Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5](Br)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>C(#N)C>[F:1][CH2:2][C:3]([CH2:20][F:21])([CH3:19])[C:4](=[O:18])[CH:5]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: CC(CF)(CF)C(=O)C(Br)Oc1cccc(C(F)(F)F)c1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: CC(CF)(CF)C(=O)C(Oc1cccc(C(F)(F)F)c1)n1cncn1
Yield: 82.5 %

Procedure:
100 g (0.267 mole) of 3,3-bis fluoromethyl-1-bromo-1-(3-trifluoromethylphenoxy)-butan-2-one and 37.2 g (0.54 mole) of 1,2,4-triazole in 600 ml of acetonitrile were heated to 65° C. for 6 hours, while stirring. The solvent was then distilled off under a waterpump vacuum, the residue was taken up in 800 ml of methylene chloride and the mixture was washed twice with 1,000 ml of water each time. The organic phase was dried over sodium sulphate and concentrated. The oily residue was distilled under a high vacuum. 80 g (82.4% of theory) of 3,3-bisfluoromethyl-1-(1,2,4-triazol-1-yl)-1-(3-trifluoromethylphenoxy)-butan-2-one of boiling point 136°-41° C./0.1 mm Hg were obtained.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>O1CCOCC1.O.O>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:21])=[O:3])(=[O:9])=[O:10])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
To a solution of 0.67 g (2.07 mmol) of 2-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-propionic acid ethyl ester in THF/water (4/1, 10 mL) were added 100 mg (4.14 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with isopropanol/chloroform (1/1, 3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 461 mg of 2-(4-methanesulfonyl-benzenesulfonyl)-2-methyl-propionic acid. (73% yield) 1H NMR (400 MHz, DMSO-d6) ppm 1.51 (6H, s), 3.35 (3H, s), 8.08 (2H, d, J=22 Hz), 8.20 (2H, d, J=21 Hz), 13.64 (1H, s)
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)c(F)c1
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a stirred solution of methyl 2-fluoro-4-nitrobenzoate (10.0 g, 49.7 mmol, 1 eq.) in methanol (100 mL) was added sodium borohydride (9.40 g, 248.7 mmol, 5 eq.) at RT and stirred for 4 h. The methanol was evaporated and the residue was diluted with ethyl acetate (50 mL×2) washed with water (50 mL) and brine (50 mL). The ethyl acetate layer was dried over Na2SO4, evaporated under vacuum to get (2-fluoro-4-nitrophenyl)methanol (8 g, 94%, off-white solid; TLC system: EtOAc/PE (3:7), Rf: 0.30).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)N2CCCCC2)[C:6]=1[OH:29])([CH3:4])([CH3:3])[CH3:2].[CH:30](O)=[O:31]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:6]2[O:29][C:30](=[O:31])[CH:15]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:7]=2[CH:8]=1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(C(c2ccc(F)cc2)N2CCCCC2)c(O)c(C(C)(C)C)c1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(F)cc1
Temperature: 140 °C
Yield: 89.5 %

Procedure:
A solution of 11.13 g (28.0 mmol) of compound (205), prepared according to Example 2a, in 150 ml of dry toluene is degassed using argon and then 33.6 mg (0.057 mmol) of dichloro-[1,3-bis(diphenylphosphino)propane]palladium(II) and 4.22 ml (112 mmol) of formic acid are added. The autoclave is flushed with carbon monoxide and sealed, and a carbon monoxide pressure of 6 bar is then applied. The reaction mixture is maintained at 140° C. for 14 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted three times using ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Filtration of the residue on silica gel using ethyl acetate and crystallisation of the pure fractions from methanol yields 8.53 g (90%) of compound (105) (Table 1), m.p. 146-147° C. Molecular weight C22H25FO2 (340.44). Analysis, calculated: C 77.62; H 7.40%. Analysis, found: C 77.66; H 7.35%. 1HNMR (300 MHz, CDCl3, ppm): 1.22 (s, 9H); 1.36 (s, 9H); 4.74 (s, 1H); 6.99 (m, 3H); 7.16 (m, 2H); 7.26 (d, 1H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:41])[C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:41])[C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(CCCO)C(=O)OCc1ccccc1

Procedure:
TBAF (12.8 ml, 1.0 M solution in THF, 12.8 mmol) was added to the solution of benzyl 3-(tert-butyldimethylsilyloxy)propyl(methyl)carbamate obtained in step 3 (3.6 g, 10.7 mmol) in THF (30 ml). After reaction complete, water and EtOAC work-up and then drying were followed to give benzyl 3-hydroxypropyl(methyl)carbamate (formula 31). After further purification, alcohol was treated with triphenylphosphine (3.35 g, 12.8 mmol) and carbon tetrabromide (12.8 mmol) in acetonitrile (20 ml). The reaction progress was monitored by TLC or LS/MS. After reaction complete, the organic layer was extracted and evaporated. The residue was purified with silica gel column chromatography (EtOAC:Hx=1:5) to give the title compound (2.5 g, 82%, 2 steps) as light yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([N:21]2[CH2:42][CH2:41][C:24]3([NH:28]/[C:27](=[N:29]/[C:30]([C:32]4[C:37]([NH2:38])=[N:36][C:35]([NH2:39])=[C:34]([Cl:40])[N:33]=4)=[O:31])/[NH:26][CH2:25]3)[CH2:23][CH2:22]2)=[O:20])[CH:14]=1)(=[O:12])=[O:11])(C)(C)C.CCCC(C)C>Cl.O1CCOCC1>[NH2:38][C:37]1[C:32]([C:30](/[N:29]=[C:27]2/[NH:28][C:24]3([CH2:41][CH2:42][N:21]([C:19]([C:15]4[CH:14]=[C:13]([S:10]([NH:9][CH2:8][CH2:7][C:6]([OH:43])=[O:5])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=4)=[O:20])[CH2:22][CH2:23]3)[CH2:25][NH:26]/2)=[O:31])=[N:33][C:34]([Cl:40])=[C:35]([NH2:39])[N:36]=1
Reactant: CC(C)(C)OC(=O)CCNS(=O)(=O)c1cccc(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)c1
Agent: Cl
Solvent: CCCC(C)C
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)c4cccc(S(=O)(=O)NCCC(=O)O)c4)CC3)N2)nc1Cl

Procedure:
A solution of 3-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid tert-butyl ester (step 1) (900 mg, 1.415 mmol) in 4N HCl in dioxane (10 ml) was stirred for 16 h at RT. Iso-hexane (10 ml) was added to the reaction mixture and resulting suspension was sonicated for 1 hour at RT. The solvent was decanted off and the solids washed with iso-hexane (10×25 ml). The resulting pale yellow crystals were dried under vacuum @45° C. for 36 h to afford the title compound; LC-MS Rt 0.80 mins; 580.0 [M+H]+, Method 2minLC_v003.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:11][CH:12]=1)=[O:7].[OH-].[Na+].CO>O>[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][C:10]1[S:9][C:8]([C:6](=[O:7])[CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)CCC(=O)c1ccc(Cc2ncc[nH]2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCC(=O)c1ccc(Cc2ncc[nH]2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.17 g of 4-[5-(1-imidazolylmethyl)-thien-2-yl]-4-oxo-butyric acid methyl ester, 0.8 g of sodium hydroxide and 20 ml of methanol is stirred at room temperature for 8 hours. The solvent is then stripped off and the residue is taken up in water. The solution is extracted several times with chloroform, and the chloroform phase is discarded. The aqueous solution is brought to about pH 7 with dilute hydrochloric acid and is concentrated to dryness. The residue is purified by column chromatography (silica gel/CHCl3 /methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:17]1[N:22]=[C:21]([C:23]2[CH:35]=[CH:34][C:26]3[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=3[CH:24]=2)[CH:20]=[CH:19][N:18]=1>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([C:17]2[N:22]=[C:21]([C:23]3[CH:35]=[CH:34][C:26]4[N:27]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[S:29][C:25]=4[CH:24]=3)[CH:20]=[CH:19][N:18]=2)[CH3:13])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: CNS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)N(C)c2nccc(-c3ccc4nc(NC(C)=O)sc4c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methoxy-N-methylbenzenesulfonamide (228 mg, 1.13 mmol) was dissolved in DMSO (1.6 mL) and NaH (57.5 mg, 60% in mineral oil, 1.44 mmol) was added and the reaction was stirred under nitrogen at RT. After 1 hour, N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (82.3 mg, 0.270 mmol) was added, and the reaction flask was heated in a preheated oil bath (125° C.) and stirred under nitrogen overnight. The reaction was cooled to RT and filtered through a pad of Celite®(diatomaceous earth). Filtrate was concentrated and the crude material was purified on HPLC (10-95% MeCN/water with 0.1% TFA over 30 minutes) to provide N-(6-(2-(4-methoxy-N-methylphenylsulfonamido)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 470 (MH+). Calculated exact mass for C21H19N5O4S2: 469. 1H NMR (400 MHz, DMSO-d6): 12.52 (s, 1H), 8.64 (d, J=5.0 Hz, 1H), 8.56 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz, 1H), 7.72 (d, J=5.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 2H), 3.82 (s, 3H), 3.69 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23]O)=[N:21][N:20]=[C:19]1[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH2:23][N:35]2[C:31](=[O:41])[C:32]3=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]3[C:34]2=[O:36])=[N:21][N:20]=[C:19]1[CH2:25][CH2:26][N:27]([CH3:28])[CH3:29]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 1B, 2'-chloro-5-nitro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in 1,2-dimethoxyethane is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 2'-chloro-5-nitro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[CH:10](O)=O.C=O>O>[CH3:10][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1
Reactant: O=CO
Reactant: OCCC1CCNCC1
Agent: C=O
Solvent: O
Product: CN1CCC(CCO)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 129 %

Procedure:
2-Piperidin-4-yl-ethanol (2.37 g, 18.3 mmol) was dissolved in formic acid (2.1 mL, 55.7 mmol), 35% aqueous formaldehyde solution (4.5 mL, 55.4 mmol) and water (20 mL). The reaction mixture was heated at 95° C. for 2 hours, and then cooled to room temperature. The reaction mixture was quenched by slowly pouring it onto a saturated NaHCO3 solution (200 mL) and concentrated in vacuo. The residue was suspended in MeOH (100 mL) and stirred for 2 hours, filtered, and the filtrate was concentrated in vacuo to give 2-(1-methyl-piperidin-4-yl)-ethanol (3.38 g, 129%) as a colourless oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([OH:29])=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].C(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([O:29][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OCOC(=O)C(C)(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a solution of 4-(((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.12 g, 0.23 mmol) and TEA (0.06 g, 0.6 mmol) in DMF (6 mL) was added chloromethyl pivalate (0.12 g, 0.8 mmol). And the mixture was stirred at 60° C. for 3 hours, and cooled to 25° C. To the reaction mixture was added DCM (100 mL). The organic layer was washed with brine (80 mL×6) and dried over unhydrous Na2SO4. The crude product was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=8/1) to give the title compound as yellow oil (0.09 g, 62%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([F:18])[CH:20]=3)=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: OCc1cccc(F)c1
Reactant: COC(=O)[C@@H]1CC(=O)N(c2ccc(O)cc2)C1
Product: COC(=O)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1

Procedure:
In an analogous manner to that described in Example 28b), the alkylation of the (R)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 28a)] with 3-fluorobenzylalcohol yields the (R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: [H-].[Na+].CC(C)(OC([NH:9][C:10]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)C.I[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH3:27][CH:26]([NH:9][C:10]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:28]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1NC(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4.8 g (0.12 mol) of a 60% sodium hydride solution are added, at 0° C., under argon, and in portions, to a solution of 34 g (0.11 mol) of ethyl 2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-nitrobenzoate in 100 ml of dimethylformamide. The mixture is left stirring for 20 minutes at 0° C. 55.9 g (0.33 mol) of 2-iodopropane are then added and the mixture is heated at 80° C. for 4 hours and then at room temperature for 48 hours. Hydrolysis is carried out by adding water and extraction is carried out 3 times with ethyl acetate. The organic phase is collected and washed successively with water and with a saturated sodium chloride solution. It is dried and evaporated.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH3:14])[C:10](OC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Li+]>C1COCC1>[Si:1]([O:8][C@@H:9]([CH3:14])[CH2:10][OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 84.6 %

Procedure:
To a solution of 17A (1.33 g, 6.09 mmol) in THF (20 mL) at 0° C., was added lithium borohydride (0.531 g, 24.36 mmol). The resultant suspension was stirred at rt for 7 h. The reaction was cooled to 0° C., then was quenched with sat. NH4Cl (5 mL). The mixture was diluted with H2O and hexanes. The reaction mixture was acidified with 1 N HCl, then was extracted with hexanes (3×). The combined organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (0 to 60% ethyl acetate/hexanes) to give 17B (980 mg, 5.15 mmol, 85% yield) as a colorless oil. MS (ESI) m/z: 191.2 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ ppm 3.87-3.96 (m, J=6.3, 6.3, 6.3, 6.3, 3.6 Hz, 1H) 3.51 (ddd, J=11.0, 7.7, 3.6 Hz, 1 H) 3.37 (ddd, J=11.1, 6.3, 5.1 Hz, 1H) 1.93 (dd, J=7.8, 5.3 Hz, 1H) 1.12 (d, J=6.3 Hz, 3H) 0.90 (s, 9H) 0.09 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:34][C:33]([CH3:40])([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:32]2)[N:3]=1.CC(O)=O>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:32][C:33]([CH3:40])([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[CH2:34]2)[N:3]=1
Reactant: CC1(N2CCCC2)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C1
Solvent: CC(=O)O
Solvent: O
Product: CC1(N2CCCC2)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)C1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A solution of [(2R)-3-(2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (145 mg) in 4:1 AcOH:water (20 mL) was stirred at room temperature overnight. LCMS indicated ˜45% completion of the deprotection. Another portion of the mixed solvents (4:1 AcOH:water, 20 mL) was added, and stirring continued overnight. The solvents were then removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (45 mg, 36%). LCMS: (M+H)+: 498.2.
Reaction SMILES: O[C@H]1CC[C@H]2[C@H]3[C@H](CC[C@]12C)[C@]1(CO)C(=CC(=O)CC1)CC3.[CH3:23][O:24][C:25]1([O:30][C@H:31]2[CH2:36][CH2:35][C@H:34]3[C@H:37]4[C@H:55]([CH2:56][CH2:57][C@:32]23[CH3:33])[C@:45]2([CH2:46][O:47][C:48]3([O:53][CH3:54])[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:40](=[CH:41][C:42](=[O:58])[CH2:43][CH2:44]2)[CH2:39][CH2:38]4)[CH2:29][CH2:28][CH2:27][CH2:26]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O1CCCC1>[CH3:23][O:24][C:25]1([O:30][C@H:31]2[CH2:36][CH2:35][C@H:34]3[C@H:37]4[C@H:55]([CH2:56][CH2:57][C@:32]23[CH3:33])[C@:45]2([CH2:46][O:47][C:48]3([O:53][CH3:54])[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:40](=[CH:41][C@@H:42]([OH:58])[CH2:43][CH2:44]2)[CH2:39][CH2:38]4)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC1(OC[C@]23CCC(=O)C=C2CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC4(OC)CCCC4)CC[C@@H]23)CCCC1
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC1(OC[C@]23CC[C@H](O)C=C2CC[C@@H]2[C@@H]3CC[C@]3(C)[C@@H](OC4(OC)CCCC4)CC[C@@H]23)CCCC1

Procedure:
The compound 17β,19-dihydroxyandrost-4-en-3-one is similarly etherified to form the 17β-OR4, 19-OR1, derivatives of androst-4-en-3-one. Reduction as previously described yields the corresponding 3-hydroxy analogues. For example, 17β,19-dihydroxyandrost-4-en-3-one is converted to 17β,19-di-triphenylsiloxyandrost-4-en-3-one and 17β,19-di-(1-methoxy-1-cyclopentyloxy)-androst-4-en-3-one as previously described. These compounds are then reduced using lithium aluminum hydride in an ether or tetrahydrofuran solution to produce 17β,19-di-triphenylsiloxyandrost-4-en-3β-ol and 17β,19-di-(1-methoxy-1-cyclopentyloxy)-androst-4-en-3β-ol, respectively.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[CH:16]=[C:15]([O:17]C)[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.B(Br)(Br)Br.ClCCl.[Cl-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OC)cc1Nc1ccc(F)cc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(O)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.7 %

Procedure:
Methyl 2-(4-fluoroanilino)-4-methoxybenzoate 2.2 g was added to 1.0 mol/L boron tribromide/dichloromethane 24 mL, and it was stirred at room temperature for 5 hours. Saturated sodium chloride aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=5:1] to give methyl 2-(4-fluoroanilino)-4-hydroxybenzoate 0.60 g of purple solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C>[Si:21]([O:1][CH2:2][CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCNC(CO[Si](C)(C)C(C)(C)C)C1
Reaction time: 20 h

Procedure:
To a solution of racemic tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.5 g, 6.9 mmol, AstaTech) and 1H-imidazole (1.4 g, 21 mmol) in DMF (20 mL) cooled to 0° C. was added tert-butyldimethylsilyl chloride (2.1 g, 14 mmol). The mixture was then allowed to reach RT and stir for 20 h. The mixture was quenched by the addition of saturated ammonium chloride. The product was extracted with two portions of ethyl acetate. The organic extract was washed with water, brine, dried over sodium sulfate and concentrated to afford a clear oil. Flash chromatography on a 120 g silica gel cartridge, eluting with a slow gradient from 0-6% MeOH in DCM afforded purified product (1.15 g, 50%). 1H NMR (400 MHz, CDCl3): δ 4.00-1.63 (m, 9H), 1.45 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H); LCMS (M+H)+: 331.2.