Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:3][C:4](=[O:11])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]=1.[N:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O>COCCO>[N:12]1([CH2:18][CH2:19][NH:20][C:2]2[NH:3][C:4](=[O:11])[C:5]3[N:6]=[CH:7][NH:8][C:9]=3[N:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NCCN1CCCCC1
Reactant: O=c1[nH]c(Br)nc2nc[nH]c12
Solvent: COCCO
Solvent: O
Product: O=c1[nH]c(NCCN2CCCCC2)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A mixture of 2-bromohypoxanthine (6 g, 28 mmol) and 2-piperidinoethylamine (7 ml, 56 mmol) in 2-methoxyethanol (30 ml) was heated to reflux overnight. The mixture was cooled to ambient temperature, giving rise to a yellow precipitate. Additional precipitate was generated on addition of water (50 ml). After stirring for 1 hour, the suspension was filtered and the solid obtained was washed with water and dried under vacuum to give the title compound (5.6 g). LC/MS SYSTEM C Rt=0.82 mins, m/z=263 MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CC1CCCCC1)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(CC1CCCCC1)c1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
To a stirred and cooled (ice-bath) mixture of 22 parts of 2,4-dichloro-β-(cyclohexylmethyl)benzeneethanol and 50 parts of pyridine are added dropwise 8.8 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water and the product is extracted twice with trichloromethane. The combined extracts are washed twice with a diluted hydrochloric acid solution and once with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 16.5 parts of 3-cyclohexyl-2-(2,4-dichlorophenyl)propyl methanesulfonate; mp. 105.1° C.
Reaction SMILES: CC([S@@]([NH:7][CH:8]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:16]2=[N:17][CH:18]=1)[C:9]([F:12])([F:11])[F:10])=O)(C)C.[ClH:32]>CO.CCOCC>[ClH:32].[F:11][C:9]([F:10])([F:12])[CH:8]([C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19]([S:22]([C:25]3[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=3)(=[O:23])=[O:24])[C:16]2=[N:17][CH:18]=1)[NH2:7]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C(N[S@@](=O)C(C)(C)C)C(F)(F)F)cnc32)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(N)C(F)(F)F)cnc32)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of (S)-2-methyl-N-(2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethyl)propane-2-sulfinamide (1.40 g, 2.95 mmol) in MeOH (20 mL) was added HCl (4 N in 1,4-dioxane, 7.38 mL, 29.5 mmol). After about 2 h, the reaction mixture was partially concd in vacuo and diluted with Et2O until solids began to form. After about 30 min, the resulting solids were collected by filtration and dried in vacuo to provide 2,2,2-trifluoro-1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanamine hydrochloride (0.840 g, 70%) as a solid. LC/MS (Table 1, Method a) Rt=2.16 min; MS m/z 371 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[C:11]([C:15]1[CH:16]=[C:17]([S:26][C@H:27]([CH3:31])[C:28](Cl)=[O:29])[CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].O>C1(C)C=CC=CC=1>[C:22]([C:19]1[CH:18]=[C:17]([S:26][C@H:27]([CH3:31])[C:28]([N:9]2[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]2=[O:10])=[O:29])[CH:16]=[C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])[C:20]=1[OH:21])([CH3:23])([CH3:24])[CH3:25]
Reactant: C=CC1CCC(=O)N1
Reactant: C[C@@H](Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@@H](C)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of 60% sodium hydride (665 mg, 19.0 mmol) and toluene (40 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (2.0 g, 18.0 mmol) in toluene (20 mL) over a 30 min period. The cooling bath was removed and the solution was allowed to warm to room temperature and stir there for a 30 min period to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoyl chloride (29, 6.21 g, 19.0 mmol) in toluene (20 mL) over a 20 min period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 2:1). Water (100 mL) was added to the reaction and the phases were separated. The aqueous phase was extracted with t-butyl methyl ether (2×100 mL). The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution (1×250 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×24 cm length) using hexane and ethyl acetate (10:1) afforded 2.32 g (32%) of (5S)-N-((2R)-2-(3,5-di-t-butyl-4-hydroxyphenyl)thiopropanoyl)-5-ethenylpyrrolidin-2-one (33a) as a white crystalline material: mp 105°-106° C.; 1H NMR (CDCl3) δ1.37-1.42 (m, 21 H), 1.79-1.86 (m, 1 H), 1.97-2.05 (m, 1 H), 2.32-2.41 (m, 1 H), 2.57-2.67 (m, 1 H), 4.71-4.75 (t, J=6.8 Hz, 1 H), 5.03-5.17 (m, 3 H), 5.33 (s, --OH, 1 H), 5.78-5.87 (m, 1 H), 7.23 (s, 2 H); 13C NMR (CDCl3) δ174.7, 172.6, 154.7, 136.3, 135.7, 132.7, 120.9, 115.3, 58.8, 44.1, 34.3, 31.9, 30.2, 23.9, 16.4; IR (KBr) 3581 (s), 2964 (s), 1748 (vs), 1684 (vs), 1426 (s), 1345 (s), 1227 (vs), 1198 (s), 917 (w), 885 (w) cm-1.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:7]=[C:8]([N:12]=[C:13]=[S:14])[CH:9]=[CH:10][CH:11]=1>C(O)C>[C:2]([NH:3][C:13]([NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[CH:7]=1)=[S:14])#[N:1]
Reactant: S=C=Nc1cccc(Cl)c1
Reactant: N#CN
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was slowly treated with 3-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (5.4 g), m.p. 258°-260° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12](O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:22])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([F:22])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](F)CC1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a solution of (t-butoxy)-N-(4-hydroxycyclohexyl)carboxamide (1 equivalent) in CH2Cl2 (1 M) cooled to −78° C. was added dropwise a solution of DAST (1 equivalent) in CH2Cl2 (0.5 M). The mixture was stirred at −78° C. for 4 hours, and then allowed to rise to room temperature. The solution was poured into saturated NaHCO3 and extracted with chloroform, dried, and evaporated. The resulting crude product was purified on silica gel, eluting with ethyl acetate/hexane 5:95.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[NH:32][C:33](=[O:36])[CH2:34]Br)([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:36])[CH2:34][N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)([CH3:21])[CH3:22]
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (4) synthesized in Reference Example 4 and the compound (24) synthesized in Reference Example 24 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH2:20][CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH:24]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([F:18])[CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[C:10]([F:18])[CH:9]=2)=[N:6][C:5]([C:19]2[CH2:20][CH2:21][CH2:22][NH:23][CH:24]=2)=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(C3=CN(C(=O)OC(C)(C)C)CCC3)cnc2N)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2nc(C3=CNCCC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To tert-butyl 5-(5-amino-6-(3-fluoro-4-(methoxycarbonyl)phenyl)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (150 mg, 0.350 mmol) (inseparable mixture) in DCM (4 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 30-45 min. The reaction mixture was evaporated on rotovap, and azeotroped with toluene. The crude product was proceeded to next step without purification. LCMS (m/z): 329.2 (MH+), 0.502 min.
Reaction SMILES: [CH3:1][C@@:2]1(O)[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].S(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6][CH3:7])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CO[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@](C)(O)[C@H](C)O1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=C1[C@@H](NC(=O)C(F)(F)F)C[C@H](OC)O[C@H]1C
Temperature: 25 °C

Procedure:
A solution of 1 g (3.7 mmol) of methyl 2,3,6-trideoxy-4-C-methyl-3-trifluoroacetamido-α-L-lyxo-hexopyranoside (VII) in 90 ml of anhydrous benzene was treated with 2.75 ml of freshly distilled thionyl chloride and heated under reflux for 2 hours. The reaction mixture, after being cooled to room temperature, was washed with water and then treated under stirring with an aqueous solution of sodium hydrogen carbonate. The organic phase was separated off, washed with water and evaporated under vacuum to dryness to give compound (VIII), 0.82 g, 87% as a white solid; m.p. 160°-162° C., [α]D20° -180° (c=1, CHCl3). The PMR spectrum (CDCl3) showed absorptions at 1.35 (d, CH3 --C--5), 3.37 (s, CH3O), 4.37 (q, H--C--5), 4.83 (broad s, CH2 =C--4) and 4.95 δ (broad s, C--1--H).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15](OS(C)(=O)=O)[CH2:14][C@H:13]2[CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:38][C:36](=[O:39])[CH3:37])[CH2:14][C@H:13]2[CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[O:11])=[CH:34][CH:35]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
A solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (10 g: 19.88 mmole) and potassium thioacetate (4.54 g: 2 eq.) in dimethylformamide (60 ml) is stirred at 60° C. for 3 hours. The reaction mixture is poured into ice water (200 ml) and filtered. The precipitate is dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (8.7 g). Yield: 90%. NMR δ(CDCl3) ppm: 1.65 to 1.97(m, 1H), 2.47 to 2.67(m, 1H), 3.24 to 3.34(q, 1H), 3.73 to 4.24(m, 4H), 4.30 to 4.54(m, 1H), 5.02(dd, J=14 Hz, J=7 Hz, 1H), 5.20(d, J=14 Hz, 1H), 7.42 (d, J=9 Hz, 1H), 7.45(d, J=9 Hz, 1H), 7.60 to 8.86(m, 4H), 8.17(d, J=9 Hz, 2H). IR ν (CHCl3) cm-1 : 1773, 1714, 1605.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH:2]([CH2:4][OH:5])[OH:3].N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[Si:14]([O:5][CH2:4][CH:2]([OH:3])[C:1]([O:7][CH3:8])=[O:6])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(O)CO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: COC(=O)C(O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To a solution of methyl glycerate (25.88 g, 215 mmol) and imidazole (22.0 g, 323 mmol, 1.5 eq) in tetrahydrofuran (250 mL) was added t-butyldiphenylsilyl chloride (53.0 mL, 204 mmol, 0.95 eq) at 0° C. After stirring for 18 h the reaction was quenched by the addition of saturated ammonium chloride and the aqueous phase was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and evaporated under reduced pressure. The crude material was purified by flash chromatography with a mixture of hexanes and ethyl acetate (80:20) to give the compound (68.89 g) in 94% yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:24]=[CH:25][C:26]#[N:27])=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O>[Pd].CO>[NH2:27][CH2:26][CH2:25][CH2:24][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:13]([CH2:22][CH3:23])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC1CCOCC1
Reaction time: 18 h
Yield: 87 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (1 g), methanol (50 mL), 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile (4.0 g, 11.1 mmol) and trifluoroacetic acid (6.3 g, 55 mmol). The vessel was evacuated, charged with hydrogen gas (40 psi, 2.8×105 Pa) and shaken for approximately 18 hours. The mixture was filtered and concentrated under reduced pressure to a yellow oil. The oil was dissolved in 10% aqueous hydrochloric acid and stirred for 18 hours. Chloroform (100 mL) was added followed by slow addition of potassium carbonate until the pH equaled 11. The fractions were separated and the aqueous fraction was extracted with chloroform (4×50 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile provided 3.55 g of the desired product as a white solid. A small amount of this material was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-30% CMA over 1000 mL followed by 30% CMA over 1000 mL). A final recrystallization from acetonitrile provided 7-(3-aminopropyl)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 217-220° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][N:20]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([O:5][C:6]([CH:8]([NH:17][CH:18]1[CH2:24][S:23][CH:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][N:20]([CH2:30][C:31]([OH:33])=[O:32])[C:19]1=[O:38])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)O)C1=O

Procedure:
Following the procedure described in Example 43, 120 mg of isomer B of t-butyl α-[6-(1-butoxycarbonyl-3-phenylpropylamino)-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (prepared as described in Example 52) were de-t-butylated using trifluoroacetic acid, to afford 75 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].[CH2:5]([O:7][CH2:8][CH3:9])[CH3:6]>OS(O)(=O)=O>[CH2:1]([O:4][C:1](=[O:4])[CH2:2][C:3]1[CH:3]=[CH:2][C:1]([OH:4])=[C:5]([O:7][CH2:8][CH3:9])[CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCO
Reactant: CCOCC
Agent: O=S(=O)(O)O
Product: CCCOC(=O)Cc1ccc(O)c(OCC)c1
Temperature: 90 °C

Procedure:
Compound B3 (1.40 g, 5.87 mmol) was dissolved in an excess of 1-propanol (50 mL), concentrated H2SO4 (3 drops) was added, and the mixture was heated at 90° C. for ˜18 hours. The volume of 1-propanol was reduced under vacuum, then the mixture was diluted with diethyl ether, washed with saturated sodium bicarbonate solution (2×), distilled water (1×), brine (1×), dried over magnesium sulfate and solvent was removed under vacuum, giving 3-ethoxy-4-hydroxyphenylacetic acid propyl ester as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:24](=O)[CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[C:3]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N2CCNCC2)c1C1=CC(C)(C)CC(C)(C)C1
Reactant: CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN1CCN(c2cccc(C)c2C2=CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a mixture of 1-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (115 mg, 0.368 mmol) produced in Example (71c), propionaldehyde (0.079 mL, 1.1 mmol) and tetrahydrofuran (2 mL) was added sodium triacetoxyborohydride (246 mg, 1.1 mmol), followed by stirring for 1 hour and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 124 mg of 1-[3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-propylpiperazine as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]#[C:22][CH3:23]>>[C:1]([O:5][C:6](=[O:18])[C:7]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9])([CH2:16][C:11]#[C:12][CH3:13])[CH2:20][C:21]#[C:22][CH3:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CS(=O)(=O)c1ccc(F)cc1
Reactant: CC#CCBr
Product: CC#CCC(CC#CC)(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(F)cc1
Yield: 77 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid tert-butyl ester was prepared according to the procedure as outlined in Example 9. Starting from 2-(4-fluoro-benzenesulfonyl)-acetic acid tert-butyl ester (4.87 g, 20 mmol) and 1-bromo-2-butyne (5.36 g, 40 mmol), 6.0 g of the product was isolated. Yield 77%; white solid; mp 85° C.; MS: 379.1 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>C1(C)C=CC=CC=1>[C:7]1(=[O:13])[C:12]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrCCCCCBr
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCCC12CCCCC2
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a suspension of potassium tert-butoxide (24.4 g) in toluene (100 mL) was added a solution of cyclohexanone (10.67 g) and 1,5-dibromopentane (25 g) in toluene (50 mL) while stirring. The mixture was stirred at 100° C. for 4 hours. After cooling down to room temperature, the resulting solid was filtered and washed with toluene. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:15) to give spiro[5.5]undecan-1-one (11.85 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:25][CH3:26])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c3ncnc(N)c23)ccc1N
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
A suspension of tert-butyl N-(4-{4-amino-1-[4-nitrophenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (0.386 g, 0.808 mmol) in dichloromethane (8 mL) at 0° C. was treated with trifluoroacetic acid (1.6 mL). The reaction mixture stirred for 20 min at 0° C., then ice bath was removed to stir at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 18 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and sodium hydroxide 1N solution were added to the oil residue. The precipitate formed was filtered and dried over night on the lyophilizer to give 0.286 g (94%) of 4-amino-3-(4-amino-3-methoxyphenyl)-1-[4-nitrophenyl]-1H-pyrazolo[3,4-d]pyrimidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.7826-8.759 (m, 2H), 8.4892-8.4296 (m, 3H), 7.1861-7.1338 (m, 2H), 6.8320-6.8121 (d, 1H, J=7.96 Hz), 5.2225 (s, 2H), 3.8672 (s, 3H); LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min) tR=3.48 min M+ 377.6.