole (0.87 g, 10 mmol) is added and heating continued for an additional 2.5 hours. The mixture is then cooled, stirred into ice water (300 mL) and acidified with concentrated HCl. The precipitate is filtered off, washed with 4N HCl, rinsed with water and dried to afford the product (3.5 g); mp 235° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1cccc(F)c1
Yield: 53 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (110 mg, 0.393 mmol) was reacted with 3-fluorophenyl boronic acid (2 eq) to give 3-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyridin-3-yl]-acrylic acid ethyl ester (70 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OC)=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[N:14]=2)[CH:3]=1.CO.[NH3:25]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[N:14]=2)[CH:3]=1
Reactant: N
Reactant: COC(=O)c1nnc(Cl)cc1Nc1cccc(C2CCC2)n1
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
In a 100 mL round bottom flask, methyl 6-chloro-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxylate (350 mg, 1.1 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). The flask was sealed and stirred at room temperature for 18 h. The solid formed was separated by filtration and dried in high vacuum to give 6-chloro-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxamide (281 mg, 84.3% yield) as a white solid. 1H NMR (DMSO-d6) δ: 11.95 (s, 1H), 9.34 (s, 1H), 8.85 (s, 1H), 8.20 (s, 1H), 7.69 (t, J=7.7 Hz, 1H), 6.91 (dd, J=7.7, 3.6 Hz, 2H), 3.66 (quin, J=8.6 Hz, 1H), 2.19-2.40 (m, 4H), 1.78-2.15 (m, 2H); LC-MS 304.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C-]#N.[Na+].IC1C=CC(C[C:20]#[N:21])=CC=1>>[Br:8][C:6]1[CH:7]=[C:3]([CH2:2][C:20]#[N:21])[S:4][CH:5]=1
Reactant: N#CCc1ccc(I)cc1
Reactant: BrCc1cc(Br)cs1
Agent: [C-]#N
Agent: [Na+]
Product: N#CCc1cc(Br)cs1
Yield: 37 %

Procedure:
A mixture of the above 4-bromothiophen-2-ylmethanol (4.83 g, 25 mmol) and 63 ml of 47% hydrobromic acid was stirred vigorously for 30 minutes at room temperature. The reaction mixture was extracted with pentane to give 5.31 g (yiel: 82.8%) of 2-bromomethyl-4-bromothiophene as a pale yellow oil. Thus obtained 5.12 g of 2-bromomethyl-4-bromothiophene was reacted with sodium cyanide according to the same procedure as in the synthesis of 4-iodophenylacetonitrile of example 5 to give 1.50 g (yield: 37.0%) of 4-bromothiophen-2-ylacetonitrile as a white crystal, removing by-product of α,α-bis[(4-bromothiophen-2-yl)methyl]-4-bromothiopheneaetonitrile by means of recrystalization.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(N(CC)CC)C.Cl[C:23](OC1C=CC=CC=1)=[O:24].CS(O)(=O)=O.[NH2:37][C:38]1[N:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[N:39]=1>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([NH:14][C:23]([NH:37][C:38]1[N:39]=[C:40]([O:46][CH3:47])[CH:41]=[C:42]([O:44][CH3:45])[N:43]=1)=[O:24])(=[O:12])=[O:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NS(=O)(=O)c1c(Cl)nc2ccccn12
Reactant: COc1cc(OC)nc(N)n1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2c(Cl)nc3ccccn23)n1
Yield: 82.8 %

Procedure:
In 30 ml of acetonitrile are dissolved 2.32 g (0.01 mole) of 2-chloroimidazo[1,2-a]pyridine-3-sulfonamide and 2.02 g (0.02 mole) of triethylamine, followed by addition of 1.60 g (0.01 mole) of phenyl chloroformate with stirring at 10° to 20° C. The mixture is further stirred at 20° to 25° C. for 30 minutes, and to the mixture are added 1.00 g (0.010 mole) of methanesulfonic acid and then 1.55 g (0.01 mole) of 2-amino-4,6-dimethoxypyrimidine. The mixture is stirred at 60° C. for 15 minutes. After cooling, the crystals which separates out are collected by filtration and washed with water 3 times with 10 ml of water each. The crystals were then dried in vacuo over P2O5 to give 3.42 g (yield 83.0%) of the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5]N[CH2:3][CH2:2]1.[C:10]([Si:14]([CH3:34])([CH3:33])[O:15][Si:16]([CH:26]([CH2:29][CH:30]1[CH2:32][O:31]1)CC)([CH3:25])[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([CH3:13])([CH3:12])[CH3:11]>C(O)C>[O:15]([Si:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([CH3:25])[CH2:26][CH2:29][CH2:30][O:31][CH2:32][CH:8]([OH:9])[CH2:7][N:1]1[CH2:6][CH2:5][CH:26]([CH2:29][CH2:30][OH:31])[CH2:3][CH2:2]1)[Si:14]([C:10]([CH3:11])([CH3:13])[CH3:12])([CH3:34])[CH3:33]
Reactant: OCCN1CCNCC1
Reactant: CCC(CC1CO1)[Si](C)(O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[Si](C)(CCCOCC(O)CN1CCC(CCO)CC1)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C

Procedure:
2-piperazin-1-yl-ethanol (0.61 g) and ethanol (20 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,5-Di(tert-butyl)-3-(oxiranylmethylpropyl)-1,1,3,5,5-Pentamethyltrisiloxane (2.0 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, the ethanol was removed by rotovap, and the mixture was distilled under reduced pressure to remove impurities.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])=[CH:33][CH:34]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(OCc2ccccc2)cc1
Yield: 54.8 %

Procedure:
1-(4-(benzyloxy)benzyl)-5-(2,6-dimethoxyphenyl)pyrrolidin-2-one was prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate (400 mg; 1.38 mmol) with commercially available 4-(benzyloxy)benzaldehyde (293 mg; 1.38 mmol). Subsequent purification by preparative HPLC afforded 1-(4-(benzyloxy)benzyl)-5-(2,6-dimethoxyphenyl)pyrrolidin-2-one (316 mg; 55%). LC-MS (conditions A): tR=0.91 min.; [M+H]+: 417.76 g/mol.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:22][CH3:23])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Br:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].N1C=CC=CC=1>O1CCCC1>[Br:24][CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:21][CH2:20][CH:19]([O:22][CH3:23])[CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:30]
Reactant: O=C(Cl)c1cccc(CBr)c1
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(COC(=O)c1cccc(CBr)c1)OC
Reaction time: 48 h
Yield: 78.3 %

Procedure:
A mixture of 8 g of 3-(hexadecyloxy)-2-methoxypropanol, 6.22 g of m-bromomethylbenzoyl chloride, 2.11 g of pyridine and 80 ml of tetrahydrofuran was stirred for 48 hours, then filtered and evaporated. The residue was purified by chromatography and crystallized giving 10 g of 3-(bromomethyl)benzoic acid, 3-(hexadecyloxy)-2-methoxypropyl ester as white solid.
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:22])([CH3:21])[CH2:15][C:16]([O:18]CC)=[O:17])(=O)C.C(=O)([O-])[O-].[Ca+2].BrBr>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.O>[C:16]([CH2:15][C:14]([CH3:22])([CH3:21])[CH2:13][CH2:12][CH2:11][CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)CC(C)(C)CCCCC1=C(OC(C)=O)CCC1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(CCCCC1=CCCC1=O)CC(=O)O

Procedure:
To a rapidly stirred mixture of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g., 0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate (11.8 g.) cooled in an ice-bath is added dropwise over a period of thirty minutes a solution of bromine (18.8 g.) in carbon tetrachloride (31 ml.). After stirring in the cold for an additional 45 minutes the orange colored chloroform layer is separated and washed with dilute sodium bisulfite and saturated saline solution, dried over magnesium sulfate and taken to dryness in vacuo (bath temperature: 35°-40°) leaving an amber colored oil. A slurry of 100 ml. of N,N-dimethylacetamido and 16.5 g. of CaCO3 is stirred and heated to reflux under nitrogen flow. The above dried oil is added from a dropping funnel rapidly, maintaining reflux and nitrogen flow for thirty minutes. The cooled reaction mixture is filtered, and the precipitate is washed with ether. The filtrate is poured into two liters ice-cold water and is extracted with ether. The combined extracts and washing is washed with water, saturated saline, treated with decolorizing charcoal, filtered. The solvent evaporated in vacuo to give 24 g. (77%) of subject product.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:13](=O)([O-:15])[O-:14].[Cs+].[Cs+].C(=O)=O.C(Br)C1C=CC=CC=1>CN(C)C=O>[CH2:2]([O:3][C:13](=[O:14])[OH:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[C:1]([O:11][CH3:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: COC(=O)[C@@H](O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: BrCc1ccccc1
Agent: O=C=O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(O)c1ccccc1
Product: O=C(O)OCc1ccccc1
Temperature: 25 °C
Yield: 122.5 %

Procedure:
Methyl (S)-(+)-mandelate (332 mg, 2 mmol) is dissolved in anhydrous N,N-dimethylforamide (8 mL), and powdered cesium carbonate (1.95 g, 6 mmol, 3 eq) is added. The suspension is then stirred at room temperature while passing carbon dioxide gas for 1 hour before benzyl bromide (0.71 mL, 6 mmol, 3 eq) is added to the solution. Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed. The reaction is quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc) to yield 390 mg of the desired methyl mandelate benzyl carbonate (65%): IR (thin film) 3004, 2956, 2839, 1748, 1613, 1516, 1455, 1383, 1246, 1175, 1115, 1027, 953, 824,789 cm−1; 1H NMR (360 MHz, CDCl3) d 3.72 (s, 3 H), 5.20 (s, 2 H), 5.86 (s, 1 H), 7.3˜7.5 (m, 10 H); 13C NMR (90 MHz, CDCl3) d 52.65, 71.17, 127.53, 128.31, 128.51, 128.56, 128.73, 129.38, 133.07, 134.69, 154.31, 168.91.
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:17](Cl)Cl.CO.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>C(OCC)C>[CH2:1]([C:3]1([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: ClCCl
Reactant: CCC1(CC(=O)O)CCc2ccc(O)cc21
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: CCC1(CC(=O)OC)CCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A 25 mL conical flask was charged with 42.3 (0.11 g, 0.50 mmol) and 10:1 DCM/MeOH (5 mL). To the orange solution was added (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, commercially available from Aldrich) (0.30 mL, 0.60 mmol) dropwise (vigorous gas evolution). The resulting solution was stirred for 15 minutes at room temperature, quenched with acetic acid (0.029 mL, 0.50 mmol), and concentrated. The residue was purified by silica gel flash chromatography (0-30% EtOAc/hexanes) to afford 42.4 (0.104 g, 89% yield) as a yellow oil.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:24][C:25]1[CH:26]=[C:27]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:28]=[C:29]([F:32])[C:30]=1O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:30]3[C:29]([F:32])=[CH:28][C:27]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:26][C:25]=3[F:24])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)CCc1cc(F)c(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCC(=O)OC(C)(C)C)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methyl methanesulfonate (445 mg, 1.22 mmol, 1.00 equiv), tert-butyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (prepared according to PCT Application WO2010/048207A2) (378 mg, 1.46 mmol, 1.20 equiv), potassium carbonate (542 mg, 3.92 mmol, 3.22 equiv), N,N-dimethylformamide (10.0 mL). The resulting solution was stirred overnight at 25° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×15 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 0.52 g (81%) of tert-butyl 3-(4-[[3-(4-ethylphenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C21H17F5NOS3, 427.1 (M+H). found 427.1.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C:10]3[C@@H:23]2[CH2:22][C@H:21]([O:28][C:29](=[O:35])[C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[C@@:20]2([CH3:36])[C:11]=3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:19])[CH2:16][CH:17]=[CH2:18])[CH2:6]1)(=[O:3])[CH3:2].C(O)(C)(C)C.[OH2:42].[OH2:43].C[N+]1([O-])CCOCC1>C(OCC)(=O)C.CCOCC.[Os](=O)(=O)(=O)=O>[C:1]([O:4][C@@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C:10]3[C@@H:23]2[CH2:22][C@H:21]([O:28][C:29](=[O:35])[C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[C@@:20]2([CH3:36])[C:11]=3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:19])[CH2:16][CH:17]([OH:43])[CH2:18][OH:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CC[C@@H](C)[C@H]1CCC2=C3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(=O)C(C)(C)CC)[C@@]21C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCC(C)(C)C(=O)O[C@H]1C[C@H]2C(=C3CC[C@H]([C@H](C)CC(O)CO)[C@]31C)CC[C@@H]1C[C@H](OC(C)=O)CC[C@@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3α-acetoxy-12α-(2,2-dimethyl)butyryloxy-5β-chola-8(14),23-diene (2.5 g), osmium tetroxide (0.092 g), tert-butyl alcohol (8 ml), and water (2.3 ml) is added 4-methylmorpholine-N-oxide hydrate (0.334 g). The mixture is stirred for about 2 hours at room temperature, diluted with 20% ethyl acetate in ether and washed with aqueous sodium bisulfite. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product which is used, without further treatment, for the next step.