Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8]O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[CH:21]=O)=[CH:19]/[OH:20])=[CH:14][CH:13]=1>C(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:21]=[N:8][O:20][CH:19]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(/C(C=O)=C/O)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-c2cnoc2)cc1
Temperature: 80 °C
Yield: 86.4 %

Procedure:
A round-bottomed flask was charged with potassium carbonate (1.45 g, 10.5 mmol) and ethanol (14 ml). To this mixture was added hydroxylamine hydrochloride (730 mg, 10.5 mmol), and 2-(4-methoxyphenyl)-malondialdehyde (1.25 g, 7.00 mmol). The reaction mixture was heated at about 80° C. for about three hours. The reaction mixture was then concentrated in vacuo to approximately one-quarter volume and partitioned between water and ethyl acetate. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to a dark oil. This crude material was purified by column chromatography (10% ethyl acetate/hexanes) to afford 1.06 g (86% yield) of the desired product. LRMS ([M−H]−)=174.1.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:27])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([Br:20])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:21])[C:12]=2[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CC([OH:31])C.C(=O)=O.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.C(Cl)Cl>[CH2:1]([O:4][C:5]1([CH3:27])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([Br:20])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:21])[C:12]=2[C:22](=[O:31])[C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c(CC(=O)OC)c(C)nc3cc(Br)nn23)CC1
Reactant: CC(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)nc3cc(Br)nn23)CC1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (17.7 g, 40.5 mmol, 1 equiv) in THF (200 mL) was cooled to −78° C. (IPA/CO2). KHMDS (72 mL of a 0.91 M solution in THF, 64.9 mmol, 1.6 equiv) was added dropwise over ˜2 min. Reaction turned a deep orange color. After 30 min, 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (15.9 g, 60.8 mmol, 1.2 equiv) was added in a single portion. The reaction significantly darkened. After 30 min, the reaction was added to saturated aqueous sodium bicarbonate and extracted with ether (×2). The combined ether extracts were dried (MgSO4) and concentrated in vacuo to provide the crude product as a brown oil. This was taken up in DCM (200 mL) and Dess-Martin periodinane (20.6 g, 48.6 mmol, 1.2 equiv). After 30 min, the reaction was added to saturated aqueous sodium bicarbonate and extracted with DCM (×3). Combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the crude product. The crude product was purified via silica gel flash chromatography (0-50% EtOAc/hex) to provide methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-bromo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (9.2 g, 50%). 1H NMR (500 MHz, CDCl3) δ 6.55 (s, 1H), 6.07-5.87 (m, 1H), 5.38 (dq, J=17.2, 1.7 Hz, 1H), 5.20 (dq, J=10.4, 1.6 Hz, 1H), 3.95-3.92 (m, 5H), 3.69 (d, J=12.6 Hz, 2H), 3.59-3.50 (m, 2H), 2.56 (s, 3H), 1.96-1.82 (m, 4H), 1.28 (s, 3H). LCMS (M+1)=450.95.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.O.[CH2:14](OCC)C>>[OH:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOCC
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O
Product: CCOC(=O)C1CCC(C)(O)CC1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 25.0 g of ethyl 4-oxocyclohexanecarboxylate in 500 ml of diethyl ether, 150 ml of 1.6N methyl lithium-ether solution was added at −60° C. in nitrogen atmosphere, followed by 30 minutes' stirring at −60° C. Water was added to the reaction liquid which then was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried on anhydrous magnesium sulfate and the solvent was distilled off. The residue was separated and purified on silica gel column chromatography (ethyl acetate/hexane=1/4) to provide 22.7 g of the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:30])([F:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[NH:14][C:13]([CH3:23])=[C:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].C1(C)C=CC=CC=1.Cl[CH2:39][CH2:40][N:41]([CH2:46][CH2:47][O:48][CH3:49])[CH2:42][CH2:43][O:44][CH3:45]>CN(C=O)C>[F:30][C:4]([F:29])([F:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([CH3:23])[N:14]([CH2:39][CH2:40][N:41]([CH2:46][CH2:47][O:48][CH3:49])[CH2:42][CH2:43][O:44][CH3:45])[C:15]([CH3:22])=[C:16]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: COCCN(CCCl)CCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(CCN(CCOC)CCOC)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Temperature: 50 °C

Procedure:
To a suspension of sodium hydride (5.2 gms.; 0.11 mole) (50% suspension mineral oil) in 100 ml of dry distilled DMF is added a solution of diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (39.7 gms.; 0.1 mole) in 150 ml of DMF. After the gassing has ceased, the reaction mixture is heated on a water bath for 1 hour and then is cooled to 50° C. and to the hot solution is added a toluene solution of 2-chloro-N,N-bis(methoxyethyl)ethylamine. The reaction mixture is heated at 100°-110° C. for a period of 8 hours and then cooled. The unreacted NaH and NaCl is filtered off and the solvent removed from the filtrate. The residue is extracted with hot hexane which, on cooling, affords the desired product. Recrystallization from heptane yields the pure product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH2:5][Mg]Br.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:27][C:28](=[O:30])[CH3:29])=[N:17][C:18]=1[CH:19]=[N:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22].[Cl-].[NH4+]>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:27][C:28](=[O:30])[CH3:29])=[N:17][C:18]=1[C@@H:19]([NH:20][S:21]([C:23]([CH3:25])([CH3:26])[CH3:24])=[O:22])[CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: Fc1cc(F)cc(C[Mg]Br)c1
Reactant: CC(=O)Nc1ccc(Br)c(C=N[S@@](=O)C(C)(C)C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)c([C@H](Cc2cc(F)cc(F)c2)NS(=O)C(C)(C)C)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
(3,5-Difluorobenzyl)magnesium bromide (0.25 M in ether, 10 ml, 2.5 mmol) was added dropwise to a solution of (S)—N-(5-bromo-6-(((tert-butylsulfinyl)imino)methyl)pyridin-2-yl)acetamide (1D, 0.47 g, 1.36 mmol) in DCM (5 ml) at 78° C. The reaction was stirred for 3 h at −78° C. Ammonium chloride (aq, 10 mL) was added to the reaction and the mixture was allowed to warm to r.t. The mixture was extracted with EtOAc (2×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product contained a mixture of diastereomers which were used in the next step without further purification. MS (m/z) 474.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33](OC)=O)=[CH:26][C:25]=2[O:24]1.ClCCl.C(=O)([O-])O.[Na+]>CC(C)([O-])C.[K+]>[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33]3[NH:22][C:20](=[O:21])[C:3]4[C:4]([CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:2]=4[N:1]=3)=[CH:26][C:25]=2[O:24]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: CCc1nn(C(C)CCCc2ccccc2)c(N)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3ccc4c(c3)OCO4)[nH]c(=O)c12
Yield: 50 %

Procedure:
19 mg (0.063 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-3-ethyl-1H-pyrazole-4-carboxamide and 35 mg (0.180 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.9 ml of 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 14 mg (48%) of a solid, Rf=0.64 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[C:7]2[CH3:24].[Si]([O:40][C:41]([O:43][CH3:44])=[CH2:42])(C(C)(C)C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:44][O:43][C:41](=[O:40])[CH2:42][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: Cc1nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-yl ester (0.11 g), 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (0.22 mL), sodium acetate (0.019 g), bis(dibenzylideneacetone) palladium (0.006 g) and 1,1′-bis(diphenylphospino) ferrocene (0) (0.006 g) in N,N-dimethylformamide (1.0 mL) was heated by microwave irradiation at 120° C. for 20 minutes. The mixture was diluted with ethyl acetate and this solution was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1:0 to 99:1 by volume) gave title compound as a brown oil, 0.050 g.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](#[N:14])[CH3:13].[Sn](Cl)(Cl)(Cl)Cl>ClCCCl>[NH2:14][C:12](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH3:13]
Reactant: CC#N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C(C(=O)OCC)=C(C)N
Temperature: 125 °C
Yield: 96.8 %

Procedure:
To a solution of diethyl malonate (19.05 mL, 124 mmol) and acetonitrile (6.46 mL, 124 mmol) in 1,2-dichloroethane (DCE) (80 mL) under nitrogen atmosphere was slowly added tin(IV) chloride (31.9 mL, 272 mmol) in 30 min and then the mixture was heated to 125° C. for 2.5 h. The mixture was concentrated to a paste and then dissolved in acetone (350 mL), transferred to a beaker vigorously stirred and saturated Na2CO3/water (250 mL) was added dropwise to pH˜9-10. The slush was filtered through a bed of celite stirring the surface of the Celite™ to facilitate filtering. The filter cake was washed with dichloromethane (4×200 mL). The aqueous phase was separated from the filtrate and the organic phase was dried (Na2SO4), concentrated and dried in vacuo to provide diethyl 2-(1-aminoethylidene)malonate (25.51 g, 120 mmol, 97% yield) as a pale amber oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (m, 6 H), 2.15 (s, 3 H), 4.06-4.32 (m, 4 H), 4.81-5.20 (m, 1 H), 8.72-9.18 (m, 1 H); LCMS (m/z) ES+=202 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:23])[CH2:9][C:10]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)(O)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[N:18]1([C:10]([C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:23])[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC(C)(C)C(=O)C(O)(CC(=O)c1ccc(Cl)cc1)n1cncn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)C(=CC(=O)c1ccc(Cl)cc1)n1cncn1
Reaction time: 192 h
Yield: 97.4 %

Procedure:
A suspension of the product (16.7 g) of Stage 1 in pyridine (100 ml) was treated with p-toluene sulphonyl chloride (11 g) and shaken vigorously. The mixture was allowed to stand for 8 days with occasional shaking, during which time the solid dissolved and a dark red solution was obtained. The solution was then quenched with 2 N-hydrochloric acid (500 ml) and the resultant solid filtered off, washed with water and dried. Crystallization from petroleum ether gave the title product (15.4 g; 97%), m.p. 140°-140.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([S:12]([CH3:14])=[O:13])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:19]1(=O)[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1.N1C=CC=CC=1.S(Cl)(Cl)=O>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[C:11]([S:12]([CH3:14])=[O:13])=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][C:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH:20]=1)=[O:6]
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Reactant: O=C1CCCC(=O)C1
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1c(C(=O)OC2=CC(=O)CCC2)ccc(C(F)(F)F)c1S(C)=O
Temperature: 0 °C
Yield: 89.2 %

Procedure:
3.0 g of 2-methoxy-3-methylsulfinyl-4-trifluoromethylbenzoic acid and 1.68 g of 1,3-cyclohexanedione are suspended in 20 ml of ethyl acetate and 5.61 ml of pyridine under an inert atmosphere and cooled to −25° C. with stirring. 1.73 g of thionyl chloride are then slowly added dropwise such that the temperature always remains below −20° C. Following the complete addition of the thionyl chloride, the mixture is stirred for a further 20 minutes. 38 μl of cold water are added, and the mixture is warmed to 0° C. 10 ml of ethyl acetate and a further 10 ml of water are then added. After separating the organic phase from the aqueous phase, the aqueous phase is extracted twice with 5 ml of ethyl acetate in each case. The combined organic phases are dried, giving 3.57 g of 3-[2-methoxy-3-(methylsulfinyl)-4-(trifluoro-methyl)benzoyloxy]cyclohex-2-en-1-one (85.5% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][CH2:4][CH:5]([OH:12])[CH2:6][CH2:7][C:8]([F:11])([F:10])[F:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:13])([F:14])[CH2:3][CH2:4][C:5](=[O:12])[CH2:6][CH2:7][C:8]([F:10])([F:11])[F:9]
Reactant: OC(CCC(F)(F)F)CCC(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCC(F)(F)F)CCC(F)(F)F
Reaction time: 4 h

Procedure:
1,1,1,7,7,7-Hexafluoroheptan-4-ol (1.4 g, 6.25 mmol) was dissolved in CH2Cl2 (12 mL) and pyridinium chlorochromate (PCC) (1.48 g, 6.87 mmol) was added. The mixture was stirred for 4 h. Additional PCC (800 mg) was added and the mixture stirred for 1 h. The mixture was filtered through celite and silica, washing with DCM. The resulting pale yellow solution was evaporated at room temperature to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:25]3[CH2:26][CH2:27][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(N1CCN(c2ccccc2)CC1)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1.6 g (0.01 mole) of 1-phenylpiperazine added all at once, a solid formed instantaneously and after stirring for 2 hr, the reaction mixture was diluted with 200 ml of water, the solid did not dissolve. The solid was removed by filtration and when triturated with chloroform, all but about 1 g of solid dissolved. The chloroform solution was dried over magnesium sulfate then concentrated in vacuo. The oily residue crystallized when triturated with ligroin. Recrystallization from benzene/ligroin yielded 2.0 g (48.1%) of fine white crystals, m.p. 160°-161° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[N:28][CH:29]=3)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(C)=O)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 75 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A solution of N-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)acetamide (0.060 g, 0.098 mmol) and trifluoromethanesulfonic acid (TCI) (40 μL, 0.450 mmol) in TFA (2 mL) was stirred at rt for 2.5 h. Then the mixture was stirred at 75° C. for 2 h. Most of the TFA was removed in vacuo and then the residue was taken up in a small amount of DCM. Solid NaHCO3 was added in portions until no more effervescence was observed. Water was added and the resulting solid was collected by filtration. The crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18 100×30 mm column (0%-10% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The fractions containing product formed a precipitate which was collected by filtration and dried in a vacuum oven to give N-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)acetamide (0.0173 g, 36% yield) as a yellow solid. 1H NMR (300 MHz, d6-DMSO) δ 11.87 (s, 1H); 10.43 (s, 1H); 8.67-8.78 (m, 2H); 8.37 (br. s., 1H); 8.15-8.24 (m, 1H); 7.93-8.07 (m, 2H); 7.84 (br. s., 1H); 2.45 (s, 3H); 2.09 (s, 3H). m/z (ESI, +ve ion) 371.0 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:20]2)[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[C:11]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:21][CH2:20]2)[C:12]2[C:17]([CH3:18])=[CH:16][S:15][C:13]=2[N:14]=1
Reactant: COc1ccccc1-c1nc(N2CCC(NC(=O)OCC(C)C)CC2)c2c(C)csc2n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1csc2nc(-c3ccccc3O)nc(N3CCC(NC(=O)OCC(C)C)CC3)c12
Temperature: 25 °C

Procedure:
A solution of isobutyl 1-(2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (0.127 g, 0.28 mmol) in CH2Cl2 (2 mL) was cooled to −50° C., and a solution of BBr3 in CH2Cl2 (1 M, 1.7 mL, 1.7 mmol) was slowly added. The reaction was allowed to gradually warm to room temperature over 1 h, and saturated aqueous NaHCO3 was slowly added. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give Isobutyl 1-(2-(2-hydroxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate. LC/MS: m/z 441.5 (M+H)+ at 4.02 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:49][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:40][CH:41]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
A solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (59 mg, 0.088 mmol) in DCM (2 ml) was treated with TFA (0.6 ml, 7.6 mmol) and the mixture was stirred at rt for 12 h. The solvent was removed in vacuo to provide the title compound as a white solid (40 mg, 0.065 mmol, 74.0% yield). LCMS: m/e 615.7 (M+H)+, 2.00 min (method 7). 1H NMR (400 MHz, MeOD) δ ppm 7.94 (d, J=8.3 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 5.33 (d, J=4.8 Hz, 1H), 4.78 (s, 1H), 4.67 (s, 1H), 3.73-3.42 (m, 4H), 3.33 (m, 1H), 2.99-2.94 (m, 1H), 2.93 (s, 6H), 2.53 (td, J=10.6, 5.6 Hz, 1H), 2.99-1.29 (m, 2H), 1.98-1.22 (m, 20H), 1.76 (s, 3H), 1.20 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [OH:1]O.[CH3:3][C:4]1[CH:14]=[C:13]([O:15][CH2:16]/[CH:17]=[C:18](/[C:33]2[CH:38]=[CH:37][C:36]([S:39][CH3:40])=[CH:35][CH:34]=2)\[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9]>C(O)(=O)C.O>[CH3:40][S:39]([C:36]1[CH:35]=[CH:34][C:33](/[C:18](/[C:19]2[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:21][CH:20]=2)=[CH:17]/[CH2:16][O:15][C:13]2[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:3])[CH:14]=2)=[CH:38][CH:37]=1)=[O:1]
Reactant: OO
Reactant: CSc1ccc(/C(=C/COc2ccc(OCC(=O)O)c(C)c2)c2ccc(C#CCn3cccn3)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OC/C=C(\c2ccc(C#CCn3cccn3)cc2)c2ccc(S(C)=O)cc2)ccc1OCC(=O)O

Procedure:
30% Aqueous hydrogen peroxide (0.0618 mL, 0.6 mmol) was added to a solution of (E)-[4-[3-[4-(methylsulfanyl)phenyl]-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetic acid (262 mg, 0.5 mmol; example 48) in glacial acetic acid (7 mL) at 5° C. under stirring. The mixture was left to stand over night at ambient temperature, diluted with water (40 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were alkalized with 15% aqueous solution of ammonium hydroxide; the solution was washed with water (10 mL) and brine (10 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was triturated with hexanes (3×15 mL) to yield the title compound as pale solid.