Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C([N:29]1CCO[C@H:31]([CH2:35][C:36]2C=CC=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30]1)(OC(C)(C)C)=O.C(C1C=CC=CN=1)=C.C(O)(C(F)(F)F)=O>>[N:29]1[CH:30]=[CH:31][CH:35]=[CH:36][C:37]=1[CH2:38][CH2:42][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(Br)c2)C1
Agent: C=Cc1ccccn1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CCc2cccc(C[C@@H]3CNCCO3)c2)nc1

Procedure:
Example 69 was prepared using the procedure as described for example 31, but starting with N-Boc-(R)-2-(3-bromobenzyl)morpholine, example 31, intermediate (b), and 2-vinylpyridine. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 68 as a yellow oil (16 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](N2CCCC2)=[O:9])=[N:6][C:5]([Cl:15])=[CH:4][N:3]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O1CCCC1>O>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:6][C:5]([Cl:15])=[CH:4][N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Nc1ncc(Cl)nc1C(=O)N1CCCC1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(Cl)nc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-5-chloropyrazine-3-carboxylic acid pyrrolidide (9 g. or 0.04 mol) was added to a freshly prepared solution of 36.2 g. (0.2 mol) of phenylmagnesium bromide in 300 ml. of tetrahydrofuran cooled to 20°. After addition, the reaction mixture was stirred for 3 hours at room temperature and was then hydrolyzed by addition of 150 ml. of water. The organic layer was separated, dried over alumina, filtered and evaporated. Crystallization of the oil obtained from ether yielded 2 g. (50%) of the above-named product as yellow crystals, m.p. 158°-161°. The analytical sample was recrystallized from ethyl acetate, m.p. 160°-161°.
Reaction SMILES: [CH:1]1([C:6]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[C:11]([O:17]C)[CH:10]=2)([CH3:8])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)C>[CH:1]1([C:6]([C:9]2[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:17])[CH:10]=2)([CH3:8])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(C)(C)C2CCCC2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(c1cc(O)cc(O)c1)C1CCCC1

Procedure:
Compound 20 was prepared from Compound 13 using the same procedure as described above for Compound 16. Yield 1.29 g (72.9%) as a viscous oil. Rf=0.28 (hexane:diethyl ether 6:4); 1H NMR δ 6.44 (d, J=2.1 Hz, 2H), 6.20 (t, J=2.1 Hz, 1H), 5.70 (br s, 2H), 2.02–1.98 (m, 1H), 1.57–1.35 (m, 6H), 1.18 (s, 6H); 13C NMR δ 156.22, 154.66, 105.10, 99.83, 53.24, 50.33, 36.21, 24.99, 24.75; MS: (ESI, Neg.) m/z 219 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14].N1CCCCC1.CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)c1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Temperature: 130 °C

Procedure:
Alternatively, a mixture of 5-methoxyindolin-2-one (0.50 g, 3.1 mmol), 2-acetylpyrrole (0.28 g, 2.4 mmol) and piperidine (0.60 g, 0.6 mmol) was placed in a sealed tube and melted. The reaction vessel was sealed and the mixture was heated to 130° C. overnight. The reaction was then cooled to ambient temperature and dissolved in ethyl acetate (2 mL). Chromatography (SiO2, 15 g) using 2:1 hexane/ethyl acetate afforded 5-methoxy-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (0.24 g); 1H NMR (400 MHz, DMSO-d6) δ 2.78 (s, 3H), 3.82 (s, 3H), 6.38 (m, 1H), 6.70–6.80 (m, 2H), 6.98 (m, 1H), 7.16 (m, 1H), 7.30 (m, 1H), 7.68 (m, 1H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH2:11]OC)[CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].C(C1[CH:28]=[C:27]([CH2:29][OH:30])[CH:26]=C(C(C)(C)C)C=1O)(C)(C)C.C(=O)C(C)C>[OH-].[K+]>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][C:27]([CH3:28])([CH3:26])[CH:29]=[O:30])[CH:8]=[C:7]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:6]=1[OH:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1O
Reactant: COCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(C)C=O
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A process comprising reacting 2,6-di-tert.butyl-4-methoxymethylphenol or 2,6-di-tert.butyl-4-hydroxymethylphenol with isobutyraldehyde in the presence of potassium hydroxide as a catalyst to yield 3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropionaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:23](=[O:24])[CH2:22][C:21]([CH3:20])=[O:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)NCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
2-{[4-(2-Aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (3.0 g) synthesized in Example 7 was dissolved in N,N-dimethylformamide (50 mL), and diketene (0.88 g) was added dropwise under ice-cooling. After raising to room temperature, the mixture was stirred for one hour. The mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-({4-[2-(acetoacetylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (3.4 g) as a colorless oil. This compound was used in the next step without particular purification. [4-(Trifluoromethoxy)phenyl]hydrazine hydrochloride (390 mg) was dissolved in ethanol (8 mL), pulverized sodium hydroxide (65 mg) was added at room temperature. The insoluble material was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was dissolved again in ethanol (8 mL), 2-({4-[2-(acetoacetylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (600 mg) obtained earlier was added at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (8 mL), diphosphorus pentasulfide (345 mg) and sodium carbonate (329 mg) were added, and the mixture was heated under reflux for 2 hr. The solvent was evaporated, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (690 mg) as a colorless oil.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C:8]([CH3:10])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].[Cl-].[Na+]>C1COCC1.CCO.CCO.CCO.CCO.[Ti]>[Si:5]([O:6][CH2:7]/[C:8](=[N:19]/[S@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH3:10])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Ti]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C(CO[Si](C)(C)C(C)(C)C)=N\[S@@](=O)C(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 761 mg of 1-{[tert-butyl (dimethyl)silyl]oxy}acetone in 20 ml of THF were added 2.1 ml of tetraethyl orthotitanate and 490 mg of (S)-2-methylpropane-2-sulfinamide, followed by stirring at 70° C. for 8 hours. The reaction mixture was left to be cooled to room temperature and a saturated aqueous sodium chloride solution was then added thereto, followed by stirring and filtering over Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (S)—N-[(2E)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ylidene]-2-methylpropane-2-sulfinamide.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:41])[C@@H:28]2[CH2:32][C@H:31]([OH:33])[CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-]>ClCCl.CN(C)C1C=CN=CC=1>[O:13]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:41])[C@@H:28]2[CH2:32][C@H:31]([O:33][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:30][N:29]2[C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1ccc(Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (4.40 mL) and methanesulfonyl chloride (1.95 mL) was added to a cold (0° C.) stirred solution of cis-4-hydroxy-N-tert-butoxycarbonyl-L-proline 4-phenoxyphenylamide (C, 5.02 g) in dichloromethane (100 mL). The mixture was stirred at 0° C. for 2 hr and at room temperature for 45 min. Triethylamine (4.40 mL) and mehanesulfonyl chloride (1.95 mL) was added to the cold (0° C.) stirred mixture. The mixture was stirred at 0° C. to room temperature for 2 hr, and 4-dimethylaminopyridine (1.54 g) was added at 0° C. The mixture was stirred at room temperature for 1 hr and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (6.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:13][CH3:14])=[CH:5][C:6]2[Te:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1.[F:15][C:16]([F:25])([F:24])[S:17]([O:20][CH2:21][C:22]#[CH:23])(=[O:19])=[O:18]>ClCCl>[F:15][C:16]([F:25])([F:24])[S:17]([O-:20])(=[O:19])=[O:18].[CH3:1][O:2][C:3]1[C:4]([O:13][CH3:14])=[CH:5][C:6]2[Te:10][C:9]([CH3:11])=[N+:8]([CH2:23][C:22]#[CH:21])[C:7]=2[CH:12]=1
Reactant: C#CCOS(=O)(=O)C(F)(F)F
Reactant: COc1cc2nc(C)[te]c2cc1OC
Solvent: ClCCl
Product: C#CC[n+]1c(C)[te]c2cc(OC)c(OC)cc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5,6-Dimethoxy-2-methylbenzotellurazole (Example 19) (1.0 g, 0.033 mole) was dissolved in dichloromethane (25 ml). The solution of 2-propyn-1-yl trifluoromethanesulfonate, prepared as described above, was added from a dropping funnel under a nitrogen atmosphere. After completion of the addition the mixture was stirred for 16 hours at room temperature. The solid was isolated by filtration, washed with diethyl ether, and dried under vacuum at room temperature. Yield, 1.14 g (70% of theory). The infrared, nuclear magnetic resonance, and mass spectra were in agreement with that expected for the structural formula.
Reaction SMILES: [Cl:1][CH:2]([Cl:36])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@H:24]([NH:26]C(=O)OC(C)(C)C)[CH3:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:26][C@@H:24]([C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C@@H:8]([OH:7])[C@H:9]([NH:5][C:3](=[O:4])[CH:2]([Cl:36])[Cl:1])[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:19][CH:20]=1)[CH3:25]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@@H](N)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of the product of step 1 (130 mg. 0.241 mmol) in DCM (3 mL) is added TFA (0.7 mL) and stirred at room temperature for 1 hour. Reaction is diluted with toluene (10 mL) and concentrated. The crude product is dissolved in DMF (2 mL) and DIPEA (200 μL), and purified using HPLC eluting from 5% acetonitrile/water to 100 acetonitrile/water to give the title compound (60 mg). 1H NMR (400 MHz, CD3OD) δ 1.69 (d, 3H, J=4.0 Hz), 4.31-4.41 (m, 1.5H), 4.44-4.55 (m, 1.5H) 4.56-4.63 (m, 0.5H), 4.68-4.74 (m, 0.5H), 5.02 (d, 1H, J=4.0 Hz) 6.31 (s, 1H), 7.48-7.57 (m, 4H), 7.63 (d, 2H, J=8.0 Hz), 7.72 (d, 2H, J=8.0 Hz). m/z (Cl) 382 [M-OH].
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1)#N.O.C(Cl)Cl.N([O-])=O.[Na+].[C:19]([OH:22])(=[O:21])[CH3:20]>>[C:19]([O:22][CH2:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: N#Cc1ccc(CN)cc1
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCc1ccc(C#N)cc1
Yield: 84 %

Procedure:
p-Cyanobenzylamine (13.2 g), water (18 g), and methylene chloride (18 g) were mixed, and the mixture was stirred with cooling with ice. Acetic acid (18 g) was added to the mixture. Subsequently, a 20 wt % aqueous solution (51.8 g) of sodium nitrite was added dropwise to the mixture over a one hour period. The mixture was stirred at the same temperature for four hours. The reaction mixture was subjected to extraction with methylene chloride, and the organic solvent was concentrated. Water was added to the concentrated solution, and the residual organic solvent was removed through distillation, to thereby obtain 14.7 g of p-cyanobenzyl acetate (yield 84%). The purity of the product was 98%.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([OH:9])[CH:5]=[C:4]([OH:10])[C:3]=1[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[O:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cl-].[NH4+]>[CH2:17]([C:7]1([OH:8])[C:6]([OH:9])=[C:5]([CH2:11][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:4]([OH:10])=[C:3]([C:11](=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:2]1=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)CC(=O)c1c(O)cc(O)c(O)c1O
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)CC(=O)C1=C(O)C(Cc2ccccc2)=C(O)C(O)(Cc2ccccc2)C1=O
Yield: 46.1 %

Procedure:
Under a stream of argon, 212 mg (5.31 mmol, 2.40 equivalents) of an oily dispersion of 60% sodium hydride was washed with hexane to remove the oil component. While the dispersion kept cooled with cold water, 11.0 ml of dry dimethyl sulfoxide was added and stirred. To this, was added 500 mg (2.21 mmol) of 2-methylpropyl-(2,3,4,6-tetrahydroxyphenyl) ketone (9) and stirred for 40 minutes. To the produced mixture, 0.525 ml (4.42 mmol, 2.00 equivalents) of benzyl bromide was added dropwise and stirred for four hours. The resultant mixture was combined with 10 ml of a saturated aqueous ammonium chloride solution and extracted by ether. The organic layer was washed with saturated brine, dried over sodium sulfate, concentrated under a reduced pressure, and subjected to silica gel chromatography (100 g of Wako Gel C-200, eluted with hexane:ethyl acetate=3:2) to obtain 207 mg (yield 23.1%) of the product (33) in the form of yellow powdery crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.OO.C(OCC)(=[O:24])C.[OH2:28]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:15]([C:16]([F:17])([F:19])[F:18])(=[O:24])=[O:28])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Reactant: O
Agent: OO
Solvent: CC(=O)O
Product: N#Cc1cc(S(=O)(=O)C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 2-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole-3-carbonitrile (0.6 g, 0.002 mol) in acetic acid is treated portionwise with 30% hydrogen peroxide solution (0.6 mL, 0.006 mol), stirred for 11/2 hours at 90° C., treated with additional hydrogen peroxide (0.3 mL, 0.003 mol), stirred for two hours at 90° C., stirred for 16 hours at room temperature and diluted with an ethyl acetate/water mixture. The organic phase is separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from ethylene dichloride to give the title product as a beige solid (mp 228°-230° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[C:26]([CH:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=N[CH:28]=[CH:29][N:30]=2)[CH2:20][CH2:19]1>C(Cl)Cl>[NH:34]1[CH2:33][CH2:32][CH:31]([C:26]2[C:25]([O:24][CH:21]3[CH2:20][CH2:19][N:18]([C:9]4[CH:10]=[CH:11][C:16]5[C:17](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:8]=4)[CH2:23][CH2:22]3)=[N:30][CH:29]=[CH:28][CH:2]=2)[CH2:36][CH2:35]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Solvent: ClCCl
Product: c1cnc(OC2CCN(c3ccc4ccccc4n3)CC2)c(C2CCNCC2)c1
Temperature: 25 °C
Yield: 27 %

Procedure:
Trifluoroacetic acid (0.272 mL, 3.53 mmol) was added to a solution of tert-butyl 4-(3-(1-(quinolin-2-yl)piperidin-4-yloxy)pyrazin-2-yl)piperidine-1-carboxylate (1726 mg, 3.53 mmol) in DCM (2 mL) and stirred at RT until the starting material was completely consumed. The mixture was then diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated. The brown solid was triturated with acetone and dried to give the title compound as a white solid (370 mg, 27% yield). [M+1] 390.2. IC50 (uM) 0.05444.1H NMR (CDCl3, 400 MHz) δ (ppm): 1.53-1.69 (m, 1H) 1.86-2.00 (m, 2H) 2.12-2.34 (m, 6H) 3.03-3.14 (m, 2H) 3.23-3.32 (m, 1H) 3.53-3.71 (m, 4H) 4.13-4.22 (m, 2H) 5.35-5.43 (m, 1H) 7.06 (d, J=9.19 Hz, 1H) 7.20-7.26 (m, 1H) 7.52-7.59 (m, 1H) 7.62 (d, J=7.82 Hz, 1H) 7.67-7.82 (m, 1H) 7.89-7.95 (m, 1H) 7.97 (d, J=2.74 Hz, 1H) 8.06 (d, J=2.74 Hz, 1H)
Reaction SMILES: [CH:1]#[C:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](Cl)(=[O:15])[O:11][CH:12]([CH3:14])[CH3:13]>>[CH:12]([O:11][C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1)=[O:15])([CH3:14])[CH3:13].[OH:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]=[CH2:1])=[CH:4][CH:5]=1
Reactant: CC(C)OC(=O)Cl
Reactant: C#Cc1ccc(O)cc1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(=O)OC(C)C)cc1

Procedure:
Using 12.0 g of poly(p-hydroxystyrene) obtained according to (2) of Preparation Example 18 and 4.5 g of isopropyl chlorocarbonate, the procedure of (2) of Preparation Example 6 was carried out to obtain 11.7 g of poly(p-isopropoxycarbonyloxystyrene/p-hydroxystyrene) as white powdery crystals. P-isopropoxycarbonyloxystyrene unit/p-hydroxystyrene unit molar ratio in the polymer≈3:7 (1H NMR). Mw≈9,000; Mw/Mn=1.64 (GPC with polystyrene calibration).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH:31]=O)=[N:26][N:25]=[N:24]1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:31][C:30]4[CH:33]=[CH:34][CH:35]=[C:28]([C:27]5[NH:23][N:24]=[N:25][N:26]=5)[CH:29]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(-c2nnn[nH]2)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4cccc(-c5nnn[nH]5)c4)c23)c1

Procedure:
Analogously to Example 32, 260 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine and 172 μl of acetic acid are dissolved in 25 ml of methanol and reacted with 261 mg (1.5 mmol) of 3-(tetrazol-5-yl)-benzaldehyde (Step 59.1) to form 4-(3-chloro-phenylamino)-3-{[3-(tetrazol-5-yl)-phenyl)-methyleneamino}-1H-pyrazolo[3,4-d]pyrimidine. With ice-cooling, 8 ml (8 mmol) of DIBAL-H are added to the above intermediate in 15 ml of DMEU and the reaction mixture is stirred for 30 min. 15 ml of ethyl acetate are added and the mixture is stirred for 15 min, diluted with 150 ml of methanol and 1 ml of water and concentrated by evaporation in a rotary evaporator. The residue is poured into 0.5 liter of water and 0.5 liter of ethyl acetate, and acidified to pH=3 with 1 N HCl, and the aqueous phase is separated off and extracted a further 3× with ethyl acetate. The organic phases are washed several times with water and finally with brine, dried (Na2SO4) and concentrated by evaporation. Stirring in ether yields 4-(3-chloro-phenylamino)-3-[3-(tetrazol-5-yl)-benzylamino-]-1H-pyrazolo[3,4-d]pyrimidine; TLC: Rf=0.13 (CHCl3/methanol/H2O/acetic acid=85:13:1.5:0.5); HPLC: tRet(grad20-100)=7.4; FAB-MS: (M+H)+=419.
Reaction SMILES: Cl[CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[N-:34]=[N+:35]=[N-:36].[Na+].CN(C)C=O>CO.O>[N:34]([CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)=[N+:35]=[N-:36]
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CN=[N+]=[N-])[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Yield: 34.7 %

Procedure:
A stirred mixture of (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (500 mg), sodium azide (140 mg), N,N-dimethylformamide (1.25 ml) in methanol (10 ml) and water (0.25 ml) was heated under reflux for 2 h, then cooled and poured into water (50 ml). The resulting precipitate was filtered off and dissolved in dichloromethane. After washing the solution with water and drying over sodium sulfate, the solvent was removed under reduced pressure and the residue (422 mg) was chromatographed on silica gel. The purified product was crystallised from dichloromethane-methanol to give (2β,3α,5α)-21-azido-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (176 mg). δ (CDCl3) 0.62 (s,3H), 1.06 (s,3H), 1.22 (s,3H), 1.24 (s,3H) and 3.85 (s,2H).