Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:25][C@@:24]2([CH3:26])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:27][C:28](=[O:30])[CH3:29])[C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([F:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH2:6][CH2:5]1.O1CCOCC1>C(Cl)(Cl)Cl>[OH:1][C@H:2]1[CH2:25][C@@:24]2([CH3:26])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:27][C:28](=[O:30])[CH3:29])[C:17](=[O:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([F:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH:6]=[CH:5]1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A mixture of 3 g of 11β-hydroxy-17α,21-diacetoxy-6α-fluoro-pregn-4-ene-3,20-dione [compound 4, the product of Example 3] , 2.5 g of 2,3-dichloro-4,5-dicyanobenzoquinone, and 30 ml of dioxan was heated under reflux for 2 hours. The resulting dark colored suspension was cooled, filtered from dichloro-dicyanohydroquinone, and then evaporated to dryness. The residue so obtained was dissolved in chloroform and filtered through neutral alumina (50 g). The solvent was evaporated under reduced pressure. The residue crystallized from methanol as colorless prisms, m.p.: 235°-240°, λmax, 241 nm (ε= 14,200). The analytical sample of 11β-hydroxy-17α,21-diacetoxy-6α-fluoro-pregna-1,4-diene-3,20-dione (compound 5) was obtained by an additional recrystallization from methanol.
Reaction SMILES: COC(=O)CCC1(C)CCCCC1=O.COC(=O)CCC1(CC)CCCCC1=O.[CH3:30][O:31][C:32](=[O:45])[CH2:33][CH2:34][C:35]1([CH2:42][CH2:43][CH3:44])[CH2:40][CH2:39][CH2:38][CH2:37][C:36]1=O.COC(=O)CCC1(CC)CCCCC21[C:56](=[O:57])[CH2:55][CH2:54][C:53]2=[O:58]>>[CH3:30][O:31][C:32](=[O:45])[CH2:33][CH2:34][C:35]1([CH2:42][CH2:43][CH3:44])[CH2:40][CH2:39][CH2:38][CH2:37][C:36]21[C:56](=[O:57])[CH2:55][CH2:54][C:53]2=[O:58]
Reactant: CCC1(CCC(=O)OC)CCCCC12C(=O)CCC2=O
Reactant: CCCC1(CCC(=O)OC)CCCCC1=O
Agent: CCC1(CCC(=O)OC)CCCCC1=O
Agent: COC(=O)CCC1(C)CCCCC1=O
Product: CCCC1(CCC(=O)OC)CCCCC12C(=O)CCC2=O

Procedure:
In the same manner but replacing 1-methyl-2-oxocyclohexane-propionic acid methyl ester with an equivalent amount of 1-ethyl-2-oxocyclohexanepropionic acid methyl ester or 1-propyl-2-oxocyclohexanepropionic acid methyl ester, described in Example 6, 6-ethyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester, νmaxCHCl3 1730 cm-1 and 6-propyl-1,4-dioxospiro[4.5]decane-6-propionic acid methyl ester, νmaxCHCl3 1735 cm-1, are obtained, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[N:31]1([C:35]([C:37]2[CH:38]=[CH:39][C:40](Cl)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1.[H-].[Na+].Cl>CS(C)=O>[N:31]1([C:35]([C:37]2[CH:38]=[CH:39][C:40]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: O=C(c1ccc(Cl)nc1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cn2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (84 mg, 0.195 mmol) synthesized in Example (38d) and 5-(azetidin-1-ylcarbonyl)-2-chloropyridine (110 mg, 0.559 mmol) synthesized in Example (59a) were dissolved in dimethyl sulfoxide (3.0 mL), and sodium hydride (60%, 30 mg, 0.75 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 2N hydrochloric acid (30 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=75%-90%) to afford the desired compound (56 mg, yield 59%) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC[Si](C)(C)C)=[O:23])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: C[Si](C)(C)CCOC(=O)CCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)CCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
2-(Trimethylsilyl)ethyl 5-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]valerate (0.23 g, 0.52 mmol) was dissolved in N,N-dimethylformamide (2 ml), and 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (1.3 ml, 1.3 mmol) was added thereto. The reaction mixture was stirred for 15 minutes and concentrated under reduced pressure. Trifluoroacetic acid (2.5 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was subjected to a silica gel (25 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethanol-acetone to give the titled compound (0.10 g, 55%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:17]([O:16][C:14]([C:12]1[N:11]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:24]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:13]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccc(Cl)c(Cl)c2)n[nH]1
Reactant: COC(=O)c1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)OC(C)(C)C)nc1

Procedure:
To a solution of the intermediate from step C (522 mg, 1.66 mmol) in DMF (10 mL) was added the intermediate from step D (460 mg, 2.0 mmol), followed by cesium carbonate (815 mg, 2.5 mmol). After stirring the reaction at room temperature for 3 hours, it was quenched by adding water and extracting with ethyl acetate (3×). The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate-hexanes. 1H NMR (CDCl3, 500 MHz): 9.21 (d, J=2.1 Hz, 1H), 8.25 (dd, J=2.2, 8.2 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.69 (dd, J=2.1, 8.3 Hz, 1H), 7.5 (d, J=8.2 Hz, 1H), 7.18 (s, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.01 (s, 2H), 3.97 (s, 3H), 1.53 (s, 9H). LC-MS: 2.87 min; (M+H−56)=406.0.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>C(#N)C.CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][C:9](=[O:10])[NH:11][C:14]2=[O:15])=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)CNCc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Temperature: 0 °C
Yield: 20.6 %

Procedure:
A mixture of 2-(4-bromobenzylamino)acetamide (1B3) (45.9 mmol, 11.2 g) and carbonyldiimidazole (68.8 mmol, 11.2 g) in acetonitrile (223 ml) was cooled to 0° C. with stirring and 4-dimethylaminopyridine (45.9 mmol, 5.60 g) was added. The mixture was stirred at 0° C. for 24 h and then heated at 80° C. for 18 h. The reaction mixture was diluted with water and the acetonitrile removed under reduced pressure. The mixture was acidified to pH 4 with aqueous HCl and the precipitate collected by filtration and dried in a vacuum oven to give 1-(4-bromobenzyl)imidazolidine-2,4-dione (1B4) 2.55 g (20.2%); 1H NMR (400 MHz, DMSOd6) δ 10.94 (bs, NH) 7.55 (d, 2H) 7.24 (d, 2H) 4.42 (s, 2H) 3.86 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].CN(C=O)C>C(=O)([O-])[O-].[Na+].[Na+]>[NH:18]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[CH:12]=[CH:11][C:10]4[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=4[S:8][C:7]=3[CH:17]=2)=[N:2][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C1=Cc2ccc(-c3nnn[nH]3)cc2Sc2ccccc21

Procedure:
A mixture consisting of 4 g. 3-cyanodibenzo[b,f]thiepin (17 millimoles); 1.8 g. sodium azide (28 millimoles); 1.63 g. ammonium chloride (30.5 millimoles) and 50 cc. DMF is refluxed for 17 hours. The mixture is cooled and diluted with aqueous sodium carbonate solution. The solution is extracted with ether, then acidified with aqueous HCl solution. The tetrazole precipitates and is filtered. Crystallization from methanol affords 3.93 g. (83%) yellow product, m.p., 213° C.-214° C.
Reaction SMILES: [C:1]1([S:7](C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Mg]Cl.C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].[NH2:32]OS(O)(=O)=O>C1COCC1.C(OCC)(=O)C.O>[C:1]1([S:7]([NH2:32])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NOS(=O)(=O)O
Reactant: CS(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: C[Mg]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of (phenylsulfonyl)methane (10 mmol) in 5 mL of THF at 0° C. was treated with 4.5 mL (12.6 mmol) of methylmagnesium chloride (2.8M in THF), and the resulting solution was stirred at room temperature for 30 minutes. The solution was cooled to 0° C., treated with 15 mL (15 mmol) of tributylborane (1M in THF), stirred at room temperature for 30 minutes, and then stirred at reflux for 18 hours. To the resulting mixture at 0° C. was added 5.7 g of sodium acetate, 25 mL of water, and 3.95 g of hydroxylamine-O-sulfonic acid; the resulting mixture was stirred at room temperature for 3 hours. The organic layer was diluted with ethyl acetate, washed with saturated NaHCO3 and then brine, dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography gave 1.06 g (67%) of phenylsulfonamide.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23][CH3:24])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)Cl>[CH2:1]([N:8]([C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]2[N:20]([C:25]3[C:30]([Cl:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:26]=3[Cl:33])[N:21]=[C:22]([S:23]([CH3:24])=[O:42])[C:14]=12)[CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2nc(C)nc(N(CCCO)Cc3ccccc3)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(N(CCCO)Cc2ccccc2)c2c(S(C)=O)nn(-c3c(Cl)cc(Cl)cc3Cl)c2n1
Yield: 110.9 %

Procedure:
A solution of 3-{benzyl-[6-methyl-3-methylsulfanyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}propanol (42 mg, 0.077 mmol) and m-chloroperbenzoic acid (14 mg, 0.081 mmol) in 0.5 ml of methylene chloride was stirred at room temperature for 3 hours. The mixture was quenched with water and saturated sodium thiosulfate, and extracted with methylene chloride. The organic layer was washed with saturated sodium bicarbonate, dried and concentrated to give an oil which was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 46 mg of the title compound as a white glass form. 1H NMR (CDCl3): 1.88(m,2H), 2.54(s,3H), 2.73(s,3H), 3.5-3.7(m,4H), 4.3(m,1H), 5.15(ABq,JAB=16Hz,2H), 7.2-7.4(m,5H), 8.47(ABq,2H)ppm.
Reaction SMILES: Cl.[F:2][C:3]1([F:47])[CH:9]([NH:10]C(=O)C(F)(F)F)[CH2:8][CH2:7][N:6]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:39]3[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=3[F:46])[S:29][C:30]=2[NH:31]C(=O)OC(C)(C)C)=[O:25])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CO>[NH2:31][C:30]1[S:29][C:28]([C:39]2[C:40]([F:46])=[CH:41][CH:42]=[CH:43][C:44]=2[F:45])=[N:27][C:26]=1[C:24]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[N:6]1[CH2:7][CH2:8][CH:9]([NH2:10])[C:3]([F:2])([F:47])[CH2:4][CH2:5]1)=[O:25]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)C(F)(F)F)C(F)(F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)C(F)(F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.6 %

Procedure:
HCl in 1,4-dioxane (4 M, 2 mL) was added to a solution of Example 55 (20 mg, 0.03 mmol) in MeOH (0.5 mL). This mixture was stirred at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude product re-dissolved in MeOH/water (1:1, 5 mL). K2CO3 (0.3 g, 7, 2.2 mmol) was added and the mixture heated and stirred at 60° C. for 3 hr before being cooled to room temperature. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 351 as a white solid (4 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 7.88 (s, 1H), 7.37-7.28 (m, 1H), 7.08-6.98 (m, 2H), 6.15 (s, 2H), 3.73 (s, 3H), 3.39-3.13 (m, 6H), 2.46-2.34 (m, 1H), 2.22-2.03 (m, 2H), 1.99-1.89 (m, 1H), 1.83-1.78 (m, 1H). LCMS (ES+) m/z 484.0 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCCCCCOC1CCNCC1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Intermediate 22 (157 mg, 0.387 mmol) was dissolved in MeOH (5 mL) then added 10% (w/w) Pd/C (41 mg, 0.0387 mmol). The reaction vessel was attached to 3-way valve with balloon containing hydrogen gas. The vessel was evacuated 3 times then back flushed with hydrogen. The resulting suspension was stirred overnight, filtered, and concentrated to give the title compound (120 mg) as clear oil. The compound was used with no further purification. ES/MS calcd for C17H38NO2Si+ 316.3. Found m/z=316.3 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.[OH:23][C:24]1[CH:25]=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: CCOC(=O)c1cc(O)ccc1-c1ccccc1
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)OCC)c1
Yield: 85.9 %

Procedure:
The above-prepared 6.20 g (19.1 mM) of 10-undecenyl p-toluenesulfonate, 4.62 g (19.1 mM) of ethyl p-hydroxybiphenylcarboxylate and 6 ml of dimethylformamide (DMF) were mixed and sufficiently stirred. To the mixture, 0.77 g (19.3 mM) of 60% -sodium hydride was added, followed by heat-refluxing for 7 hours. After the reaction, the reaction mixture was subjected to distilling-off of DMF and addition of water, followed by extraction with ether to obtain an extract. The extract was dried with anhydrous sodium sulfate, followed by distilling-off of ether and purification by column chromatography (eluent: methylene chloride) to obtain 6.46 g (16.4 mM) of ethyl p-(10-undecenyl)oxybiphenylcarboxylate (Yield: 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[C:17](Cl)(=[O:23])[O:18][CH2:19][CH2:20][O:21][CH3:22]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[O:23])[CH2:13][CH2:12]3)=[N:7][C:6]=12
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Reactant: COCCOC(=O)Cl
Solvent: CCOC(C)=O
Product: COCCOC(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 10.00 g (35.44 mmol) of 3-bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine dissolved in 120 mL of EtOAc, at 0° C. was added 5.40 g (38.99 mmol) of 2-methoxyethyl carbonochloridate, followed by 9.86 mL (70.88 mmol) of TEA. After 5 minutes, the ice bath was removed, and the reaction mixture stirred at RT. After 5 hr, LCMS showed that the reaction was complete. It was diluted with EtOAc, quenched with brine, and the organic layer dried over MgSO4. It was concentrated and purified on the ISCO with a 330 g column eluting with 0-9% MeOH/DCM to obtain the desired product, 12.63 g (93%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.42 (s, 3 H) 3.62-3.69 (m, 6 H) 3.73-3.82 (m, 4 H) 4.26-4.35 (m, 2 H) 6.36 (d, J=7.83 Hz, 1 H) 7.86 (s, 1 H) 8.27 (d, J=7.83 Hz, 1 H). LRMS (ESI) m/e 384 [(M+H)+, (doublet), calcd for C14H15BrN5O3 383].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([O:38]CC)=[O:37])(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:45])(=[O:44])[N:19]=1.CO>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32][C:33]3[CH:34]=[C:35]([CH:41]=[CH:42][CH:43]=3)[C:36]([OH:38])=[O:37])(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:44])(=[O:45])[N:19]=1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)Nc2ccc3c(c2)S(=O)(=O)N=C(c2c(O)c4cccnc4n(CCC(C)C)c2=O)N3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)Nc4cccc(C(=O)O)c4)ccc3N2)c(O)c2cccnc21
Yield: 8.8 %

Procedure:
A solution of the product of Example 454 (25.5 mg, 0.389 mmol) in 1 mL of 1N aqueous sodium hydroxide and 1ML of methanol was stirred at 25° C. for 17 hours, and concentrated under a stream of warm nitrogen. The residue was treated with 2 mL of 1N aqueous hydrochloric acid. The resulting solid was isolated by vacuum filtration, washed with 10 mL of water, and dried to provide the title compound (21.4 mg, 88% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.56 (m, 2 H) 1.68 (m, 1 H) 4.48 (m, 2 H) 7.32-7.53 (m, 4 H) 7.59 (m, 2 H) 7.69 (d, J=8.82 Hz, 1 H) 7.75 (s, 1 H) 8.55 (dd, J=8.09, 1.84 Hz, 1 H) 8.88 (dd, J=4.78, 1.47 Hz, 1 H) 10.79 (s, 1 H) 10.88 (s, 1 H) 13.01 (bs, 1 H) 14.12 (bs, 1 H). MS (ESI+) m/z 627.1 (M+H)+, 649.1 (M+Na)+, (ESI−) m/z 625.1 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>>[CH2:25]([NH:27][CH2:20][C:19]1[CH:18]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[N:16]=2)[CH:24]=[CH:23][CH:22]=1)[CH3:26]
Reactant: CCN
Reactant: O=Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CCNCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 28 was coupled with ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 349. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (d, 1H) 7.9 (m, 2H) 7.4 (m, 2H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.2 (m, 1H) 3.9 (s, 2H) 3.7 (m, 2H) 2.8 (m, 2H) 2.7 (m, 2H) 1.2 (m, 3H).
Reaction SMILES: [OH-].[K+].[C:3]1(/[C:9](/[C:19]2[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=2)=[C:10](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][C:28]#[N:29]>O>[C:3]1([C:9]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:27][C:28]#[N:29])=[CH:21][CH:20]=2)=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC#N
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=O)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(=C(c1ccccc1)c1ccc(C=CC#N)cc1)c1ccccc1
Yield: 57 %

Procedure:
A suspension of potassium hydroxide (85%, 260 mg, 3.9 mmol) in CH3CN (25 mL) was heated to reflux and (Z)-1,2-Diphenyl-1-(4-formylphenyl)-1-butene (4a) (Willson J. Med. Chem. 1994, 37, 1550-1552) (1.0 g, 3.18 mmol) was added in portions. After refluxing 5 min the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine and dried (MgSO4). The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 15% EtOAc/hexanes) to give the nitrile (4b) as a white solid (616 mg, 57%): 1H NMR (CDCl3) δ 7.39-7.07 (m, 13H), 6.91 (d, J=8.4 Hz, 2H), 5.69 (d, J=16.9 Hz, 1H), 2.48 (q, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); HRMS calcd. for C25H21N (M+H+) 335.1674; found 335.1679.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[C:24]#N)[O:17][N:16]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:51])C>CCCCCC>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=[O:51])[O:17][N:16]=1
Reactant: CCOC(C)=O
Reactant: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2C#N)on1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1sc(-c2ccccc2)nc1COc1cc(COc2ncccc2C=O)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
To a mixture of 2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile (1.90 g) and anhydrous toluene (100 mL) was dropwise added a solution (0.95 M, 16.3 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1.5 hrs. A saturated aqueous ammonium chloride solution (30 mL) was dropwise added to the mixture and the mixture was further stirred at room temperature for 30 min. Ethyl acetate was added to the mixture and, after stirring the mixture at room temperature for 30 min., an insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (0.80 g, 42%) of 2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 123-124° C.