Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[Cu][C:42]#[N:43]>CN1CCCC1=O>[C:42]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=5)[N:24]([CH3:32])[N:23]=4)[N:20]=3)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[CH:14]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1)#[N:43]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccc(Br)cc1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccc(C#N)cc1
Temperature: 200 °C
Reaction time: 2.5 h

Procedure:
To a 20 ml microwave vial was added 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-bromophenyl)-ethyl]-amide (62 mg, 0.10 mmol), copper (I) cyanide (18 mg, 0.20 mmol), and N-methyl-pyrrolidinone (6 ml) (HPLC grade, dried with 4A powdered molecular sieves). The resulting solution was purged with nitrogen then the vial sealed, and heated in an oil bath at 200° C. After 2.5 h the reaction was allowed to cool to room temperature over 17 h. The reaction was separated into two vials and each was independently subjected to heating in a microwave reactor at 200-230° C. for 2.5 h. The reactions were combined, diluted with water (50 ml), and extracted with ethyl acetate (50 ml) two times (5 ml of brine was added to clear phases). The organic layers were washed with brine (25 ml), combined, dried over magnesium sulfate, filtered, and further dried under a stream of nitrogen. The crude brown solid was purified by flash chromatography (4 g silicycle) with 0% to 60% EtOAc in hexanes. The appropriate fractions were combined and dried from a mixture dichloromethane and hexanes yielding 32 mg (56%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-phenyl)-ethyl]-amide as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][N:13](C(OCC4C=CC=CC=4)=O)[CH2:12]3)=[C:8]([C:28](=[O:30])[NH2:29])[CH:7]=[N:6][N:5]2[CH:31]=1.[I:32][Si](C)(C)C>C(#N)C>[IH:32].[Br:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][NH:13][CH2:12]3)=[C:8]([C:28]([NH2:29])=[O:30])[CH:7]=[N:6][N:5]2[CH:31]=1
Reactant: C[Si](C)(C)I
Reactant: NC(=O)c1cnn2cc(Br)nc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Solvent: CC#N
Product: I
Product: NC(=O)c1cnn2cc(Br)nc2c1N[C@@H]1CNC[C@@H]1CF
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (240 mg, 0.488 mmol) in acetonitrile (3 ml) at 0° C. was added iodotrimethylsilane (0.266 ml, 1.954 mmol) dropwise. The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 1.5 h. The reaction was cooled to 0° C. and quenched with MeOH (2 ml). The resulting suspension was stirred at 0° C. for 30 min, filtered, washed with ethyl ether, and dried under vacuum to afford 2-bromo-8-(((3S,4S)-4-(fluoromethyl)pyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide, hydroiodide as an off-white solid. ESI-MS (analytical LCMS Method A): m/z 357.0 ([M+H]+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.Cl.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1.CN(C=O)C.[C:23]1([CH:29](O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: OC(Cc1ccccc1)c1ccccc1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCC(C(=O)OC(Cc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
Oxalyl dichloride (141 μl, 1.67 mmol) was added dropwise to a solution of 1-methylpiperidine-4-carboxylic acid hydrochloride (300 mg, 1.67 mmol) in DCM (20 ml) and few drops of DMF (catalytic amount). The reaction was stirred at room temperature for 2 hours. The volatiles were removed under vacuum, and the crude was taken up with pyridine (20 ml). 1,2-Diphenylethanol (331 mg, 1.67 mmol) was added, and the resulting suspension was heated under microwave irradiation at 140° C. for 1 hour. Pyridine was removed under vacuum, and the crude was purified by flash chromatography (DCM/MeOH=97/3 to 94/6) to obtain 1,2-diphenylethyl 1-methylpiperidine-4-carboxylate (200 mg).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([NH:13][C:14](=[O:34])[NH:15][C:16]2[N:17]=[CH:18][N:19]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:20]=2[C:21]([O:23]CC)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]CC.[Na+]>C(O)C>[CH2:1]([O:8][CH:9]1[CH2:10][CH:11]([N:13]2[C:21](=[O:23])[C:20]3[N:19]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[CH:18]=[N:17][C:16]=3[NH:15][C:14]2=[O:34])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(NC(=O)NC2CC(OCc3ccccc3)C2)ncn1Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c2ncn(Cc3ccc(Cl)cc3)c2c(=O)n1C1CC(OCc2ccccc2)C1
Yield: 85.8 %

Procedure:
To a solution of ethyl 4-(3-(3-(benzyloxy)cyclobutyl)ureido)-1-(4-chlorobenzyl)-1H-imidazole-5-carboxylate (310 mg, 0.64 mmol) in ethanol (50 mL) was added freshly prepared sodium ethoxide (87.4 mg, 1.28 mmol) and the reaction was heated at reflux for 4 h. The reaction was cooled and concentrated. The residue was partitioned between ethyl acetate and brine. The organic layer was dried and concentrated to give 1-(3-(benzyloxy)cyclobutyl)-7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (240 mg, 85.5% yield) as a yellow solid. LCMS retention time 1.764 min; LCMS MH+ 437.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl.[CH3:35][NH:36][CH3:37].C(O)(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH3:35][N:36]([CH3:37])[C:29]1[CH:30]=[N:31][C:26]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=2)=[N:27][CH:28]=1
Reactant: CNC
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N(C)C)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and dimethylamine hydrochloride as starting materials and by an operation similar to that of Example 442-2 (solvent was changed to tert-butanol) was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32]([NH2:34])[C:31]([C:35]#[N:36])=[C:30](Cl)[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:29]=[C:30]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:32]([NH2:34])[N:33]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 95 °C
Yield: 35.8 %

Procedure:
To a 25 mL pear flask were added tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (0.076 g, 0.21 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile (0.054 g, 0.32 mmol) in DMSO (1 mL) to give a yellow suspension. Triethylamine (0.088 mL, 0.63 mmol) was added and the mixture was heated to 95° C. for 2 hours. The reaction appeared to stall so 1 equivalent of triethylamine was added. After a total of 4 hours of heating, the mixture was cooled and the reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by preparative HPLC (acid mode, 20-25% ACN/water gradient). The product-containing fractions were combined, neutralized with a small amount of saturated NaHCO3, concentrated in vacuo to remove ACN, and then extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a pale beige solid (37 mg, 36%). 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 11H), 1.87 (br s, 2H), 2.72 (br s, 2H), 2.97 (br s, 2H), 3.70 (s, 3H), 4.80-5.11 (m, 4H), 5.92 (br s, 1H), 6.59 (d, J=2.27 Hz, 1H), 6.76 (d, J=6.06 Hz, 1H), 7.16 (d, J=2.78 Hz, 2H), 7.32 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C24H32N10O2, 493. found 493.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([I:17])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.Cl>[OH-].[Na+].O>[I:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1c[nH]c2c(I)cccc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1c[nH]c2c(I)cccc2c1=O
Temperature: 25 °C
Yield: 81.7 %

Procedure:
8-Iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (2 g, 5.83 mmol) was suspended in 10% NaOH in water (20 mL). The mixture was stirred under reflux for 1 h. The crude was cooled to room temperature and acidified with concentrated HCl. The solid was filtered off and thoroughly washed with water to afford 8-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid as a pinkish solid (1.5 g, 81.6%). 1H NMR (DMSO-d6, 400 MHz) δ 7.04 (t, 1H), 8.12–8.16 (m, 2H), 8.71 (s, 1H). Exact mass calculated for C10H6INO3 314.94, found 316 (MH+).
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH2:7].[OH-].[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C@H:6]1[O:1][CH2:7]1
Reactant: C=Cc1cccc(Cl)c1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: 0 °C
Yield: 92 %

Procedure:
A 2-necked round-bottom flask equipped with a water-cooled overhead stirrer was charged with 3-chlorostyrene (5.01 g, 3.61×10−2 mol), CH2Cl2 (45 mL), (R,R)-3 (0.578 g, 9.10×10−4 mol), and 4-PPNO (0.924 g, 5.40×10−3 mol). The solution was cooled to 0° C., and precooled buffered bleach (0.6 M, 75 mL, 4.50×10−2 mol, Clorox®, buffered to pH=11.3 with 0.05 M Na2HPO4 and 1M NaOH) was added. The two phase system was stirred vigorously, and the course of the reaction was monitored by GC. Upon complete consumption of starting olefin (<6 h), the reaction mixture was filtered through a plug of Celite on a coarse glass frit and washed with CH2Cl2 (75 mL). The organic layer of the filtrate was washed with distilled water (2×25 mL), and the aqueous layers were extracted with CH2Cl2 (2×25 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Removal of the catalyst was effected by elution through a pad of SiO2 (30 g) using pentane and CH2Cl2 (1:1). The eluent was concentrated in vacuo, and subsequent bulb-to-bulb distillation (70° C., 0.6 mm Hg) from CaH2 afforded (R)-3-chlorostyrene oxide (5.15 g, 92%) as a pale yellow liquid in 32% ee.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH:10](=O)[CH:11]=O>C(O)(=O)C.C([O-])(=O)C.[Na+].O>[N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:9])[C:2]=2[N:1]=[CH:11][CH:10]=1
Reactant: O=CC=O
Reactant: Nc1cccc(O)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc2nccnc12
Temperature: 60 °C

Procedure:
2,3-Diaminophenol (2 g) in 10 ml acetic acid and 20 ml 4M sodium acetate and a solution of oxalaldehyde (4.8 g) dissolved in 20 ml water were combined and the resulting mixture was heated at 60° C. for 1.5 h. After cooling to RT water (100 ml) was added and the mixture extracted with EtOAc. The organic layer was dried over Na2SO4, and concentrated to give quinoxalin-5-ol. MS (ESI+) for m/z 147 [M+H]+.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17](=[NH:21])OCC)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH3:25]>C(O)C>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[C:17]([NH2:21])=[NH:25])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=N)c1cccc(OCc2ccccc2)c1
Reactant: N
Agent: F[B-](F)(F)F
Solvent: CCO
Product: N=C(N)c1cccc(OCc2ccccc2)c1
Temperature: -70 °C
Reaction time: 69 h

Procedure:
A suspension of 8.57 g of ethyl m-benzyloxybenzimidate tetrafluoroborate in ethanol (120 ml) was cooled to −70° C. and then treated with liquid ammonia (100 ml). The cooling bath was removed and the reaction mixture stirred for 69 h until the reaction was complete (TLC analysis). The solvent was removed in vacuo to give the desired m-benzyloxybenzamidine tetrafluoroborate as a white solid, mp 125°-127° C., that was essentially pure and used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:19]=[C:18]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17]3)[C:11]=2[CH3:20])=O)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][C:10]1[C:11]2[C:12]([CH:18]=[CH:17][CH:16]=[CH:15][CH:20]=2)=[C:13]([CH3:14])[CH:19]=1
Reactant: Cc1c(C(=O)c2cccc(Br)c2)cc2cccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cc2cccc(Br)c2)c2cccccc1-2
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
Boron trifluoride-diethyl ether complex (1.17 ml) was added to a solution of (3-bromophenyl)(1-methylazulen-2-yl) methanone (0.5 g) in diglyme-ether (ratio: 1:1, 2.0 ml) at 0° C. and the mixture was stirred for 20 minutes. Then, sodium borohydride (0.68 g) was added to the reaction mixture and the mixture was stirred at room temperature for one hour. The reaction mixture was added to ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ether) to obtain 1-(3-bromobenzyl)-3-methylazulene (0.21 g).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:12](=O)([O-])[O-:13].[K+].[K+]>C(=O)(OCC)OCC>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]2[CH2:3][O:4][C:12](=[O:13])[NH:1]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC(CO)c1ccc(F)cc1
Agent: [K+]
Solvent: CCOC(=O)OCC
Product: O=C1NC(c2ccc(F)cc2)CO1
Temperature: 130 °C
Reaction time: 2.5 h
Yield: 581.7 %

Procedure:
600 mg of 2-amino-2-(4-fluorophenyl)ethan-1-ol and 80 mg of potassium carbonate were suspended in 914 mg of diethyl carbonate, and the mixture was stirred at 130° C. for 2.5 hours, and further stirred at 100° C. for 2.5 hours while removing the ethanol that was generated. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 610 mg of the objective compound as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N+:16]([O-])=[CH:15][CH:14]=3)[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)=[N:9]2)=[CH:5][CH:4]=1.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>FC(C1C=CC=CC=1)(F)F.ClCCl>[C:31]([NH:35][C:15]1[CH:14]=[C:13]([C:11]2[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)=[N:9][N:8]([CH2:7][C:6]3[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]=2)[CH:18]=[CH:17][N:16]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: FC(F)(F)c1ccccc1
Product: COc1ccc(Cn2cc(-c3ccnc(NC(C)(C)C)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reaction time: 6 h
Yield: 75 %

Procedure:
580 mg (1.44 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine 1-oxide were suspended in a mixture of 16 ml of trifluoromethylbenzene and 4 ml of dry dichloromethane and 756 μl of tert-butylamine were added. At 0° C. 936 mg (7.2 mmol) of p-toluensulfonic anhydride were added. After 6 hours under stirring in the same conditions the solvent was removed under reduced pressure, the residue partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and evaporated. The crude was then purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 19/1), giving 500 mg (75%) of the title compound.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:11]1([CH3:40])[CH3:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[C:1]([O:9][C@H:10]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:12]([CH2:13][CH2:14][C:15]3[C:16]4[C@:30]([CH3:38])([CH2:31][CH2:32][C:33]=32)[C@@H:19]([C@@H:20]([OH:22])[CH3:21])[CH2:18][CH:17]=4)[C:11]1([CH3:39])[CH3:40])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([O:9][C@H:10]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:12]([CH:13]=[CH:14][C:15]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C:16]=3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([OH:22])[CH3:21])[C:11]1([CH3:39])[CH3:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H](O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](OC(=O)c2ccccc2)C(C)(C)[C@@H]1CC3
Product: C[C@H](O)[C@H]1CCC2=C3C=C[C@H]4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
xii)—A mixture of compound 12a (36.6 g), toluene (91 ml), ethanol (622 ml; 96%) and concentrated hydrochloric acid (91 ml) was heated under reflux for 4 h. The mixture was cooled and poured into a saturated aqueous solution of sodium hydrogen carbonate (1 l). The product was extracted into ethyl acetate, the combined organic phases were washed with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography and crystallization afforded (3β,5α,20S)-4,4-dimethylpregna-8,14-diene-3,20-diol 3-benzoate (compound 13a; 7.89 g) and (3β,5α,20S)-4,4-dimethylpregna-6,8(14)-diene-3,20-diol 3-benzoate (3.69 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[O:12][C:13]2[C:14](=[C:16]([S:22](Cl)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH:15]=1)(=[O:10])[CH3:9].[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>ClCCl>[C:8]([C:11]1[O:12][C:13]2[C:14](=[C:16]([S:22]([NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH:15]=1)(=[O:10])[CH3:9]
Reactant: COc1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12
Reactant: NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCc2cccnc2)c2cc(C(C)=O)oc12

Procedure:
Triethylamine (0.43 ml) was added to a solution of 2-acetyl-7-methoxy-4-benzofuransulphonyl chloride (600 mg) and 3-(aminomethyl)pyridine (0.25 ml) in dichloromethane at room temperature. The resultant mixture was stirred for 20 hours and then diluted with dichloromethane (20 ml). The solution was washed with water (20 ml) and brine (20 ml) and dried (MgSO4). Concentration in vacuo provided a dark oil which was applied to a silica column and eluted with 2% methanol in dichloromethane. The title compound was obtained as a pale yellow solid (161 mg). Mp 168°-170° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([NH:5][CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[CH2:7][CH:8]=[CH2:9])=O.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:7]([C:6]1[N:5]=[C:3]([C:2]([CH3:15])([CH3:14])[CH3:1])[O:13][C:10]=1[CH2:11][CH3:12])[CH:8]=[CH2:9]
Reactant: C=CCC(NC(=O)C(C)(C)C)C(=O)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CCc1nc(C(C)(C)C)oc1CC
Reaction time: 4 h

Procedure:
2.10 g of the above prepared 2,2-dimethyl-N-(1-propionyl-but-3-enyl)-propionamide (9.94 mmol) were treated with 16.74 ml of trifluoroacetic acid (219 mmol) and 8.29 ml of trifluoroacetic anhydride (6 eq.) and kept for 4 h at 50°, when TLC indicated the disappearance of starting material. The reaction mixture was then poured onto crashed ice/Na2CO3, the aqueous layer (pH ˜8), extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=95/5) delivered 1.29 g of the title compound as yellowish liquid.
Reaction SMILES: C([O:8][C:9]1[C:34]([F:35])=[CH:33][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[C:11]([F:36])[CH:10]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:35][C:34]1[CH:33]=[C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:31])[CH3:32])[CH:24]([CH3:25])[CH3:26])[CH:15]=2)[C:11]([F:36])=[CH:10][C:9]=1[OH:8]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(OCc3ccccc3)cc2F)c2cccnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(O)cc2F)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(4-Benzyloxy-2,5-difluoro-benzyl)-1-triisopropylsilanyl-1 yl-pyrrolo[2,3-b]pyridine (49, 0.70 g, 0.0014 mol) in methanol (30.0 mL) was added 50% palladium hydroxide on carbon (0.1 g) under an atmosphere of hydrogen. The reaction was stirred at room temperature overnight. The reaction was filtered and concentrated to give a colorless oil (50, 0.47 g, 82.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][C:7]=1[Br:8].[CH2:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)[CH2:11][CH3:12].O>C(NCC)C.[Cu](I)I>[F:1][C:2]1[CH:3]=[C:4]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:10][CH2:11][CH3:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: Fc1cc(I)ccc1Br
Agent: I[Cu]I
Solvent: O
Solvent: CCNCC
Product: CCCc1ccc(C#Cc2ccc(Br)c(F)c2)cc1
Yield: 100 %

Procedure:
To a solution of 33 mmol of 3-fluoro-4-bromo iodobenzene, 0.6 mmol of copper iodide and 1.1 mmol of dichlorobistriphenylphosphine palladium in 100 ml of diethylamine were added dropwise 33 mmol of 4-propyl phenylacetylene under an argon stream while stirring. After completion of the addition, the solution was stirred at room temperature for a further 2 hours and placed into water. The solution was extracted with heptane, washed with water and concentrated under reduced pressure to afford a brown oily product. The product was isolated and purified by a silica gel column chromatography to afford 33 mmol of 2-fluoro-4-[2-(4-propylphenyl)ethynyl]bromobenzene as a pale yellow oily product.