Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11](OC)=[O:12].[H-].C([Al+]CC(C)C)C(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][OH:12]
Reactant: COC(=O)c1n[nH]c2ccc(Cl)cc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1n[nH]c2ccc(Cl)cc12
Temperature: -10 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A solution of methyl 5-chloro-1H-indazole-3-carboxylate (2.11 g, 10.0 mmol) in THF (70 mL) was cooled to −10° C., and added dropwise with a 1 M solution of diisobutylaluminum hydride in toluene (36.0 mL). After completion of the addition, the mixture was stirred at −10° C. for 1 hour, and then stirred overnight at room temperature. The reaction mixture was added dropwise with saturated aqueous sodium sulfate under ice cooling to terminate the reaction, and then the reaction mixture was filtered through Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the objective (5-chloro-1H-indazol-3-yl)methanol (0.210 g, 11%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][CH:69]([CH2:72]O)[CH2:68][CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60]>C(Cl)Cl>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:72][CH:69]4[CH2:70][CH2:71][N:66]([C:64]([O:63][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:65])[CH2:67][CH2:68]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diisopropyl azodicarboxylate (139 μl, 0.71 mmol) was added to a mixture of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 7), triphenylphosphine (186 mg, 0.71 mmol) and 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine, (also known as tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate), (152 mg, 0.71 mmol) in methylene chloride (3 ml), cooled in an ice/water bath. The mixture was allowed to warm to ambient temperature and was stirred overnight. The mixture was concentrated under reduced pressure and the residue purified by column chromatography, eluting with 1% methanol/methylene chloride and 0.1% triethylamine to give tert-butyl 4-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]piperidine-1-carboxylate (293 mg containing 13.5 mmol % triphenylphospine oxide, 86%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f13) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: BrC[CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=O.[CH2:16]([O:18][C:19](=[O:23])[C:20]([NH2:22])=[S:21])[CH3:17]>CCO>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]1[N:22]=[C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:23])[S:21][CH:3]=1
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CCBr)c1ccc2ccccc2c1
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc3ccccc3c2)cs1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of bromoethyl-2-naphthyl ketone (1.78 g, 6.8 mmol), 2-thio-oxalamic acid ethyl ester (1 g, 7.5 mmol) in EtOH (absolute) was kept under reflux for 6 h. The mixture was cooled to room temperature. The product separated as a solid, which was filtered, washed with ethanol and dried to provide the desired ester, ethyl 4-(2-naphthyl)-1,3-thiazole-2-carboxylate, (IIIb) (0.862 g, 48% yield). MS: 284 (M+H). To a mixture of the ester, (IIIb) (800 mg, 2.82 mmol) in dry methylacetate (10 mL) was added NaH (60% dispersion in mineral oil, 135 mg, 3.37 mmol). The mixture was stirred at room temperature for 0.5 h and at reflux for 2 h. The mixture was poured into cold water and was neutralized with conc. HCl. After saturating the mixture with NaCl, the mixture was extracted from dichloromethane (twice). The combined extract was washed with brine. After drying over magnesium sulphate, solvent was evaporated to furnish the β-ketoester, ethyl 3-(4-(2-naphthyl)(1,3-thiazol-2-yl))-3-oxopropanoate, which was used for the next step without further purification. To the above β-ketoester was added absolute ethanol (10 mL) and hydrazine hydrate (1 mL, excess). The mixture was kept under reflux for 4 h. After cooling, solvent was evaporated from the reaction mixture. The resulting mixture was chromatographed over silica gel and was eluted with EtOAc. The product pyrazolone (VIg) was isolated as a solid which was further purified via washing with diethyl ether (i.e. stirring in ˜50 mL of diethyl ether followed by filtration and washing with diethyl ether). Yield 287 mg, (35% in two steps). MS: 294 (M+H).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[O:12][C:11]([C:13]3[O:14][C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)[C:16]=4[C:17]=3[CH3:18])=[N:10][C@H:9]2[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:43])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH:1]1([CH2:7][C@@H:8]2[O:12][C:11]([C:13]3[O:14][C:15]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]5[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=5)[C:16]=4[C:17]=3[CH3:18])=[N:10][C@H:9]2[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]2)=[O:43])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C2=N[C@@H](C(=O)N3CCN(C)CC3)[C@H](CC3CCCCC3)O2)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C2=N[C@@H](C(=O)N3CCN(C)CC3)[C@H](CC3CCCCC3)O2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 0.75 h
Yield: 75.7 %

Procedure:
dl-[5-Cyclohexylmethyl-2-(3-methyl-4-{3-[tert-butoxycarbonyl-(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-yl)-trans-4,5-dihydro-oxazol-4-yl]-(4-methyl-piperazin-1-yl)-methanone (11.9 mg) was dissolved in 1:1 mixture of trifluoroacetic acid and dichloromethane (1 ml) and was allowed to stand at room temperature for 45 minutes. The resulted solution was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. After evaporation of the solvent the crude product was purified by silica gel column chromatography (Fuji Silysia, DU-3050) using 1000:10:1 mixture of dichloromethane, methanol and triethylamine as an eluent to give the title compound (7.7 mg) as a white solid. FAB-MS: m/z 588 (MH+); NMR (CDCl3): δ 0.9-2.0 (13H, m), 2.06 (2H, quintet, J=6.27 Hz), 2.34 (3H, s), 2.43 (2H, t, J=4.95 Hz), 2.55 (2H, m), 2.62 (3H, s), 2.89 (2H, t, J=6.93 Hz), 3.70 (2H, m), 3.81 (1H, m), 3.84 (2H, s), 4.07 (1H, m), 4.16 (2H, t, J=5.93 Hz), 4.55 (1H, d, J=6.60 Hz), 5.54 (1H, m), 6.61 (1H, d, J=7.92 Hz), 7.10 (1H, d, J=8.25 Hz), 7.15-7.30 (2H, m), 7.67 (1H, dt, J=7.92 Hz, 1.98 Hz), 8.49 (1H, dd, J=1.65 Hz, 4.95 Hz), 8.57 (1H, d, J=1.98 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:17][CH3:18])[CH2:9][C@H:10]([CH2:14][CH:15]=[CH2:16])[C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:19].OS(O)(=O)=O.[CH3:25]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:17][CH3:18])[CH2:9][C@H:10]([CH2:14][CH:15]=[CH2:16])[C:11]([O:13][CH3:25])=[O:12])=[CH:4][C:3]=1[CH3:19]
Reactant: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: C=CC[C@@H](C[C@@H](OC)c1ccc(F)c(C)c1)C(=O)OC
Reaction time: 16 h

Procedure:
To a solution of (5)-2((R)-2-(4-fluoro-3-methylphenyl)-2-methoxyethyl)pent-4-enoic acid in 5 mL methanol was added concentrated H2SO4 (50 mL) at room temperature and the resulting solution stirred for 16 h. The reaction mixture was concentrated under reduced pressure, the residue treated with water, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over Na2SO4. The product was isolated by flash column chromatography eluting with 0% to 10% ethyl acetate/hexane gradient solvent to give 122 mg of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1.[ClH:52]>O1CCOCC1.CO>[ClH:52].[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:43]=[CH:44][C:45]([CH3:46])=[CH:47][CH:48]=3)(=[O:40])=[O:41])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Yield: 99 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (191 mg, 0.270 mmol) was deprotected in HCl in dioxane/MeOH (5/5 ml). This afforded 173 mg (99% yield) of the titled. MS: m/z=606.8 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1>ClCC(Cl)(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[CH:17][C:18]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: Fc1cccc(F)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: ClCC(Cl)(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1F
Temperature: 90 °C
Yield: 75.3 %

Procedure:
To a mixture of phthalic anhydride (64.8 g, 438 mmol), tetrachloroethane (600 mL) and 1,3-difluorobenzene (100 g, 877 mmol) was added anhydrous A1C13 (141 g, 964 mmol) over 20 minutes while maintaining the reaction temperature below 40° C. The temperature was increased to 90° C. for 2 hours, the reaction mixture was cooled and poured into ice/6N HCl. The mixture was extracted with ether (2×1.2 L) and the combined ether extracts were dried over Na2SO4. The solvent was removed in vacuo and the residue was recrystallized from hot ethyl acetate to afford 86.5 g (75%) of 2-(2,4-difluorobenzoyl)benzoic acid, m.p. 129°-131 ° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][F:26]>CS(C)=O.CO>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][F:26])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: FCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCF
Temperature: 120 °C
Yield: 60.1 %

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (200 mg, 0.88 mmol, 1eq) in anhydrous DMSO (1 ml) in a 1.5 ml microwave vial equipped with a stirrer was added sodium bicarbonate (113 mg, 1.07 mmol, 1.2eq) followed by 1-bromo-4-fluorobutane (114 ul, 165 mg, 1.06 mmol, 1.2eq). The vial was sealed and heated with stirring using a microwave, maintaining the temperature at 120° C. for 25 min with a maximum power output of 300 W. The resulting dark brown solution was diluted with methanol (1 ml) and purified by mass directed autopreparative HPLC to give the title compound as a white solid (159 mg, 60%). m/z 301.3[MH+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]=[N:9][OH:10].ClN1C(=O)CCC1=O.[CH:20]1([C:23](=O)[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21]1.[O-]CC.[Na+].C(O)C>CN(C)C=O.O1CCCC1.O>[CH:20]1([C:23]2[O:10][N:9]=[C:8]([C:7]3[C:6]([Cl:11])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[C:24]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:21]1
Reactant: ON=Cc1c(Cl)cncc1Cl
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2c(Cl)cncc2Cl)noc1C1CC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 8.7 %

Procedure:
To a solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (1.44 g, 7.53 mmol) in N,N-dimethylformamide (6 mL) was added N-chlorosuccinimide (1.00 g, 7.53 mmol). The mixture was heated to 65° C. and all solids dissolved. The solution was stirred at 65° C. for approximately 1.5 hr, poured into water and extracted with ether. The ether layer containing the crude imidoyl chloride was washed with brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclopropyl-3-oxopropanoate (1.41 g, 9.03 mmol) in tetrahydrofuran (2 mL) at 0° C. was added a 25 wt % solution of sodium ethoxide in ethanol (2.83 mL, 9.03 mmol) and the mixture was stirred for approximately 7 min. Then the above imidoyl chloride in tetrahydrofuran (6.5 mL) was added at a slow rate. A solid precipitated and the mixture was allowed to warm to ambient temperature and stir overnight. The mixture was concentrated and taken up with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and purified by chromatography (silica gel, 0-10% ethyl acetate in hexanes gradient elution). The isolated solid was washed with hexanes to afford ethyl 5-cyclopropyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (214 mg, 9%). 1H-NMR (400 MHz, DMSO-d6) δ 8.84 (s, 2H), 4.07 (q, J=7 Hz, 2H), 2.88-2.81 (m, 1H), 1.37-1.27 (m, 4H), 0.95 (t, J=7 Hz, 3H). LRMS (APCI) m/z 327 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH2:13][CH2:12][N:11]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([CH2:16][OH:17])[CH2:13][CH2:12][N:11]2[C:25]([O:27][CH3:28])=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)N1CCC(CO[Si](C)(C)C(C)(C)C)CC1Cc1ccc(C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)N1CCC(CO)CC1Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
To a suspension of methyl 2-(4-tert-butylbenzyl)-4-((tert-butyldimethylsilyloxy)methyl)-piperidine-1-carboxylate (6.27 g, 14.46 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (18.79 mL, 18.79 mmol, 1 M in THF) and the reaction mixture was stirred at room temperature for 90 minutes. The solvents were evaporated, the residue dissolved in ethyl acetate and washed with satd NaHCO3 (×1), then brine (×2). The organic layer was dried over MgSO4 and evaporated. The residue was purified by automated column chromatography (Biotage, (340 g KP-SIL) eluent EtOAc/heptane, gradient 20-90% EtOAc) to yield the product (3.21 g, 70%) as an oil. 1H NMR (400 MHz, cdcl3) δ 1.30 (s, 9H), 1.42-1.50 (m, 2H), 1.65-1.91 (m, 2H), 2.68 (m, 1H), 2.89-3.07 (m, 2H), 3.39-3.62 (m, 3H), 3.67 (m, 3H), 3.87 (m 1H), 4.07 (m, 1H), 7.11 (m, 2H), 7.30 (m, 2H). MS m/z 320 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16][OH:17])[O:12][C:8]3=2)[N:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C.C(Cl)(Cl)Cl>C(Cl)Cl.O>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(CO)O3
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4nc(C)ccc4c3O2)cc1
Yield: 86.5 %

Procedure:
A solution of [8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol (0.13 g, 0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) and triethylamine (0.65 mL, 4.7 mmol) in CH2Cl2 (8 mL) was stirred at room temperature for 18 h. CHCl3 (30 mL) and H2O (30 mL) were added. The two layers were separated. The aqueous layer was extracted with CHCl3 (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluting with (1:1) hexane:EtOAc gave 0.19 g (88%) of the title compound as a brown syrup.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[N:23]1[C:32]2[C:27](=[CH:28][C:29](B(O)O)=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:23]=[CH:24][CH:25]=[CH:26]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: OB(O)c1ccc2ncccc2c1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5ncccc5c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and quinolin-6-ylboronic acid (Combi-Blocks, Cat. No. BB-5182). LCMS (M+H)+=420.1.
Reaction SMILES: BrC1C=C(C([N:16]2C[CH2:20][NH:19][C:18](=[O:22])[CH2:17]2)=O)OC=1C1C=CC=C(Cl)C=1.[Br:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][C:25]=1[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=1.C(N(CC)C(C)C)(C)C>>[Br:23][C:24]1[O:28][C:27]([C:29]([N:16]2[CH2:17][C:18](=[O:22])[NH:19][CH2:20]2)=[O:31])=[CH:26][C:25]=1[C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([Cl:39])[CH:33]=1
Reactant: O=C1CN(C(=O)c2cc(Br)c(-c3cccc(Cl)c3)o2)CCN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)c(Br)o1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)c(Br)o2)CN1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 27A starting with the compound from Example 23A and the compound from Example 35A. 5 equivalents of N,N-diisopropylethylamine are used. The product is precipitated by the addition of water to the reaction solution. The precipitate is collected by suction filtration, washed with tetrahydrofuran and dried under high vacuum. 587 mg (97% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[N+:30]([O-])=O)[O:5][C:6]1[C:15]2[C:10](=[C:11]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([OH:26])[CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[K+].[Br-]>>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:11]2[C:10]3[C:15](=[C:6]([O:5][C:4]4[CH:27]=[CH:28][C:29]([NH2:30])=[C:2]([OH:1])[CH:3]=4)[CH:7]=[CH:8][CH:9]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:18][C:19]=1[OH:26]
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c(Oc4ccc([N+](=O)[O-])c(O)c4)cccc23)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2cccc3c(Oc4ccc(N)c(O)c4)cccc23)cc1O
Yield: 78.9 %

Procedure:
1,5-Bis(4-amino-3-hydroxyphenoxy)naphthalene was synthesized in a manner analogous to Example 2 from 1,5-bis(3-hydroxy-4-nitrophenoxy)naphthalene. Yield: 78.9%; mp 251˜253° C., IR (KBr) 3292, 3365, 1498 cm−1; MS (EI) m/z 374 (M+, 100); Elemental Anal. Calcd. for C22H18N2O4: C, 70.59; H, 4.81; N, 7.49. Found: C, 70.48; H, 4.88; N, 7.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:28][C:29](O)=[O:30].[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:32]1([C:29](=[O:30])[CH2:28][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[O:24][N:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=4)[CH2:16][CH2:15]3)=[CH:7][C:2]=2[F:1])[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-fluoro-4-{2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (80.0 mg, 0.185 mmol) in 1 ml anhydrous DMF at RT was added azetidine (12.6.2 mg, 0.221 mmol) and N,N-diisopropylethylamine (0.097 ml, 0.554 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.369 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 473.2 (M+H)+. GPR119 Human EC50: 5.8 nM
Reaction SMILES: [N:1]1([C:6]2([CH:9]=O)[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)=[N:17][C:18]=1[NH2:19]>C(O)(=O)C>[N:1]1([C:6]2([C:9]3[NH:19][C:18]4=[N:17][C:16]([N:20]5[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]6[CH2:32][CH2:31][CH2:30][CH2:29]6)=[O:27])[CH2:21]5)=[CH:15][CH:14]=[C:13]4[N:12]=3)[CH2:7][CH2:8]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CC1(n2ccnc2)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: [S]
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5ccnc5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 80 °C

Procedure:
1-(1H-Imidazol-1-yl)cyclopropanecarbaldehyde (60 mg, 0.44 mmol), sulfur (10 mg), and acetic acid (0.5 mL) were added to the filtrate containing (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared in the previous step, The reaction mixture was heated at 80° C. for 24 h. The solvent was removed under reduced pressure and the resulting crude material was purified via preparative TLC (10% methanol in dichloromethane) to afford the title compound. MS (ES+APCI) 406.1; LCMS retention time 4.739 min (Method R1).