Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH:26]([F:28])[F:27])=[N:9]2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 90 °C

Procedure:
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide (200 mg, 0.49 mmol) was dissolved in DMF (5 mL), 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl ester (263 mg, 0.74 mmol) and cesium carbonate (240 mg, 0.74 mmol) were added and the mixture heated at 90° C. for 2 hours. The mixture was allowed to cool to room temperature, diluted with water and extracted with DCM (×3). The combined organic extract was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant yellow oil was purified by flash chromatography on silica eluting with 0-2% MeOH in DCM. The appropriate fractions were collected and evaporated to afford 4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl ester a yellow oil. The crude product was taken onto the next step without further purification. LCMS (Method 4) [M+Na]+=610.0; RT=4.30 min.
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[OH:7][C:8]1[CH:9]=[C:10]([C@@:14]2([OH:35])[C@H:19]([CH2:20][N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:18]3[CH2:31][C@@H:16]([C:17]3([CH3:33])[CH3:32])[C@H:15]2[CH3:34])[CH:11]=[CH:12][CH:13]=1>CC(=O)CC>[ClH:6].[OH:7][C:8]1[CH:9]=[C:10]([C@@:14]2([OH:35])[C@H:19]([CH2:20][N:21]([CH3:30])[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:18]3[CH2:31][C@@H:16]([C:17]3([CH3:32])[CH3:33])[C@H:15]2[CH3:34])[CH:11]=[CH:12][CH:13]=1
Reactant: C[Si](C)(C)Cl
Agent: C[C@@H]1[C@H]2C[C@@H]([C@@H](CN(C)CCc3ccccc3)[C@]1(O)c1cccc(O)c1)C2(C)C
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add H2O (4 mg, 0.25 mmol) and TMSCl (27 mg, 0.25 mmol) to a solution of (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol (100 mg, 0.25 mmol) in 2-butanone (5 mL). Stir the reaction mixture at room temperature for 3 hours. After removal solvent by evaporation, wash the residue with EtOAc (1 mL×2) and dry under vacuum to give (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol hydrochloride (93 mg, Yield: 85.3%) as white solid. 1H NMR (400 MHz, D2O) δ 7.21-7.32 (m, 7H), 7.97-7.99 (d, J=7.2, 1H), 6.71-6.78 (dd, J1=8.0, J2=22.0, 1H), 2.86-3.33 (m, 5H), 2.43-2.68 (m, 7H), 2.11-2.20 (m, 2H), 1.73-1.75 (m, 1H), 1.23-1.25 (d, J=5.6, 3H), 1.04-1.05 (d, J=4.4, 3H), 0.69-0.71 (d, J=5.6, 3H). [α]D20=−8.6 (c=1.4 mg/mL, MeOH).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Temperature: 60 °C
Yield: 43.4 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (4.8 g, 18 mmol), potassium carbonate (6.5 g, 47 mmol) and methyl iodide (2.5 mL, 40 mmol) in DMF (10 mL) was heated at 60° C. for 1 hour. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexane, to yield the desired compound (2.2 g, 44%). LCMS calculated for C9H8BrClFO2 (M+H)+: m/z=280.9, 282.9. found: 281.0, 283.0.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].[O:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][CH:18]=O>CO>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][CH:18]([CH2:17][CH:13]1[CH2:14][CH2:15][CH2:16][O:12]1)[CH2:2][C:1]2=[O:3]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=CCC1CCCO1
Solvent: CO
Product: O=C1CC(CC2CCCO2)Oc2ccc(Br)cc21
Temperature: 25 °C
Yield: 18.3 %

Procedure:
The solution of 2-Acetyl-4-bromophenol (1.754 g, 8.16 mmol), 2-(tetrahydrofuran-2-yl)acetaldehyde (2.1 g) and purrolidine (0.4 mL) in MeOH was heated to reflux for 2 h. The reaction mixture was cool down to room temperature and evaporated. The residue was dissolved in EA, washed with 1 M HCl, 1 M NaOH (2×50 mL), brine (100 mL) successively, then, dried over anhydrous Na2SO4, and filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with EA in hexane (0-20%) to give 6-bromo-2-((tetrahydrofuran-2-yl)methyl)chroman-4-one (464 mg); MS ESI+ve m/z 311 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].CN1CCOCC1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]=[CH:32][C:33](O)=[O:34])=[C:27]([C:36]([F:39])([F:38])[F:37])[CH:26]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH:7][C:33](=[O:34])[CH:32]=[CH:31][C:28]1[CH:29]=[N:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[C:36]([F:38])([F:37])[F:39]
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: COc1cc(C(F)(F)F)c(C=CC(=O)O)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)c(C=CC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cn1
Reaction time: 0.08 h
Yield: 51.6 %

Procedure:
To a suspension of 3-fluoro-4-methansulfonylaminobenzylamine hydrochloride (40 mg, 0.16 mmol) in THF (4 mL) was added N-methylmorpholine (26 μL, 0.24 mmol). After stirring for 5 minutes, 3-[6-methoxy-4-(trifluoromethyl)pyridin-3-yl]acrylic acid (32 mg, 0.13 mmol) dissolved in THF (3 mL) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 43 mg, 0.16 mmol) were added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-fluoro-4-methanesulfonylaminobenzyl)-3-(6-methoxy-4-trifluoromethylpyridin-3-yl)acrylamide (30 mg, 42.7%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14].[N-:15]=[N+]=[N-].[Na+].CCOC(C)=O.[BH4-].[Na+]>CN(C)C=O.O>[NH2:15][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)cc(N)c1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Methyl 4,6-dichloro-3-methoxypicolinate (320 mg, 1.4 mmol) was dissolved in dry N,N-dimethylformamide (DMF; 5 mL), treated with sodium azide (130 mg, 2.0 mmol) and heated at 50° C. for 5 h. After cooling, the mixture was shaken with EtOAc (20 mL) and H2O (10 mL). The organic phase was washed with H2O (2×10 mL) and satd aq NaCl (1×10 mL), dried (Na2SO4) and evaporated. This material was dissolved in methyl alcohol (CH3OH; 15 mL), treated with sodium borohydride (NaBH4; 55 mg, 1.4 mmol) and stirred at 20° C. for 1 h. The mixture was treated with H2O (10 mL), and the volatiles were removed under vacuum. The residue was taken up in EtOAc (25 mL), washed with H2O (10 mL) and satd aq sodium chloride (NaCl; 10 mL), dried (Na2SO4), and evaporated to give the desired product as a white solid (100 mg, 33%): mp 78-79° C.; 1H NMR (400 MHz, CDCl3) δ 6.76 (s, 1H), 4.84 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H); EIMS m/z 216.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:24]1([O:27][CH2:28][CH3:29])[CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15]2[C:20]([NH:21][C:24]3([O:27][CH2:28][CH3:29])[CH2:26][CH2:25]3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC1(Br)CC1
Reactant: CN(c1ncccc1N)C1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC1(Nc2cccnc2N(C)C2CCN(Cc3ccccc3)CC2)CC1

Procedure:
A mixture of 1-benzyl-4-[N-methyl-N-(3-amino-2-pyridinyl)amino]piperidine (EXAMPLE 122, 825 mg), 1-bromo-1-ethoxycyclopropane (919 mg) and triethylamine (0.78 ml) in dry tetrahydrofuran (1.4 ml) under nitrogen is refluxed for 48 hrs, cooled to 20°-25°, diluted with methylene chloride (30 ml), washed with saline (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The residue is chromatographed (silica gel, 70-230 mesh, 140 g; eluting with a gradient of methanol/methylene chloride (1/99-5/95)) to give the title compound, NMR (CDCl3) 7.80, 7.41, 7.25, 6.93, 5.62, 3.51, 3.48, 3.03, 2.87, 2.60, 1.98, 1.71, 1.64, 1.13 and 0.85δ.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (340 mg, 1.00 mmol) [prepared according to the procedure of Example 167], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (374 mg, 1.12 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (626 mg, 1.34 mmol) in chloroform (10 mL). DIEA (980 μL, 5.61 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (229 mg, 0.35 mmol, 31%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[C:15]([C:6]2=[C:5](C(O)=O)[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.S(Cl)(Cl)=O.[CH3:29][N:30]([CH3:33])[CH:31]=[O:32].C[CH2:35][O:36]CC>C1(C)C=CC=CC=1>[OH:36][CH:35]1[CH2:33][N:30]([C:31]([C:5]2[CH:4]=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:2](=[O:1])[N:7]3[N:8]=[CH:9][C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:6]=23)=[O:32])[CH2:29]1
Reactant: CCOCC
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1cc(-c2ccccc2)c(=O)n2ncc3ccccc3c12)N1CC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.68 g of 4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxylic acid are suspended in 80 ml of toluene with the exclusion of moisture, whereupon 5.1 ml of thionyl chloride and 0.2 ml of N,N-dimethylformamide are added thereto and the mixture is stirred at room temperature for 2 hours. The reaction mixture is evaporated in vacuo; the residue is taken up in toluene, whereupon the solution is again evaporated in vacuo. The thus-obtained pure carboxylic acid chloride is taken up in 90 ml of dioxan, whereupon there are added thereto in succession 6.52 ml of triethylamine and 1.4 g of 3-hydroxyazetidine hydrochloride. The mixture is stirred at room temperature until the reaction has finished. After removing the solvent in vacuo the residue is treated with a mixture of 200 ml of water and 100 ml of saturated aqueous sodium chloride solution, whereupon the mixture is cooled to about 2° and stirred for 30 minutes. The crystals are filtered off under suction and washed twice with 15 ml of water. The thus-obtained crystals are dried at 70° in vacuo. The aqueous phase is extracted three times with methylene chloride; the combined organic phases are washed once with 50 ml of water, dried over sodium sulfate, filtered and evaporated. The crystals are combined with the material obtained above and stirred in 150 ml of ether for 30 minutes. The ether is removed by filtration and the yellow crystals are dried. There is obtained 3-hydroxy-1-[(4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazin-1 -yl)carbonyl]azetidine of m.p. 260°-264° (dec.).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.[N+:15]([O-])([OH:17])=[O:16]>C(OC(=O)C)(=O)C.C(OCC)(=O)C>[F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: FCCCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCCF)cc1

Procedure:
1-Fluoro-3-phenylpropane was dissolved in acetic anhydride (10 mL) and to the solution was added acetic acid (1 mL) and fuming nitric acid (1 mL) at 0° C. The reaction mixture was reacted at rt and to 60° C. for 1 h, then diluted with ethyl acetate (100 mL). The organic solution was washed with water (3×100 mL) and brine (100 mL), and evaporated to give 1-fluoro-3-(4-nitrophenyl)propane.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][OH:30])[C:21]=1[CH3:32])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:31])=[CH:28]\[CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[C:21]=1[CH3:32])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=C/CO)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a mixture of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-hydroxy-1-methyl-1-propenyl)benzene (120 mg) and triethylamine (32.8 mg) in dichloromethane (1.2 ml) was dropwise added methanesulfonyl chloride (34 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([O:53][CH3:54])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:19]([CH:21](/[CH:33]=[CH:34]/[C:35]1[C:40]([O:41][CH3:42])=[CH:39][C:38]([O:43][CH3:44])=[CH:37][C:36]=1[O:45][CH3:46])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([N+:30]([O-])=O)[CH:23]=1)=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CC(C)=O.O>[CH3:46][O:45][C:36]1[CH:37]=[C:38]([O:43][CH3:44])[CH:39]=[C:40]([O:41][CH3:42])[C:35]=1/[CH:34]=[CH:33]/[CH:21]([S:19]([CH:7](/[CH:6]=[CH:5]/[C:4]1[C:47]([O:53][CH3:54])=[CH:48][C:49]([O:51][CH3:52])=[CH:50][C:3]=1[O:2][CH3:1])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1)=[O:20])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c([N+](=O)[O-])c2)S(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C

Procedure:
(E)-2,4,6-Trimethoxystyryl-4-methoxy-3-nitrobenzylsulfoxide (1.3 mmol) was dissolved in a 2 to 1mixture of acetone and water (50 mL). The resulting mixture was heated to 50° C. After heating at 50° C. for 30 min, sodium dithionite (26.3 mmol) was added to the heated reaction mixture (portionwise over 20 minutes). The resulting mixture was maintained at 50° C. for 1hour, then cooled to room temperature (25° C.). Water (50 mL) was added to the cooled mixture. The resulting mixture was extracted with ethyl acetate (3×50 mL). The ethyl acetate extracts were combined and washed with saturated aqueous NaHCO3. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield the crude product. The crude product was recrystallized from 2-propanol to afford the desired (E)-2,4,6-trimethoxy styryl-3-amino-4-methoxybenzylsulfoxide, as listed in Table 6.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[C:13]([O:15]C)[CH:12]=[C:11]2[C:5]=1[C:6](=[O:17])[NH:7][S:8]2(=[O:10])=[O:9])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>>[OH:15][C:13]1[CH:12]=[C:11]2[C:5]([C:6](=[O:17])[NH:7][S:8]2(=[O:10])=[O:9])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:14]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Yield: 95.7 %

Procedure:
To a solution of 1.0 g (0.0039 mol) of 4-isopropyl-6-methoxysaccharin in 15 ml of MDC was added at ambient temperature 1.28 g (5.12 ml) of, a 1M solution of boron tribromide in MDC. When addition was complete the reaction mixture was heated under reflux for about five hours, cooled, taken to dryness in vacuo and the residue treated with ice and saturated sodium bicarbonate. The aqueous solution was extracted once with ethyl acetate and then acidified to pH 1 with concentrated hydrochloric acid. Extraction of the mixture with ethyl acetate/diethyl ether (8:2), drying the organic extracts and removal of the solvent in vacua afforded 0.9 g (96%) of 6-hydroxy-4-isopropylsaccharin as a white crystalline solid which was used as such in the next step.
Reaction SMILES: BrCCBr.[Mg].[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:26]=[O:27])=[N:19][C:20]=1[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:26]([OH:27])[CH2:29][C:30]2[CH:43]=[CH:42][CH:41]=[C:32]([CH2:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH:31]=2)=[N:19][C:20]=1[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: BrCc1cccc(COC2CCCCO2)c1
Reactant: COc1ccc(F)c(-c2ccc(C=O)nc2CC(C)(C)C)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(F)c(-c2ccc(C(O)Cc3cccc(COC4CCCCO4)c3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
Under a nitrogen atmosphere, 1,2-dibromoethane (34 μL) was added to a mixture of magnesium (578 mg) and THF (15 mL) at room temperature, and the mixture was stirred at 50° C. for 10 min. To the reaction mixture were added 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpicolinealdehyde (2.39 g) and then 2-((3-(bromomethyl)benzyl)oxy)tetrahydro-2H-pyran (4.52 g) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (980 mg) as an orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])C=O.N1CCCCC1>>[CH3:27][O:26][C:22]1[CH:21]=[C:18]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH:17]=[C:16]([O:15][CH3:14])[C:23]=1[O:24][CH3:25]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Product: COc1cc(C=Cc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC
Yield: 41 %

Procedure:
The title compound was prepared from p-nitrophenylacetic acid (18.6 g, 0.10 mol), 3,4,5-trimethoxy-benzaldehyde (19.6 g, 0.10 mol) and piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure yielded a solid, 13.0 g (0.041 mol, 41%) of the desired product. mp: 192-195° C.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:6][CH:5]([CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[CH2:9]([O:8][CH2:7][CH:5]1[CH2:6][C:3](=[O:2])[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1(OC)CC(COCc2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
To a stirring solution of [(3,3-dimethoxy-cyclobutyl)methoxymethyl]-benzene (13.0 g, 55.1 mmol) in 200 mL of a mixture of acetone:water (3:1) was added p-toluenesulfonic acid mono hydrate (2.1 g, 11.0 mmol). The reaction mixture was heated to 65 C for 45 minutes. Both TLC and GS/MS analysis indicated complete consumption of starting material. The reaction was cooled to room temperature and then the acetone was removed under reduced pressure. The resulting mixture was diluted with ethyl acetate and washed with an aqueous solution 5% NaOH. The layers were separated and the organic layer was dried over magnesium sulfate, filtered through a fritted funnel and then concentrated under reduced pressure. Purification of this material was accomplished by flash chromatography using a Biotage Column 75 small, eluting with a 10% EtOAc/hexanes. The product containing fractions were collected and concentrated under reduced pressure to yield the title compound (6.0 g, 58% yield) as a colorless oil.