Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:7][O:8][C@H:9]1[C@@H:14]([N:15]([CH3:25])[C:16]2[S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45]Cl)=[CH:37][CH:36]=1>O.CC(C)CC(=O)C>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][N:11]2[CH2:12][CH2:13][C@H:14]([N:15]([CH3:25])[C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[C@H:9]([O:8][CH3:7])[CH2:10]2)=[CH:37][CH:36]=1
Reactant: ClCCCCOc1ccc(Cl)cc1
Reactant: CO[C@@H]1CNCC[C@@H]1N(C)c1nc2ccccc2s1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CO[C@@H]1CN(CCCCOc2ccc(Cl)cc2)CC[C@@H]1N(C)c1nc2ccccc2s1
Temperature: 60 °C
Yield: 73 %

Procedure:
A mixture of 5.5 parts of cis-N-(3-methoxy-4-piperidinyl)-N-methyl-2-benzothiazolamine ethanedioate(1:1), 10.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone was stirred and refluxed for 30 minutes. After cooling to 60° C., 4.4 parts of 1-chloro-4-(4-chlorobutoxy)benzene were added. The whole was stirred and refluxed overnight. After cooling, water was added and the layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in 2-propanol. The salt was filtered off and dried, yielding 6 parts (73%) of cis-N-[1-[4-(4-chlorophenoxy)-butyl]-3-methoxy-4-piperidinyl]-N-methyl-2-benzothiazolamine ethanedioate(1:1); mp. 210.4° C. (205).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:26]Cl>C(O)(=O)C>[Cl:26][C:9]1[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Reactant: ClCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.0 g, 7.6 mmol) in acetic acid (30 ml) at room temperature was bubbled chlorine gas for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours and the resulting solution was quenched with water (100 ml). The organic solution was extracted with diethyl ether (100 ml×2). With saturated sodium bicarbonate solution, remained acetic acid was removed and organic phase was evaporated with reduced pressure. The crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to produce title compound (3.1 g, 95% yield) as white solid.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:14][C:15]([F:21])([F:20])[S:16]([OH:19])(=[O:18])=[O:17].N([O-])=O.[Na+]>O>[F:14][C:15]([F:21])([F:20])[S:16]([O:19][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)(=[O:18])=[O:17]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1nc(N)cc2cccnc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(OS(=O)(=O)C(F)(F)F)cc2cccnc12
Temperature: 25 °C

Procedure:
To a solution of 6-amino-8-methoxy-1,7-naphthyridine (19 g, 0.108 mol) in a 1:1 mixture of water and trifluoromethane sulfonic acid (380 ml) is carefully added a solution of sodium nitrite (11.2 g, 0.162 mol) in water (40 ml) at 0° C. After 1 h the cooling bath is removed and the reaction mixture stirred for an other hour at ambient temperature. Then, ethyl acetate (500 ml) is added and the solution is neutralized by adding sodium bicarbonate (4N, 1 l). The water phase is extracted again with ethyl acetate (3×500 ml). The organic solvent is evaporated and the crude product is purified by flash column chromatography on silica gel (20:3 toluene/acetone) affording the title compound. M+308; Melting point 99-101° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[CH3:23][S:24]([O:27][C@@H:28]([C@@H:30]1[C@H:34]([CH2:35][OH:36])[O:33][C:32]([CH3:38])([CH3:37])[O:31]1)[CH3:29])(=[O:26])=[O:25].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)(=O)C.N1C=CC=CC=1>[CH3:23][S:24]([O:27][C@@H:28]([C@@H:30]1[C@H:34]([CH:35]=[O:36])[O:33][C:32]([CH3:37])([CH3:38])[O:31]1)[CH3:29])(=[O:25])=[O:26]
Reactant: C[C@@H](OS(C)(=O)=O)[C@H]1OC(C)(C)O[C@H]1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](OS(C)(=O)=O)[C@H]1OC(C)(C)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
3 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H)-one (Dess-Martin Periodinane) was added to a solution of 1.8 g of (1R)-1-((4S,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate (which contained fluorotris(propan-2-yl)silane) and 1.16 mL of pyridine in 20 mL of dichloromethane at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate, a saturated sodium hydrogen carbonate aqueous solution and a sodium thiosulfate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with water and a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.7 g of (1R)-1-((4S,5R)-5-formyl-2,2-dimethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate in the form of a yellow oily product.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[C:23]([CH3:33])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH2:1]([C:3]([C:21]1[CH:32]=[CH:31][C:24]([CH:25]=[O:26])=[C:23]([CH3:33])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)N(C)OC)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)(c1ccc(C=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-N-methoxy-2,N-dimethyl-benzamide (0.76 g, 1.75 mmol) and THF (20 mL) is added 1M LAH in THF (1.75 mL, 1.75 mmol) with cooling, and the solution stirred for 1 hour. The solution is diluted with Et2O (100 mL) and washed with 1M HCl (50 mL). The aqueous phase is extracted with Et2O (50 mL). The combined organic layers are washed with 1M HCl (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.48 g, 1.21 mmol, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)C(C)(C)c1ccc(F)c(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)C(C)(C)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To a stirred solution of 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-ol (18 g, 69 mmol) in DCM (300 mL) at 0° C. was added PCC (29.7 g, 2 eq) portionwise. After stirring 24 h at room temperature, the reaction mixture was combined with water and extracted with DCM. The combined extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography (Hex/EtOAc=10:1) to give 3-(3-bromo-4-fluorophenyl)-3-methylbutan-2-one (13 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.47-7.45 (m, 1H), 7.17-7.14 (m, 1H), 7.09 (t, J=8.8 Hz, 1H), 1.98 (s, 3H), 1.45 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Cl)cnn1C
Yield: 30 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-chlorophenyl isocyanate in a similar manner as described in Example 1.53, providing 12 mg (30%) of Compound 26: LCMS m/z (%)=393 (M+H37Cl, 60), 391 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.80 (s, 1H), 8.71 (s, 1H), 7.62 (s, 1H), 7.57 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.49 (dd, J1=8 Hz, J2=2 Hz, 2H), 7.39 (d, J=4 Hz, 1H), 7.33 (dd, J1=8 Hz, J2=2 Hz, 2H), 7.17 (d, J=8 Hz, 1H), 3.77 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:24]=[CH:23][C:9]([C:10]([NH:12][CH2:13][C@@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH2:15])=[O:11])=[CH:8][CH:7]=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][C:33](SC)=[N:32][C:31]=2[CH:37]=1>[Hg](OC(C)=O)OC(C)=O>[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][C:33]([NH:15][C@H:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13][NH:12][C:10](=[O:11])[C:9]3[CH:23]=[CH:24][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:25])=[CH:7][CH:8]=3)=[N:32][C:31]=2[CH:37]=1
Reactant: CSc1nc2cc(Br)ccc2o1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Agent: CC(=O)O[Hg]OC(C)=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](Nc2nc3cc(Br)ccc3o2)C(=O)OC(C)(C)C)cc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
A mixture constituted by 890 mg of 10-5, 620 mg of 5-bromo-2-methylthiobenzoxazole (prepared according to P1 but starting from 4-bromo-2-nitrophenol) and 350 mg of Hg(OAc)2 is heated for 2 hours at 75° C. then for 2 hours at 95° C. The cooled down medium is chromatographed eluting with a CH2Cl2/AcOEt mixture 82/18. 159 mg of expected product is obtained.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[C:9]([O:17][CH2:18][C:19]4[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=4[CH3:27])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:28])[C:6]=2[C:5]([Cl:29])=[CH:4][CH:3]=1.[NH:30]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][OH:37])[NH2:31].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:29][C:5]1[CH:4]=[CH:3][C:2]2[N:30]([CH2:32][CH2:33][NH:34][CH2:35][CH2:36][OH:37])[N:31]=[C:14]3[C:13]4[C:8](=[C:9]([O:17][CH2:18][C:19]5[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=5[CH3:27])[CH:10]=[CH:11][CH:12]=4)[C:7](=[O:28])[C:6]=1[C:15]=23
Reactant: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc(Cl)c2C3=O)c(C)c1
Reactant: NNCCNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(C)c(COc2cccc3c2C(=O)c2c(Cl)ccc4c2c-3nn4CCNCCO)c(C)c1

Procedure:
A mechanically stirred mixture of 310 g (0.73 mol) of 1,4-dichloro-5-[(2,4,6-trimethylphenyl)methoxy]-9,10-anthracenedione, 260 g (2.19 mol) of 2-[(2-hydrazinoethyl)amino]ethanol, 381 ml (2.19 mol) of N,N-diisopropylethylamine, and 4.8 l of acetonitrile was heated at reflux for 22 hr. The cooled mixture was concentrated in vacuo to leave a residue, showing a ~1:4 ratio of 12:13, that was triturated with water. The solids were collected by filtration, washed with methanol, and dried at 220 mm/50° C./18 hr to leave 237 g (66%) of crude 13, mp 147°-158° C.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[I:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=1
Reactant: N#Cc1c[nH]nc1I
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C#N)c(I)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-iodo-1H-pyrazole-4-carbonitrile (compound 256.1, 5.00 g, 22.8 mmol) in tetrahydrofuran (10 mL). The solution was cooled to 0° C. under nitrogen, then sodium hydride (1.1 g, 27.4 mmol, 60% dispersion in mineral oil) was added in portions. The resulting mixture was stirred at 0° C. for 30 min, then (2-(chloromethoxy)ethyl)trimethylsilane (6.05 mL, 34.2 mmol) was added to the reaction. The resulting mixture was stirred for overnight at room temperature, then carefully quenched with water/ice (30 mL). The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (20:1) as eluent to obtain the title compound as a colorless oil (7.2 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][CH2:13][CH2:14][CH2:15][P:16]([O:21]CC)([O:18]CC)=[O:17])=[C:4]([NH2:24])[N:3]=1.Br[Si](C)(C)C>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[O:11][CH2:12][CH2:13][CH2:14][CH2:15][P:16]([OH:21])([OH:18])=[O:17])=[C:4]([NH2:24])[N:3]=1
Reactant: CCOP(=O)(CCCCOn1cnc2c(N)nc(N)nc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn(OCCCCP(=O)(O)O)c2n1
Temperature: 23 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
2,6-Diamino-9-[4-(diethoxyphosphoryl)butoxy]purine (0.07 g, 0.2 mmol) and bromotrimethylsilane (0.26 ml, 2 mmol) were dissolved in dimethylformamide (3 ml) and the reaction mixture was stirred at 23° C. for 4 hr. The solvent was evaporated under vacuum and the residue dissolved in methanol-water solution (8:2). The material crystallised from the solution to give the title compound as colourless crystals (0.05 g, 84%), m.p. 295°-297° C. 1H NMR: δH [(CD3)2SO+D2O] 1.68 (6H, m, CH2CH2CH2P), 4.31 (2H, t, J=6 Hz, NOCH2), 8.35 (1H, s, H-8).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][N:23]3C(=O)C4C(=CC=CC=4)C3=O)[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:23][CH2:22][CH2:21][C:19]1[N:20]=[C:16]([NH:15][C:10]2[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:17][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1

Procedure:
A mixture of 2-(2-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)ethyl)isoindoline-1,3-dione (13.8 g, 30.2 mmol) and hydrazine hydrate (3.03 g, 60.5 mmol) in methanol (150 mL) was heated at reflux for 3 hours, then cooled and concentrated. The crude residue was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]CC2C=CC=CC=2)[CH:11]=1)([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[OH:16][C:12]1[CH:11]=[C:10]([C:2]([CH3:1])([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH:15]=[CH:14][CH:13]=1
Reactant: CCC(C)(CC(=O)OC)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCC(C)(CC(=O)OC)c1cccc(O)c1
Reaction time: 3 h
Yield: 91.8 %

Procedure:
Into a solution of methyl 3-(3-(benzyloxy)phenyl)-3-methylpentanoate 103.E (100 mg, 320 μmol) in MeOH (5 mL) was added palladium on carbon (34.1 mg, 320 μmol). The reaction was charged with H2 to 50 psi and stirred for 3 hours. The reaction was then filtered through Celite, washed with DCM, stripped, and purified by silica gel chromatography to afford methyl 3-(3-hydroxyphenyl)-3-methylpentanoate 103.F (65.3 mg, 91.8% yield).
Reaction SMILES: [CH2:1]=O.[OH:3][CH2:4][C:5]([CH2:10][OH:11])([CH3:9])[C:6]([OH:8])=[O:7]>>[CH3:9][C:5]1([C:6]([OH:8])=[O:7])[CH2:10][O:11][CH2:1][O:3][CH2:4]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: C=O
Product: CC1(C(=O)O)COCOC1

Procedure:
Synthesis of the acetal (formal) of formaldehyde and 2,2-bis(hydroxymethyl)propanoic acid yielding 5-methyl-1,3-dioxane-5-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:12])=[O:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1ccc(O)cc1
Product: CC(=O)Oc1ccc(C(C)=O)cc1

Procedure:
acylating the 4-hydroxyacetophenone with acetic anhydride to form 4-acetoxyacetophenone; and
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[N:13][N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1.[Br:31]Br>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:31][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:8]=1[Br:7])[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[N:13]=[C:12]2[NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: BrBr
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)ccc12
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Br)c(Br)cc12
Reaction time: 18 h

Procedure:
3.3 cm3 of pyridine are added to 4 g of N-[6-bromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously in Example 51, in 80 cm3 of chloroform, followed by dropwise addition of 2 cm3 of bromine, and the mixture is then left stirring for 18 hours. The reaction medium is diluted with 100 cm3 of methylene chloride and the organic phase is washed with 2×100 cm3 of 10% sodium thiosulphate solution and then with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.), then dried (90 Pa; 45° C.) to give 4.24 g of N-[5,6-dibromo-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide in the form of a yellow solid melting at 134° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:11]O>C(O)(=O)C>[CH3:2][C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccncc1
Reactant: OO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-tert-butylpyridine (19.0 g) in acetic acid (90 ml) was added dropwise 50% of hydrogen peroxide aqueous solution (20 ml) at room temperature and stirred for 30 minutes under the same condition. The mixture was stirred for 3 hours at ca.80° C. After cooling to room temperature, to the mixture was added dropwise another 20 ml of 50% hydrogen peroxide aqueous solution and stirred for 30 minutes. The mixture was stirred for 3 hours at ca. 80° C. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was taken up with chloroform, and washed with water (50 ml), saturated sodium carbonate aqueous solution (50 ml) and water (50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 4-tert-butyl-1-oxypyridine, which was crystallized by isopropyl ether as a colorless powder (19.1 g).
Reaction SMILES: [F:1][C:2]1([CH2:9][OH:10])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:17]=[CH:18][C:19]=1F>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([S:21]([NH2:24])(=[O:22])=[O:23])[CH:17]=[CH:18][C:19]=1[O:10][CH2:9][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CN1CCC(F)(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(F)(COc2ccc(S(N)(=O)=O)cc2Cl)CC1
Reaction time: 0.25 h

Procedure:
To a solution of (4-fluoro-1-methylpiperidin-4-yl)methanol (0.265 g) in tetrahydrofuran (2 mL) was added sodium hydride (0.288 g). After 15 minutes, 3-chloro-4-fluorobenzenesulfonamide (0.377 g) was added as a solution in tetrahydrofuran (1 mL). The reaction was stirred for 2 hours, quenched with water (5 mL), adjusted to pH˜7 with 1N aqueous HCl, and extracted with dichloromethane (2×25 mL). The organic layer was washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (Reveleris 40 g) eluting with a gradient of 0.1% to 10% methanol containing 2N NH3/dichloromethane over 30 minutes gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:24])[C:10]([Se]C1C=CC=CC=1)([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:24])[C:10]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)=[CH2:11]
Reactant: CC([Se]c1ccccc1)(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: C=C(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Yield: 74 %

Procedure:
To a solution of the product of Part (B) (0.42 g, 1.0 mMole) in methylene chloride (5 ml) at -72° was added m-chloroperbenzoic acid (0.32 g, 1.5 mMole) in three equal portions over a twelve minute period. Two hours later the mixture, at -70°, was poured into an aqueous solution of saturated sodium bicarbonate and sodium sulphite (20 ml) with vigorous stirring. The organic layer was separated, washed with saturated sodium bicarbonate (3×5 ml) and water (3×5 ml), and dried over anhydrous sodium sulphate. Evaporation gave the title compound as an oil, 0.20 g, (74% yield). The compound was used directly in the next stage.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30]([O:32][CH3:33])=[O:31])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][CH:21]1[C:30]([O:32][CH3:33])=[O:31])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc(CS)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.11 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added, whilst ice-cooling, to a solution of 3.51 ml of 4-methoxybenzyl mercaptan dissolved in 60 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 30 minutes. At the end of this time, a solution of 8.13 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine [prepared as described in step (7) above] in 20 ml of dry dimethylformamide was added dropwise to the mixture, which was then stirred at room temperature for 15 minutes and then at 40° C. for 4 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with water, dried and freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 15:1 by volume mixture of benzene and ethyl acetate), to afford 6.89 g of the title compound as an oil.