Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]CCN)[CH:5]=[CH:6][C:7]=1Cl.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C=O.[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:39][CH2:38][N:37]([CH:40]([CH2:53][C:54]2[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[CH:57]=[C:56]([C:64]([F:67])([F:66])[F:65])[CH:55]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH2:44])[CH2:36][CH2:35]1)(=[O:32])[CH3:31].C1(CC=O)C=CC=CC=1>CO.ClCCl>[C:30]([NH:33][C:34]1([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:35][CH2:36][N:37]([CH:40]([CH2:53][C:54]2[CH:55]=[C:56]([C:64]([F:65])([F:66])[F:67])[CH:57]=[C:58]([C:60]([F:62])([F:61])[F:63])[CH:59]=2)[CH2:41][CH:42]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)[CH2:43][NH:44][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH2:38][CH2:39]1)(=[O:32])[CH3:31]
Reactant: NCCCCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Agent: O=CCc1ccccc1
Agent: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CNCCc2ccccc2)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
Using a procedure similar to that described in Example 1, except replacing the (3,4-dichlorophenyl)butylamine and the 3,5-bis(trifluoromethyl)benzaldehyde used therein with 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine and phenylacetaldehyde, respectively, the title compound was prepared; mp 55-57° C.; partial NMR (DMSO): 7.1-6.95 (broad m,11), 3.88 (d,1), 3.65 (d,1), 3.35(d,1), 3.15(d,1), 1.85 (s,3); MS: m/z=764(M+1,100%); TLC: Rf=0.44 (10:1 dichloromethane:methanol). Analysis for C40H41Cl2F6N3O: Calculated: C, 62.83; H, 5.40; N, 5.50; Found: C, 63.18; H, 5.71; N, 5.35.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:11]=1[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:27][NH2:28]>>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:11]=1[C:12]1[CH2:14][CH2:15][C:16](=[O:17])[NH:27][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1OCC(O)CNC(C)(C)C
Reactant: NN
Solvent: O
Product: Cc1ccc(C2=NNC(=O)CC2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
Methyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methylbenzoyl]propionate was cyclised with hydrazine hydrate in a manner similar to that described in Example 2(ii) to give 6-[2-(3 -t-butylamino-2-hydroxypropoxy)-4-methylphenyl]-4,5-dihydro-3(2H)-pyridazinone (m.p. 129.5°-130.5° C). The hydrochloride, crystallised from ethanol-ether, had m.p. 206.5°-209.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]C)=[O:23])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-]>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([CH:14]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[O:13])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2C(=O)OC)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N1CCN(C(=O)C(Cc2ccccc2C(=O)O)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-methoxycarbonylphenyl)ethyl]aminocarbonyl-4-methoxyquinoline (220 mg, 0.4 mmol) in methanol was added a solution of LiOH (3 mL, 0.25 M) and the resulting reaction mixture was stirred at ambient temperature overnight. The product was purified by preparative HPLC and lyophilization to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(2-carboxyphenyl)ethyl]aminocarbonyl-4-methoxyquinoline as an orange solid, 140 mg (50%); NMR (DMSO-d6), 1.08 (t, 3), 3.40 (m, 10), 4.00 (q, 2), 4.04 (s, 3), 5.28 (m, 1), 7.26(t, 1), 7.34 (m, 2), 7.42 (s, 1), 7.82 (m, 2), 8.06 (d, 1), 8.14 (d, 1H), 8.88 (d, 1) ppm.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[CH3:12][O-:13].[Na+].[OH-].[Na+]>CC#N.CO>[CH3:12][O:13][C:2]1[O:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=1
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: COc1ncc(C(=O)O)o1
Yield: 69.9 %

Procedure:
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 mL) and anhydrous MeOH (10 mL) is added NaOMe (628 mg, 11.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is cooled and then concentrated and is redissolved in MeOH (10 mL). To this crude is added 1 N NaOH (10 ml, 10 mmol). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCl, PH adjusted to 7 via pH paper indicator. The crude is concentrated to remove MeOH. The crude is diluted in water. The aq. layer is acidified with concentrated HCl and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2-methoxyoxazole-5-carboxylic acid (290 mg). This acid is used without further purification. HPLC retention time=0.58 minutes (condition B); MS 144.0 (M+1).
Reaction SMILES: Cl.Cl.[CH3:3][C@@:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH:29]1([NH:35][C:36]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C@:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C=NC1CCCCC1
Reactant: C[C@]1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(C(=O)NC3CCCCC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
(S)-2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 408 (236 mg, 0.88 mmol) was dissoloved in a mixture of methylene chloride (15 ml) and triethylamine (2 ml, 14.35 mmol). To the solution, cyclohexyl isocyanate (120 mg, 0.96 mmol) was added followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylic acid cyclohexylamide (164 mg, 47%) as a light yellow powder.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:3]([OH:5])=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:44][CH2:45]I>O1CCOCC1>[Cl:44][CH2:45][O:4][C:3](=[O:5])[C:2]([CH3:1])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:22])[CH3:23])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: ClCI
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCCl
Reaction time: 18 h

Procedure:
(2,2-dimethyl-3-(N-CBz-D-valyloxy)-propionic acid (4.5 g, 12.8 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 8.3 ml, 12.8 mmole). The solution was dried in vacuo, and it was coevaporated with toluene several times. The residue was dissolved in methylene chloride and then chloroiodomethane (18 ml, 260 mmole) was added to the solution. After 18 hr, the reaction solution was evaporated and the product was isolated with silica gel column chromatography. 3.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)[CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Product: COc1ccc(O)c(Cc2cccc(C(F)(F)F)c2)c1

Procedure:
Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3'-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228° C., and compound 68, mp 188-190° C., byu the procedure similar to that in Example 18 method B.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:15])[CH:12]([CH3:14])[CH3:13]
Reactant: COc1cccc(Cl)c1Cl
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (100 g., 0.565 mole) and isobutyryl chloride (66 g., 0.62 mole) in methylene chloride (400 ml.) is cooled to 5° C. and treated with aluminum chloride (83 g., 0.62 mole) during a 1 -hour period. The reaction mixture is allowed to warm to 25° C. and after 24 hours is poured into ice water (400 ml.) and hydrochloric acid (30 ml.). The organic phase is washed with 5% sodium hydroxide, water, dried over magnesium sulfate and distilled at reduced pressure affording 68 g. of 2',3'-dichloro-4'-methoxyisobutyrophenone which distills at 120°-130° C./0.5 mm.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20](COCCOC)[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:28][C@H:29]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:30]I)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CO.C(OCC)(=O)C>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:28][C@H:29]([C:32]1[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH3:30])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O[C@@H](CI)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H](O[C@@H]1CC[C@@H]2N(Cc3ccccc3)[C@@]1(c1ccccc1)C[C@@]2(F)c1nnn[nH]1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
Palladium on charcoal (60 mg) was added to a solution of (1R*,2R*,5S*,6S*)-8-benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-iodoethoxy}-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Description 46; 193 mg, 0.23 mmol) and triethylamine (38 mg, 0.38 mmol) in methanol (3 ml) and ethyl acetate (5 ml). The mixture was hydrogenated at 40 psi. for 3 hours using the Parr™ apparatus. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was taken up in a mixture of 1.0M Hydrochloric acid in diethyl ether (5 ml) and methanol (5 ml) and stirred at reflux for 18 hours. The mixture was concentrated in vacuo to yield the title compound (90 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[N:13]1([C:9]2[CH2:8][CH2:7][C:6]3[C:11]([CH:10]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: C1CCNC1
Product: C1=C(N2CCCC2)CCc2ccccc21

Procedure:
When R2 in the compounds of Formula I is methyl, the methyl-substituted 8-bromo-2-tetralone can be prepared from the corresponding unsubstituted 8-bromo-2-tetralone. The 8-bromo-2-tetralone first is treated with pyrrolidine to produce the corresponding 1,2-dihydro-3-pyrrolidinyl-naphthalene. The latter, upon treatment with methyl iodide and acid hydrolysis, gives the desired 8-bromo-1-methyl-2-tetralone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].[S:32](Cl)([CH3:35])(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(S(C)(=O)=O)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.476 mmol) in pyridine (1.5 mL), mesyl chloride (0.081 g, 0.714 mmol) was added at 0° C. and stirred it at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound. LCMS: 499.20 (M+1)+; HPLC: 98.22% (@ 254 nm) (Rt; 6.278); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.85 (t, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 6.94 (s, 1H), 5.89 (s, 1H), 5.22 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 3.98 (m, 2H), 3.42 (t, 2H, J=5.6 Hz), 2.96 (s, 3H), 2.84 (m, 2H), 2.21 (s, 3H), 2.13 (s, 3H), 1.50 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([OH:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH:16]([N+:17]([O-:19])=[O:18])[CH2:15][CH2:14][CH:13]([O:20][C:21](=[O:23])[CH3:22])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(O)CCC2[N+](=O)[O-])cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(C2CC(OC(C)=O)CCC2[N+](=O)[O-])cc1OC
Temperature: 100 °C

Procedure:
10.18 g of (±)-(1RS,3RS,4RS)-3-(3,4-dimethoxyphenyl)-4-nitrocyclohexanol (compound D1) are dissolved in 100 ml of acetic anhydride and the solution is heated to 100° C. for 1-2 h. After removal of the solvent, the residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 2/1. Concentration of the corresponding eluate fractions furnish 10.37 g (89% of theory) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]3[NH:14][CH:15]=[C:16]([C:17]#[N:18])[C:11]3=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:43]3[CH2:42][O:41]B(O)[C:39]=3[CH:38]=[CH:37][CH:36]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:21])[CH3:20].ClCCCl.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCOC(C)=O>[C:19]([C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[C:29](=[O:34])[N:28]([C:35]1[C:43]([CH2:42][OH:41])=[C:39]([N:14]3[C:12]4=[N:13][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:9][CH:10]=[C:11]4[C:16]([C:17]#[N:18])=[CH:15]3)[CH:38]=[CH:37][CH:36]=1)[N:27]=[CH:26]2)([CH3:22])([CH3:20])[CH3:21]
Reactant: CN1CCN(c2ccc3c(C#N)c[nH]c3n2)CC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CN1CCN(c2ccc3c(C#N)cn(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)c3n2)CC1
Temperature: 45 °C
Reaction time: 48 h
Yield: 16.7 %

Procedure:
In a 25 mL round-bottomed flask, 6-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (110 mg, 456 μmol), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (177 mg, 501 μmol, Eq: 1.10) and copper acetate (112 mg) were combined with 1,2-dichloroethane (3.03 ml) to give a blue suspension. Pyridine (72.1 mg, 73.7 μl, 912 μmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. The reaction mixture was poured into 20 mL EtOAc and extracted with sat NH4Cl (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM) to give 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (43 mg, 17%) of off white solid.
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][C:7]([NH:10][C:11]1[N:12]([CH3:29])[C:13](=[O:28])[C:14]2[C:15](=[N:17][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[CH:19]=2)[N:16]=1)([CH3:9])[CH3:8].O.[OH-].[NH4+]>CN(C=O)C>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:18]2[CH:19]=[C:14]3[C:13](=[O:28])[N:12]([CH3:29])[C:11]4[N:16]([CH2:6][C:7]([CH3:9])([CH3:8])[N:10]=4)[C:15]3=[N:17]2)=[CH:22][CH:23]=1
Reactant: Cn1c(NC(C)(C)CO)nc2nn(Cc3ccc(Br)cc3)cc2c1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CN1C(=O)c2cn(Cc3ccc(Br)cc3)nc2N2CC(C)(C)N=C12
Temperature: 25 °C
Yield: 92.1 %

Procedure:
Thionyl chloride (67 mL, 922 mmol) is added dropwise to a solution of 6-(1-hydroxy-2-methylpropan-2-ylamino)-5-methyl-2-(4-bromobenzyl)-2H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (134 g, 330 mmol) in DMF (800 mL). The reaction mixture is stirred at room temperature until the reaction is complete. The mixture is poured into cold water, and then adjusted to pH 8-9 with ammonium hydroxide aqueous solution. After filtration, the obtained solids are washed with water, and then dried under vacuum to give 118 g of product (yield: 92%). MS (ESI) 388.1 [M+H]+.
Reaction SMILES: [S-2:1].[Na+].[Na+].CO.[C:6]([N:10]=[N:11][C:12]1(Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7]>O>[C:6]([N:10]=[N:11][C:12]1([S:1][C:12]2([N:11]=[N:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: [S-2]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC1(SC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 15 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
A solution of 1.56 grams (0.2 moles) of sodium sulfide in 50 ml. of 75% aqueous methanol was prepared in a 200 ml. beaker and cooled to 15°C. To this solution was added 8.2 grams (.0404 moles) of 1-t-butylazo-1-chlorocyclohexane dropwise over a 15 minute period. After the addition was complete, the reaction was stirred for 45 minutes at room temperature and poured into 100 ml. of cold water. A solid formed and was filtered off and dried. The dried material weighed 2.2 grams (30% yield). The infrared spectrum of the product was in agreement with the structure of the desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)([O-:14])(=[O:13])=[S:12].[K+]>C(O)C>[C:5]1([CH2:4][CH2:3][CH2:2][O:14][S:11]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[S:12])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCCCc2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 2 using 1-bromo-3-phenylpropane (0.044 mmol), potassium thiotosylate (0.044 mmol) and absolute ethanol (125 mL) to give an oil which was used without purification. 1H NMR (CDCl3) δ 1.95 (quint., 2 H), 2.459 (s, 3 H), 2.63 (t, 2 H), 2.95 (t, 2 H), 7.0-7.4 (m, 8 H), 7.7 (d, 2 H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-:25].[Na+].OO.C(Cl)(Cl)Cl>O1CCCC1>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH:8]([O:25][C:1](=[O:11])[CH3:2])[CH3:9])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [OH-]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Agent: OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC(C)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 163.9 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.6 g (17 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-acetoxy-1-heptenylcatecholborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.5 g (yield 81%) of (+)-5-decyloxy-2-{4-(6-acetoxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =+0.9 (c=1.0, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:16][CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: COc1ccc2nc(Cl)c(N)nc2c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2nc(OC)c(N)nc2c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.3 %

Procedure:
To 3-amino-2-chloro-6-methoxyquinoxaline (1.50 g, 7.16 mmol) dissolved in tetrahydrofuran (60 ml), 25 wt % sodium methoxide (15.5 g, 71.6 mmol) in methanol was added at room temperature and stirred further at room temperature for 21 hours. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.18 g of the titled compound (yield, 80%).