Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O.CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH2:19][CH2:18]3)=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Brc1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CCN3)cn1
Temperature: 100 °C

Procedure:
1.6 g 2-(Trifluormethyl)pyridin-5-ylboronic acid, 1.66 g commercially available 5-Bromo-2,3-dihydro-1H-indole and 8.19 g cesium carbonate were dissolved in a mixture of 7 ml water and 21 ml dimethylformamide. The reaction mixture was degassed with argon and then 484 mg tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 100° C. for two hours. The cooled reaction mixture was diluted with 200 ml ethyl acetate and washed with 100 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 885 mg 5-(6-Trifluoromethyl-pyridin-3-yl)-2,3-dihydro-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([NH:10][O:11][CH3:12])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:23].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:12][O:11][N:10]=[C:8]([Cl:23])[C:7]1[CH:13]=[CH:14][CH:15]=[CH:16][C:6]=1[O:5][CH2:4][C:3]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=1[Cl:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CONC(=O)c1ccccc1OCc1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CON=C(Cl)c1ccccc1OCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
2-(2,4-Dichlorobenzyloxy)-N-methoxybenzamide (10.44 g) was dissolved in dry methylene chloride (100 ml), phosphorus pentachloride (6.66 g) was added under ice-cooling over about 3 minutes to the solution, and the mixture was stirred at 0° C. for 1 hour. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate (150 ml) was added slowly, and the mixture was extracted with methylene chloride (150 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give α-chloro-2-(2,4-dichlorobenzyloxy)benzaldehyde O-methyloxime (9.52 g) as crystals. A part of the crystals was recrystallized from ethyl acetate/n-hexane to give colorless crystals. mp 91°-92° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14](Cl)=[N:15][OH:16].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:3]3[CH:4]=[CH:5][C:6]4[B:7]([OH:13])[O:8][C:9]([CH3:12])([CH3:11])[C:10]=4[C:2]=3[F:1])[CH2:26]2)[CH:22]=[C:21]([Cl:31])[CH:20]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)c(F)c21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c(F)c21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (180 mg. 0.70 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (203 mg, 0.84 mmol) in DMF (5 mL) at rt was added TEA (117 μL, 0.84 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol [80 mg; yield 24.8% over the last 3 steps] as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.479 (s, 1H), 7.810 (t, J=1.5 Hz, 1H), 7.753 (t, J=7.5 Hz, 1H), 7.671 (d, J=1.5 Hz, 2H), 7.582 (d, J=7.5 Hz, 1H), 4.376 (d, J=18.0 Hz, 1H), 4.270 (d, J=18.0 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=462.0 (M+1, ESI+).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5](F)[N:4]=1)[CH3:2].O.[NH2:24][NH2:25].C([O-])(O)=O.[Na+]>CC(O)C>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([NH:24][NH2:25])[N:4]=1)[CH3:2]
Reactant: NN
Reactant: CCc1nc(F)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCc1nc(NN)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
2-Ethyl-6-fluoro-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 0.51 mmol) was suspended in 2-propanol (1.0 mL) in a screw-cap reaction vessel. Hydrazine hydrate (0.12 mL, 2.5 mmol) was added, the reaction vessel was sealed and the mixture was stirred at 90° C. for 18 h. Sat. NaHCO3 (aq) (20 mL) was added and the mixture was extracted wth EtOAc (4×35 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 2-ethyl-6-hydrazinyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 96%) as a light yellow solid that was used in the next step without further purification. MS (ESI) m/z: 311.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:31])[CH:3]=1.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][NH2:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([NH:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)=[O:29])=[CH:24][CH:25]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3C)sc2c1
Reactant: NOC1CCCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)NOC4CCCCO4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (50 mg, 0.115 mmol) was dissolved in DMF (2 mL). The vial was charged with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (27.0 mg, 0.230 mmol), HATU (65.6 mg, 0.173 mmol), and DIEA (0.060 mL, 0.345 mmol). The reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by column chromatography (SiO2, 1-80% Heptanes/EtOAc) to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (53 mg, 0.099 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.48-1.73 (m, 3 H), 1.73-1.96 (m, 3 H), 2.36 (s, 3 H), 3.56-3.70 (m, 1 H), 3.89 (s, 3 H), 3.98-4.14 (m, 1 H), 4.96 (br. s., 1H), 6.35 (d, J=15.66 Hz, 1 H), 6.79-6.95 (m, 3 H), 6.95-7.07 (m, 2 H), 7.26-7.39 (m, 2 H), 7.39-7.48 (m, 3 H), 7.52 (d, J=16.17 Hz, 1 H), LC/MS (m/z, MH+): 534.1.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][S:40]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]5[CH:27]=[CH:26][NH:25][C:21]=5[N:22]=[CH:23][N:24]=4)=[CH:15]3)[CH2:11]2)[CH2:6][CH2:5]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3ccn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: Cl
Product: CS(=O)(=O)N1CCC(N2CC(CC#N)(n3ccc(-c4ncnc5[nH]ccc45)c3)C2)CC1

Procedure:
Reaction of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with methanesulfonyl chloride following the procedure described for Example 246, followed by purification with HPLC (method B) provided the title compound. LC-MS: 440.1 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 11.91 (brs, 1H), 8.55 (s, 1H), 7.76 (s, 1H), 7.43 (d, 1H), 7.01 (d, 1H), 6.88 (d, 2H), 3.52 (d, 2H), 3.47 (d, 2H), 3.30 (m, 2H), 3.27 (s, 2H), 2.80 (m, 2H), 2.75 (s, 3H), 2.27 (m, 1H), 1.65 (m, 2H), 1.23 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH3:14])[C:10]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:21]([O:25][N:26]1N=NC2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>C1COCC1>[CH3:21][O:25][N:26]([CH3:27])[C:15]([C:10]1[C:11]([CH3:14])=[N:12][S:13][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:17]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nsc(NC(=O)OC(C)(C)C)c1C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1c(C)nsc1NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-3-methylisothiazole-4-carboxylic acid (2.10 g, 8.13 mmol) in THF (45 mL) at 0° C. were added HATU (3.70 g, 9.76 mmol) and Hunig's base (3.15 g, 24.4 mmol). After a period of 5 min, N,O-dimethylhydroxylamine hydrochloride (1.03 g, 10.6 mmol) was added to the previous mixture. After a period of 1.5 h at rt, the resulting mixture was evaporated under reduced pressure and purified by flash chromatography (EtOAc/hexane 1:9 to 10:0) to give tert-butyl 4-(methoxy(methyl)carbamoyl)-3-methylisothiazol-5-ylcarbamate as an oil (1.60 g). LRMS (M+H)+: 302 m/z.
Reaction SMILES: [F:1][C:2]([F:18])([CH:7]([O:12]C(=O)C(C)=C)[CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH3:6])=[O:4].[CH3:19][O:20][CH2:21]CO.C1C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[F:18][C:2]([F:1])([CH:7]([OH:12])[CH2:8][CH:9]([CH3:10])[CH3:11])[C:3]([O:5][CH2:6][CH2:19][O:20][CH3:21])=[O:4]
Reactant: COCCO
Reactant: C=C(C)C(=O)OC(CC(C)C)C(F)(F)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COCCOC(=O)C(F)(F)C(O)CC(C)C
Yield: 105.2 %

Procedure:
To a mixture of 25.0 g of Intermediate 1 (Example 1), 25 g of 2-methoxyethanol and 200 g of benzene was added 0.15 g of p-toluenesulfonic acid monohydrate. With stirring in a nitrogen atmosphere, the mixture was heated for 8 hours while water of reaction was sequentially removed out of the system. After cooling, the reaction mixture was poured into ice water and extracted with ether. The ether solution was washed, dried, and concentrated, obtaining 23.9 g (yield 73%) of crude 2-methoxyethyl 2,2-difluoro-3-hydroxy-5-methylhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O[CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=O)=O)=CC=1.[OH-].[K+]>N1C=CC=CC=1.CCOC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([S:8][CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Sc1cccc(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1CSc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To a stirred mixture of m-iodothiophenol (2.67 g, 11.31 mmol) and N-(tert-butoxy carbonyl)-2-pyrrolidinylmethyl p-toluenesulfonate (3.34 g, 9.43 mmol) in pyridine (9.4 mL) was added 8 N KOH (1.77 mL). The resulting mixture was stirred at room temp overnight. The reaction mixture was diluted with EtOAc. The solution was washed with H2O, sat. NH4Cl solution, brine, and dried over Na2SO4. The organic layer was concentrated under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane-EtOAc (5:1, v/v) as eluent to afford 1.79 g (45%) [N-(tert-butoxycarbonyl)-2-pyrrolidinyl]methyl 3-iodophenyl sulfide as an oil. 1H-NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.78–2.01 (br m, 4H), 2.71 (dt, 1H), 3.32–3.49 (br m, 3H), 3.90–4.02 (br m, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.18 (d, J=7.8 Hz, 1H), 7.57 (dd, J=2.0, 8.3 Hz, 2H); MS (FAB) m/z 420 (M++1).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([O:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[C:27]([F:39])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[F:39][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([F:31])[C:28]=1[O:32][CH2:33][CH2:34][C:35]([F:36])([F:37])[F:38]
Reactant: O=C(CBr)Nc1nc(-c2cc(F)c(OCCC(F)(F)F)c(F)c2)cs1
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(F)c(OCCC(F)(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (30 mg, 0.167 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(3,3,3-trifluoropropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (89 mg, 0.200 mmol) in the presence of NaH (10 mg, 0.416 mmol) in dry DMF (5.0 mL) to give 18 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz): 2.73-2.84 (m, 2H), 3.17 (s, 3H), 3.39 (s, 3H), 4.32-4.38 (m, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.66 (s, 1H), 7.69 (s, 1H), 7.80 (s, 1H), 12.70 (br s, 1H); APCI-MS (m/z): 542.20 [M−H].
Reaction SMILES: CC#N.C([O:6][P:7]([C:12]([CH3:16])([CH3:15])[CH2:13][NH2:14])(=[O:11])[O:8]CC)C.C[Si](Br)(C)C>CO>[NH2:14][CH2:13][C:12]([P:7](=[O:6])([OH:11])[OH:8])([CH3:16])[CH3:15]
Reactant: CCOP(=O)(OCC)C(C)(C)CN
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: CO
Product: CC(C)(CN)P(=O)(O)O

Procedure:
A solution of CH3CN (30 mL) of crude 6 (2.5 g) was cooled to 0° C., and treated with TMSBr (8 g, 52 mmol) for 5 hr. The reaction mixture was stirred with methanol for 1.5 hr at room temperature, concentrated, recharged with methanol, concentrated to dryness to give crude 7 which was used for next reaction without further purification.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[C:21]([O-])(=[O:23])C.II>C(O)(=O)C.[Cu](Cl)Cl>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[C:11]([CH2:12][CH2:13]1)=[CH:10][C:9]([OH:20])=[C:8]([O:23][CH3:21])[CH:7]=3)[CH2:4][CH2:3]2
Reactant: CC(=O)[O-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: Cl[Cu]Cl
Agent: II
Solvent: CC(=O)O
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h
Yield: 56 %

Procedure:
To this end, 2-iodo-estrone 49 was prepared by treating oestrone with mercuric-acetate and iodine in acetic acid.40 The selective halogenation at position 2 was complete within 2 hours at room temperature with an overall yield of 56% after successive recrystallizations. 2-Iodo-estrone then reacted with a large excess of a freshly prepared solution of sodium methoxyde, in presence of copper chloride in refluxing pyridine41 and gave 2-methoxy-estrone 50 with a yield: of 75%. This method has the advantage of not involving any protecting group and gives good overall yield (42%) for the synthesis of 2-methoxy-estrone in two steps from oestrone.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].O[Li].O>CO.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:17]2([C:19]([F:20])([F:22])[F:21])[O:16][N:15]=[C:14]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=34)[CH2:18]2)[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: COC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Yield: 86.2 %

Procedure:
Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methyl ester (8.1 g, 17.0 mmol) and LiOH—H2O (3.57 g, 84.9 mmol) in MeOH (64 mL) and water (16 mL) at room temperature overnight. After removal of organic solvent under vacuum, dilute the residue with ice water (80 mL). Acidify the aqueous mixture with conc. HCl to pH=1, and extract the resultant mixture with EtOAc (100 mL×3). The combined organic layers are washed brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 1:1) to afford 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid as pale yellow solid (6.8 g, 86.4%). MS (m/z): 464 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[C:41]([Cl:48])[CH:40]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:19])=[C:41]([Cl:48])[CH:40]=1
Reactant: NCCc1ccc(Br)cc1Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4Cl)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.8 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (1.15 g. 3.05 mmol), 1-hydroxybenzotriazole hydrate (0.51 g, 3.4 mmol) and 2-(4-bromo-2-chlorophenyl)ethanamine (0.75 g, 3.2 mmol) in N,N-dimethylformamide (10 mL) at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.70 g, 3.7 mmol). The resulting solution was stirred at ambient temperature for 17 hours, then diluted with water (100 mL) and extracted with ethyl acetate (100 mL). Addition of 1M hydrochloric acid (20 mL) enabled layer separation. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 75/25 hexanes/ethyl acetate, to afford ethyl 7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as an off-white solid (1.10 g, 60% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:26]([CH3:29])([CH3:28])[CH3:27]>C(COC)OC>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[CH:11]=[C:10]([Si:26]([CH3:29])([CH3:28])[CH3:27])[O:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccc(-c2ccoc2-c2ccc(F)cc2)cc1
Agent: [Li]CCCC
Solvent: COCCOC
Product: C[Si](C)(C)c1cc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)o1
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of 2,3-bis(4-fluorophenyl)furan (7.0 g, 27 mmoles) in 100 ml of dry dimethoxyethane was cooled to -35° and treated dropwise with n-butyl lithium (1.6M; 18.8 ml, 30 mmoles). The solution was stirred at -35° for one hour and treated with chlorotrimethylsilane (3.0 g, 27.6 mmoles). The reaction mixture was stirred at -35° for one hour and at room temperature for 24 hours. The mixture was concentrated in vacuo, suspended in 180 ml of carbon tetrachloride, and filtered through 50 g of silica gel. The filtrate was concentrated to an oil which crystallized on standing to yield 8.1 g (90%) of the title compound, m.p. 82°-83°. PMR (CDCl3) δ0.33 (s, 9H, Si(CH3)3); 6.87 (s, 1H, H--C=C--O), 6.9-7.8 (m, 8H, 2-p-FC6H4). MS: m/z 328.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[I:19]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[OH:1][C:2]1[C:3]([I:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1I
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@@]1(c2ccc3c(I)c(O)ccc3c2)COC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
The mixture of (R)-4-(6-Hydroxy-naphthalen-2-yl)-4-methyl-oxazolidin-2-one (221.7 mg, 0.0009114 mol), N-iodosuccinimide (226 mg, 0.00100 mol) and zirconium tetrachloride (33 mg, 0.00014 mol) in methylene chloride (16 mL, 0.25 mol) was stirred at room temperature for 3 h. After filtrating through Celite and washing with methylene chloride, the concentrated residue was chromatographed to give (R)-4-(6-hydroxy-5-iodonaphthalen-2-yl)-4-methyloxazolidin-2-one as a light yellow solid (290 mg, 86%). LCMS: Rf=1.33 min (370.07, M+1, 100%). 1H NMR (400 MHz, MeOD) δ=8.10 (d, J=8.9 Hz, 1H), 7.79 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.56 (dd, J=2.1, 8.9 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 4.52 (d, J=8.5 Hz, 1H), 4.43 (d, J=8.5 Hz, 1H), 1.80 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[NH2:11].[OH:12][CH:13](O)[C:14](=O)[CH3:15]>O>[NH2:9][C:7]1[N:8]=[C:3]([NH2:2])[C:4]2[C:5](=[N:10][CH:15]=[C:14]([CH2:13][OH:12])[N:11]=2)[N:6]=1
Reactant: CC(=O)C(O)O
Reactant: Nc1nc(N)c(N)c(N)n1
Agent: Cl
Solvent: O
Product: Nc1nc(N)c2nc(CO)cnc2n1

Procedure:
reacting tetraaminopyrimidinehydrochloride with dihydroxyacetone in the presence of air and water and at a pH in the range of 5.5±0.2 to give 2,4-diamino-6-hydroxymethylpteridine;
Reaction SMILES: C(OC(=O)[C@@H]([C@H](C(OC(=O)C1C=CC=CC=1)=O)O)O)(=O)C1C=CC=CC=1.[C:27]1([CH:33]([OH:40])[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.[OH-].[Na+]>[C:27]1([C@@H:33]([OH:40])[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OC(CN1CCCC1)c1ccccc1
Agent: O=C(OC(=O)[C@H](O)[C@@H](O)C(=O)OC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O[C@@H](CN1CCCC1)c1ccccc1
Reaction time: 48 h

Procedure:
Solutions of 35.8 g of di-O-benzoyl-L-tartaric acid in 150 ml methanol and 19.1 g of 1-phenyl-2-(1-pyrrolidinyl)-ethanol in 100 ml of methanol were mixed and the mixture left standing in a refrigerator for 2 days. The crystalline product was filtered off, washed with a small amount of cold methanol and diethyl ether and dried. The product was repeatedly recrystallised from hot ethanol, yielding an optically pure diastereomeric salt of 15.0 g. The free base was released by dissolving the salt in 100 ml of cold 20% aqueous sodium hydroxide and extracted in dichloromethane. After evaporation of the solvent, 7.2 g (38% based on the starting racemate) of the oily (R)-enantiomer of 1-phenyl-2-(1-pyrrolidinyl)-ethanol were obtained which solidified after storage in a refrigerator to become a crystalline mass. The product had a [αD20] value of −40° (methanol).