Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[K+]>O1CCOCC1.CCOC(C)=O>[O:12]1[CH2:2][CH:3]1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(CCl)CNc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(NCC2CO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of the product of Step 3 (185.7 mg, 1.0 mmol, 1 equiv) in 1,4-dioxane (3.3 mL) was added KOH powder (67.3 mg, 1.2 mmol, 1.2 equiv). The mixture was stirred at room temperature for 24 hours. The mixture was diluted with EtOAc and washed with 1M HCl and brine. The organic layer was dried with MgSO4 and concentrated to give crude product. It was further purified by silica gel chromatography using 20% EtOAc/Hex to afford 141.8 mg colorless oil as product, yield 95.0%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:12]([O:14]CC)=O)=[O:10].S(=O)(=O)(O)[OH:30].[OH-].[Na+]>C(O)C>[CH2:17]([C:11]1[C:12](=[O:14])[C:4]2[C:3]([C:8](=[O:30])[C:9]=1[OH:10])=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCC(C(=O)Cc1ccccc1C)C(=O)OCC
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCC1=C(O)C(=O)c2c(C)cccc2C1=O
Temperature: 25 °C
Reaction time: 66 h

Procedure:
Four parts of crude ethyl 2-[(2-methylphenyl)acetyl]tetradecanoate obtained in Example 3 was combined with 12 parts of cold concentrated sulfuric acid and stirred at room temperature for 66 hours. The mixture was poured into ice water and made slightly basic by the addition of 50% aqueous sodium hydroxide. Enough ethanol was added to dissolve the organic matter and air was then bubbled through the solution for 3 hours. The resulting solution was extracted with 100 parts petroleum ether (twice), acidified with hydrochloric acid and re-extracted with diethylether. The ether extract was washed with saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was taken up in acetonitrile and filtered. The filtrate was evaporated to dryness and the residue triturated with petroleum ether to give 0.2 g of 2-dodecyl-3-hydroxy-5-methyl-1,4-napthoquinone, m.p. 92°-93° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[Br:14]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:14])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccn2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)cc1

Procedure:
4-(2-Pyridyl)toluene, 2 mL (1.98 g, 11.7 mmol), N-bromosuccinimide (NBS), 2.5 g (14.0 mmol), and α,α′-azobis(isobutyronitrile)(AIBN), 23 mg (0.14 mmol) were suspended in 35 mL tetrachloromethane, and refluxed for 24 hours. The product was filtered, and the solvent removed from the filtrate by rotary evaporation. Equal amounts of chloroform and water were added and the product extracted. The chloroform layer was separated and dried, and the solvent removed. 4-(2-Pyridyl)benzyl bromide, 2 g, was obtained as a sticky yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)O)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
240 mg (purity 85%, 0.62 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 93 mg (30% of theory)
Reaction SMILES: C([C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:7]2[CH2:22][CH2:23][CH2:24][CH:6]2[C:5](=[O:25])[C:4]=1[C:26]([O-:28])=[O:27])C.[OH-].[Na+].Cl>C(O)C>[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[CH:3]=[C:4]([C:26]([OH:28])=[O:27])[C:5](=[O:25])[C:6]3[CH2:24][CH2:23][CH2:22][C:7]2=3)=[CH:15][CH:14]=1
Reactant: CCC1=C(C(=O)[O-])C(=O)C2CCCC2N1Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2c(c1=O)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above ethyl carboxylate (544 mg, 1.46 mmol) was dissolved in absolute ethanol (5 mL) and was treated with sodium hydroxide (1.75 mL, 1 N aqueous, 1.2 equiv). The mixture was stirred at ambient temperature for 2 hrs and then acidified (≦pH 4) with hydrochloric acid (1 N aqueous). The precipitate that formed was collected and washed successively with water and absolute ethanol, providing the title compound as a white solid: 1H-NMR (400 MHz, CDCl3) δ 8.52 (1H, s), 7.63 (2H, d, J=8.2 Hz) 7.57 (2H, d, J=7.0 Hz), 7.46 (2H, t, J=7.1 Hz), 7.18 (2H, d, J=8.2 Hz), 5.18 (2H, s), 2.99-2.93 (4H, m), 2.22-2.15 (2H, m) ppm; high resolution mass spectrum (ES+) m/z 346.1442 [(M+H)+; calculated for C22H20NO3: 346.1438].
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:34][CH3:35])[N:32]([CH3:33])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N+:26]([O-:9])=[CH:25][C:24]3[N:30]=[C:31]([CH2:34][CH3:35])[N:32]([CH3:33])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1C
Reaction time: 5.5 h
Yield: 8.3 %

Procedure:
A modification of the general method described in Part B of Example 3 was followed. mCPBA (60% pure, 1.39 g, 47.3 mmol) was added in portions to a solution of 8-benzyloxy-2-ethyl-1-methyl-1H-imidazo[4,5-c]quinoline (1.5 g, 47 mmol) in chloroform (75 mL), and the reaction was stirred for 5.5 hours. During the work-up, the combined aqueous washings were extracted with dichloromethane, and the product precipitated from solution. The combined dichloromethane and chloroform solutions were concentrated under reduced pressure until crystals formed and then allowed to stand overnight. The crystals were isolated by filtration. The aqueous solution was extracted with chloroform, and the combined extracts were washed with water (2×) and concentrated under reduced pressure to a small volume. Hexanes were added, and the resulting crystals were isolated by filtration. The mother liquor was concentrated under reduced pressure to afford a solid that was recrystallized from 2-propanol. The three batches of crystals were combined to yield 1.30 g of 8-benzyloxy-2-ethyl-1-methyl-5-oxido-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=1.[CH:40]12[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]1)[CH2:43][NH:42][CH2:41]2.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=[C:2]([N:42]2[CH2:41][CH:40]3[N:47]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH:44]([CH2:45][CH2:46]3)[CH2:43]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n1)C2
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (226 mg, 0.39 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 1.56 mmol), NaHCO3 (196 mg, 2.33 mmol) in NMP (4 mL) was heated at 130° C. overnight. The mixture was cooled to room temperature and diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation of solvent afforded the crude displacement compound. Purification by column chromatography afforded tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: LCMS tR=3.38 Min (5 min run, UV254nm). Mass calculated for, M+H 758.4, observed m/z 758.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][N:4]([CH3:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Br:20][C:21]1[S:25][C:24]([N:26](C(OC2C=CC=CC=2)=O)[C:27](OC2C=CC=CC=2)=[O:28])=[N:23][CH:22]=1.C1CCN2C(=NCCC2)CC1.C(O)(=O)C>CN(C=O)C.O>[Br:20][C:21]1[S:25][C:24]([NH:26][C:27]([NH:19][S:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][C:3]3[N:4]([CH3:8])[N:5]=[C:6]([Cl:7])[C:2]=3[Cl:1])=[CH:15][CH:14]=2)(=[O:18])=[O:17])=[O:28])=[N:23][CH:22]=1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1ncc(Br)s1
Reactant: Cn1nc(Cl)c(Cl)c1Oc1ccc(S(N)(=O)=O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(Cl)c(Cl)c1Oc1ccc(S(=O)(=O)NC(=O)Nc2ncc(Br)s2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(4,5-dichloro-2-methyl-2H-pyrazol-3-yloxy)-benzenesulfonamide (77.3 mg, 0.24 mmol) and diphenyl (5-bromo-1,3-thiazol-2-yl)imidodicarbonate (100 mg, 0.24 mmol) were suspended in DMF (0.4 ml). A solution of DBU (0.04 ml, 0.26 mmol) in DMF (0.1 ml) was added dropwise and the clear mixture was shaken for 1.5 h at rt and kept overnight at 4° C. The mixture was acidified using acetic acid (0.2 ml) and diluted with water (0.2 ml) and purified directly using preparative RP(C18)chromatography: lyophilisate 9 mg, MS: m/e 523.8 (MH−).
Reaction SMILES: Cl[C:2]1[C:3](=[O:25])[N:4]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:2]2[C:3](=[O:25])[N:4]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: COC(=O)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)C(Nc3ccc(OC)cc3)=C(c3ccccc3)C2=O)cc1
Temperature: 150 °C
Yield: 30.1 %

Procedure:
Methyl 4-[(3-chloro-2,5-dioxo-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]benzoate (0.24 mmol, 85 mg), 4-methoxyaniline (0.26 mmol, 33 mg) and triethylamine (0.29 mmol, 29 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 32 mg (30%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 8.03-7.99 (m, 2H), 7.52-7.46 (m, 2H), 7.21 (bs, 1H), 7.16-7.05 (m, 3H), 7.01-6.95 (m, 2H), 6.62-6.52 (m, 4H), 4.81 (s, 2), 3.90 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:10]3[CH2:25][CH2:26][C:27](=[O:28])[C:9]2=3)=[C:4]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:3]=1.O.[CH3:34][N:35](C)C=O>[C-]#N.[Zn+2].[C-]#N>[O:14]=[C:12]1[N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:10]2[CH2:25][CH2:26][C:27](=[O:28])[C:9]=2[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]#[N:35])=[CH:3][C:4]=2[S:29]([CH3:32])(=[O:30])=[O:31])[NH:13]1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1cc(Br)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CC2
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, a mixture of 4-(4-bromo-2-(methylsulfonyl)phenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-2,5-dione (intermediate 8, 110 mg, 0.21 mmol), zinc cyanide (32 mg, 0.27 mmol) and tetrakis (triphenylphosphine)palladium(0) (24 mg, 21 μmol) in N,N-dimethylformamide (2 mL) is heated at 110° C. over night and then cooled to room temperature. Water is added and the mixture is filtered. The precipitate is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 8:2 to 3:7). Yield: 40 mg; ESI mass spectrum: [M+H]+=476; Retention time HPLC: 0.94 min (Z017_S04).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:18]=[CH:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C=CC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a solution of 2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydrospiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one (1.0 g) in chloroform (20 mL), trifluoroacetic acid (20 mL) was added and the mixture was stirred for 1 hour. The reaction mixture was concentrated. The residue was dissolved in methanol and hydrogenated with 4M hydrogen chloride/ethyl acetate in the presence of 20% palladium carbon at 1 atm of hydrogen for 14 hours. The catalyst was removed by filtration and the filtrate was concentrated. To the residue, aqueous 1N sodium hydroxide (5 mL), di-tert-butyl dicarbonate (655 mg) and dioxane (10 mL) were added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (200 mg).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2c(F)cccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2c(F)cccc2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(4-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 15 (0.407 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (122 mg, 0.509 mmol) and DIPEA (0.444 mL, 2.55 mmol) in n-butanol (3 mL) was stirred in a sealed vial for 20 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc). The product containing fractions were concentrated in vacuo and the resulting residue was dissolved in EtOAc (10 mL) and stirred with 2N HCl (10 mL) for 15 min. Volatiles were removed under reduced pressure and the residue was dissolved in MeOH (2 mL) and triturated with diethyl ether affording 136 as a beige powder (126 mg, 78%). LCMS: RT 3.47 min [M+H]+ 374.0. 1H NMR (DMSO, 400 MHz): δ 10.03 (1H, s), 8.66 (1H, s), 8.55 (1H, s), 7.68-7.38 (5H, m), 7.28-7.21 (1H, m), 7.13 (1H, dd, J=10.91, 7.98 Hz), 6.94 (1H, dd, J=8.11, 0.82 Hz), 5.68-5.59 (1H, m), 1.72 (3H, d, J=6.85 Hz)
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-3-amino-1-N-Boc pyrrolidine (1.0 eq, 2.68 mmol), 4-chlorobenzyl bromide (1.0 eq, 2.68 mmol), and potassium carbonate (1.75 eq) were mixed in ethanol (10 mL) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated. The crude product was purified by flash chromatography on silica using ethyl acetate. ESI-MS m/z: 311 (M+1), UV retention time: 1.18 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[CH3:13][C:14]([OH:18])([C:16]#[CH:17])[CH3:15].CCN(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:17]#[C:16][C:14]([CH3:15])([OH:18])[CH3:13])[CH:8]=[N:7]2
Reactant: Clc1cnc2cccc(Br)c2n1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cnc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A microwave tube is charged with 200 mg (0.821 mmol) of 8-Bromo-2-chloro-quinoxaline, 159 μl (1.64 mmol) of 2-Methyl-but-3-yn-2-ol, 231 μl (1.64 mmol) of Et3N, 6.26 mg (0.0329 mmol) of CuI and 11.8 mg (0.0164 mmol) of Pd(PPh3)2Cl2. After several cycles of vacuum/purge with argon, 5 ml of n-BuOH are added. The reaction mixture is then stirred at RT for 30 min. The reaction mixture is poured onto a solution of NaHCO3 and diluted with EtOAc and the phases are separated. The organic phase is washed several times with de-ionized water and the aqueous layer re-extracted with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is dissolved in CH2Cl2 and purified by chromatography (silicagel, hexane:EtOAc=1:1) to afford the title compound as a brown oil, Rt=1.026 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 291 (M+1, 79Br)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](N)=[N:6][CH:7]=1.N([O-])=O.[Na+].[NH4+].[OH-].[ClH:18]>Cl[Cu]>[I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:18])=[N:6][CH:7]=1
Reactant: Cl
Reactant: Nc1ncc(I)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [NH4+]
Product: O=[N+]([O-])c1cc(I)cnc1Cl
Reaction time: 8 h
Yield: 36 %

Procedure:
5-iodo-3-nitro-2-aminopyridine (2.511 g, 9.48 mmol) and concentrated HCl (20 mL) were stirred at room temperature for ten minutes. Sodium nitrite (13 g, 188 mmol) was then slowly added followed by CuCl (1.0 g, 10 mmol). Stirring continued overnight. The mixture was poured into 1:1 NH4OH:H2O, extracted with ethyl acetate, dried over sodium sulfate, then concentrated. The crude residue was purified by flash chromatography using 9:1 hexane:ethyl acetate to yield 5-iodo-3-nitro-2-chloropyridine (984 mg, 36%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12.[H-].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[N:10]([S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH:11]=[CH:12][C:3]=12
Reactant: COc1ncc(Br)c2cc[nH]c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)c2ccn(S(=O)(=O)c3ccc(C)cc3)c12
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
A solution of 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (7.42 g, 32.7 mmol) in dimethylformamide (235 mL) was stirred at room temperature. To this solution was added sodium hydride (1.18 g, 1.96 g of 60% dispersion in oil, 49.0 mmol), and the reaction mixture was stirred for 10 minutes. P-toluenesulfonyl chloride (9.35 g, 49.0 mmol) was then added portion-wise, and the mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was quenched carefully with water and the resulting beige solid collected by vacuum filtration on a Buchner funnel, and washed with water. The solid was collected and dried in a vacuum oven at 50° C. to provide 12.4 g (100%) of 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine.
Reaction SMILES: [OH:1][CH:2]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]>ClCCl>[O:1]=[C:2]([CH:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=C(OCc1ccccc1)C(O)C1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C(=O)C1CCOCC1
Reaction time: 15 h
Yield: 86.3 %

Procedure:
A Dess-Martinn reagent (5.7 g, 13.44 mmol) was added to a solution of benzyl 2-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetate (2.1 g, 8.404 mmol) in dichloromethane (50 ml) at room temperature, and the mixture was stirred for 15 hr. The reaction mixture was quenched with 10% sodium thiosulfate and was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=9:1) to give the title compound as a light yellow oil (1.8 g, yield 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.C1C(=O)N([Br:32])C(=O)C1>>[Br:32][C:6]1[C:2]([CH3:1])=[N:3][O:4][C:5]=1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Br)cc2)cc1

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 207 using N-(3-methyl-5-isoxazolyl)-4-(4-methoxyphenyl)benzenesulfonamide (Example 211) and NBS (reaction time 30 min at room temperature). The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent giving the final product in 78% yield, m.p. 208° C. (dec). The product was recrystallized using hexane/ethyl acetate.