Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[K+]>C(O)C>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(OCCCCCCBr)cc1

Procedure:
A mixture of hydroquinone (16.5 g), 1,6-dibromohexane (7.32 g) and ethanol (60 ml) is added dropwise over 3-5 min to a solution of potassium hydroxide (85%, 2.0 g) and ethanol (20 ml). The mixture is heated at reflux for 4 hr and then allowed to cool. Silica gel (30 g) is added to the solution and the ethanol is removed at reduced pressure. The residue is chromatographed on silica gel (200 g) and eluted with ethyl acetate/hexane (33/67) to give the title compound, m.p. 43°-45°; MS (m/e)=272, 274 (M+).
Reaction SMILES: [C:1]1([S:7]([C:10]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][N:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[H][H]>[Pd].CN(C)C=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][CH:11]=[C:10]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[N:14][CH:15]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(NC=C(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)nc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1ccc(NC=C(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)nc1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
A mixture of 1,1-bis(phenylsulphonyl)-2-(5-nitropyrid-2-ylamino)ethene (2.23 g), concentrated hydrochloric acid (2 ml), palladium on charcoal catalyst (5% w/w; 1.5 g) and dimethylformamide (50 ml) was hydrogenated at 25° C. and atmospheric pressure until three molar equivalents of hydrogen had been taken up. After filtration to remove the catalyst, the dimethylformamide was removed under vacuum below 40° C. and the residue was treated with methanol (25 ml) and stirred for 30 minutes, and then allowed to stand for 24 hours. The resulting solid was then filtered off, dissolved in chloroform (25 ml), treated with anhydrous potassium carbonate (5 g), and stirred from 2 hours. The mixture was filtered, and the chloroform was removed in vacuo. The resulting residue was recrystallised from a mixture of acetonitrile and diethyl ether and dried thoroughly at 100° C./0.1 mmHg, to give 2-(5-aminopyrid-2-ylamino)-1,1-bis(phenylsulphonyl)ethene (0.5 g), m.p. 172°-174° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][C:20]=2[C:21]([OH:23])=O)[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([NH2:36])[CH:34]=[CH2:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:31][CH3:32])=[CH:24][C:20]=2[C:21](=[O:23])[NH:36][CH2:33][CH:34]=[CH2:35])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2C(=O)O)ccn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C=CCNC(=O)c1cc(NC(=O)OC)ccc1-c1ccnc([C@H](CC=C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
To a solution of 24D (0.06 g, 0.136 mmol), prop-2-en-1-amine (9.31 mg, 0.163 mmol), EDC (0.052 g, 0.272 mmol) and HOBT (0.042 g, 0.272 mmol) in DMF (1 mL) was added TEA (0.057 mL, 0.408 mmol). The reaction was stirred at rt for 18 h. The reaction was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, and concentrated. Purification by normal phase chromatography provided 24E (0.056 g, 86%) as a white solid. MS (ESI) m/z: 481.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:24]#[C:25][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:24]#[CH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Agent: [F-]
Solvent: CC#N
Product: C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin-2(1H)-one (1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) at 0° C. was added tetrabutylammoniun fluoride (0.611 g, 1.93 mmol). The reaction was stirred at 0° C. for 15 minutes then for 1 hour at room temperature. The reaction was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed with water. The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) using ethyl acetate in hexane (1:1 v/v). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.779 g, 72%) as a gold solid. 1H-NMR (CD3OD, 400 MHz) δ7.73 (d, 1H, J=7.6 Hz), 7.43 (d, 2H, J=7.2 Hz), 7.35 (m, 4H), 7.09 (m, 3H), 6.45 (d, 1H, J=7.6 Hz), 5.27 (s, 2H), 5.13 (s, 2H), 3.78 (s, 1H); ES-HRMS m/z 334.1243 (M+H calculated for C21H17NO2F requires 334.1234).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:10](=[O:11])[N:9]([CH:12]3[C:18](=[O:19])[NH:17][C:15](=[O:16])[CH2:14][CH2:13]3)[CH2:8][C:4]2=[C:5]([NH2:7])[CH:6]=1.[C:20](O)(=[O:42])[CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH3:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O.CN(C=O)C>[O:19]=[C:18]1[CH:12]([N:9]2[CH2:8][C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[NH:7][C:20](=[O:42])[CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28]/[CH:29]=[CH:30]\[CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH3:41])[C:10]2=[O:11])[CH2:13][CH2:14][C:15](=[O:16])[NH:17]1
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Lenalidomide (200 mg, 0.771 mmol) was taken up in 5 mL of CH3CN and 2 mL of DMF along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 253 mg, 0.771 mmol), HATU (322 mg, 0.848 mmol) and DIEA (200 μL, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 3 h and diluted with EtOAc (20 mL). The organic layer was washed with water (3×5 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (95% CH2Cl2, 5% MeOH) afforded 280 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)docosa-4,7,10,13,16,19-hexaenamide (63%). MS (EI) calculated for C35H43N3O4: 569.33; found: [M+H]+ 570.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[NH:19]1[CH:23]=[C:22]([C:24]2[S:25][C:26]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:27][N:28]=2)[CH:21]=[N:20]1>C1COCC1>[NH:20]1[CH:21]=[C:22]([C:24]2[S:25][C:26]([C:29]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:32])[CH2:30][CH3:31])=[CH:27][N:28]=2)[CH:23]=[N:19]1
Reactant: CCC(=O)c1cnc(-c2cn[nH]c2)s1
Reactant: Ic1ccncc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccncc1)c1cnc(-c2cn[nH]c2)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 7 %

Procedure:
A solution of 4-iodopyridine (133 mg, 0.65 mmol) in THF (15 mL) was cooled to −78° C., 1.6 M n-BuLi in hexane (0.81 mL, 1.3 mmol) slowly added at −78° C., the reaction mixture stirred for 20 min at −78° C., and 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-one (135 mg, 0.65 mmol) in THF (5 mL) added. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×250 mL). The combined extracts were washed with brine solution (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative TLC (mobile phase: 5% methanol in dichloromethane) to afford 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)-1-(pyridin-4-yl)propan-1-ol as pale yellow liquid (13 mg, 5% yield) in 99.4% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 13.19 (br s, 1H), 8.51 (d, 2H), 8.24 (br s, 1H), 7.87 (br s, 1H), 7.65 (s, 1H), 7.45 (d, 2H), 6.29 (s, 1H), 2.32-2.23 (m, 2H), 0.77 (t, 3H); LC-MS m/z calculated for [M+H]+ 287.09. found 287.1.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[O:20])=[CH:13][CH:12]=2)=[N:9][N:10]=1)C.C(=O)([O-])O.[Na+].Cl>C(O)C.O>[CH3:27][C:23]1[CH:22]=[C:21]([C:19](=[O:20])[CH2:18][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[O:7][C:6]([CH2:5][C:4]([OH:35])=[O:3])=[N:10][N:9]=3)=[CH:12][CH:13]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH:26]=[CH:25][N:24]=1
Reactant: CCOC(=O)Cc1nnc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)CC(c2ccc(-c3nnc(CC(=O)O)o3)cc2)c2ccccc2C)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (5-{4-[(−)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-[1,3,4]oxadiazol-2-yl)-acetic acid ethyl ester (146 mg) in a mixture of ethanol (5 mL) and water (1.25 mL) was added sodium hydrogencarbonate (104 mg) and the reaction mixture stirred at room temperature for 4 h. The solution was adjusted to approximately pH 3 by using 1 M aqueous hydrochloric acid and then extracted over a sat. solution of brine (50 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light yellow solid. MS (ESI+): m/z=442.4 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[CH:10][C:9]([O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:8][CH:7]=2)#[N:2].N>[Ni].CO>[NH2:2][CH2:1][C:3]1[C:4]([CH2:32][CH:33]([CH3:35])[CH3:34])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[CH:10][C:9]([O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:8][CH:7]=2
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCOCC(=O)OC(C)(C)C)cc23)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc(-c2c(CN)c(CC(C)C)nc3ccc(OCCOCC(=O)OC(C)(C)C)cc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
To a mixture of tert-butyl (2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethoxy)acetate (0.9 g, 1.9 mmol), 25% aqueous ammonia (5 ml) and methanol (50 ml) was added Raney-nickel (1 ml), and the mixture was stirred under a hydrogen atmosphere at 0.5 MPa, room temperature for 5 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2-{[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-6-quinolinyl]oxy}ethoxy)acetate as an oil (0.6 g). The oil and p-toluenesulfonic acid monohydrate (0.23 g, 1.2 mmol) were dissolved in ethanol (50 ml) and concentrated under reduced pressure. The residue was crystallized from diethyl ether and recrystallized from methanol-diethyl ether to give the title compound (0.7 g, yield 58%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(F)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(CCCBr)c(F)c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Compound 65-2 (940 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (1.58 g) and N-bromosuccinimide (1.07 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.03 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[C:16]([NH:23][CH2:24][CH2:25][C:26](O)=[O:27])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:26](=[O:27])[CH2:25][CH2:24][NH:23][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution containing 1.0 eq each of 1-(3-nitropyridin-4-yl)piperazine, N-Boc-beta-alanine, HOAT and EDC in DCM, at a concentration of 0.1 M, was stirred for 16 hours. The solution was diluted with EtOAc and was washed with H2O, Na2CO3(sat), NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding tert-butyl 3-(4-(3-nitropyridin-4-yl)piperazin-1-yl)-3-oxopropylcarbamate (93%). LCMS (m/z): 379.9 (MH+); LC Rt=1.92 min.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[N:15]2)[O:11][CH:12]=1)=[O:7])C.[OH-].[Na+]>C1COCC1.Cl>[C:19]([C:16]1[CH:17]=[CH:18][N:14]([CH2:13][C:10]2[O:11][CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=2)[N:15]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)c1coc(Cn2ccc(C(C)=O)n2)n1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccn(Cc2nc(C(=O)O)co2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(3-acetyl-pyrazol-1-ylmethyl)-oxazole-4-carboxylic acid ethyl ester (137 mg, 0.52 mmol) in THF (5.0 mL) was treated at rt with 1N NaOH (2.5 mL, 2.5 mmol) and the reaction mixture was stirred for 3 h at rt. The reaction mixture was poured in 1N HCl (23 mL) and extracted with EA (50 mL). The org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the crude 2-(3-acetyl-pyrazol-1-ylmethyl)-oxazole-4-carboxylic acid as a deep brown foam. LC-MS-conditions 02: tR=0.64 min, [M+H]+=236.13.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([CH3:30])[C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:21][CH:22]=3)[C:17]2=[O:31])=[C:13]([CH3:32])[CH:12]=[C:11]([CH3:33])[N:10]=1)C1C=CC=CC=1.CCOC(C)=O.CO>[Pd].CO>[CH3:32][C:13]1[CH:12]=[C:11]([CH3:33])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[CH2:25][CH2:24][C:23]2[C:18](=[C:19]([CH3:30])[C:20]([O:26][CH:27]([CH3:28])[CH3:29])=[CH:21][CH:22]=2)[C:17]1=[O:31]
Reactant: Cc1cc(C)c(CN2CCc3ccc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C)c(CN2CCc3ccc(OC(C)C)c(C)c3C2=O)c(=O)[nH]1
Yield: 76.2 %

Procedure:
A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-methyl-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (107b, 46 mg, 0.10 mmol) and 10% palladium on carbon (10 mg) in methanol (3 mL) was hydrogenated at 1 atmosphere using a balloon for 26 hours. The reaction mixture was filtered through CELITE® then the filtrate was concentrated under vacuum. The residue was purified by column chromatography (EtOAc/heptanes, 50/50-100/0 then EtOAc/MeOH, 100/0-70/30), to give the title compound (Example 107, 27 mg, 74% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.52 (br. s., 1H), 7.05-7.01 (m, 1H), 6.99 (s, 1H), 5.87 (s, 1H), 4.58 (s, 2H), 4.51 (td, J=5.9, 12.1 Hz, 1H), 2.68 (t, J=6.0 Hz, 2H), 2.42 (s, 3H), 2.13 (s, 3H), 2.11 (s, 2H), 1.25 (d, J=5.9 Hz, 6H); MS 355 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[OH:14].N12CCCN=C1CCCCC2>C(O)(C)C.C(Cl)Cl>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: OCCCBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: OCCCOc1ccc(Cl)cc1Cl
Yield: 105.9 %

Procedure:
A solution of 3-bromopropanol (53.86 g, 0.368 mol) in isopropanol is added dropwise to a mixture of 2,4-dichlorophenol (50 g, 0.307 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (70.05 g, 0.406 mol) in isopropanol at reflux. The reaction mixture is heated at reflux for 3 hours and concentrated in vacuo to obtain a residue. The residue is dissolved in methylene chloride and the organic solution is washed sequentially with 0.5N sodium hydroxide solution, 1M hydrochloric acid and brine, dried over MgSO4 and concentrated in vacuo to obtain an oil which solidifies to give the title product as a white solid (71.9 g, mp 53°-55° C.).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4](C(OCC=C)=O)[C@@H:3]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 25 °C

Procedure:
A mixture of (2S,3R)-allyl 3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidine-1-carboxylate (0.528 g, 1.48 mmol), Pd(PPh3)4 (0.086 g, 0.0074 mmol) and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (0.14 g, 0.89 mmol) in DCM (20 mL) was stirred at rt. When the starting material was consumed as judged by reverse-phase HPLC analysis, the reaction was concentrated in vacuo. The crude residue was taken up in EtOAc, and washed with satd. aq. NaHCO3, brine, dried (MgSO4), and concentrated to obtain the crude which was purified by silica gel (0˜100% DCM/EtOAc) to afford the title compound. ESI-MS (m/z): 274 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[NH2:12][OH:13].Cl.C([O-])(O)=O.[Na+]>CO>[OH:13][NH:12][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=[NH:2]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: N=C(NO)c1ccc2[nH]ccc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-Cyanoindole (1.00 g), hydroxylamine.HCl (978 mg) and NaHCO3 (2.95 g) were dissolved/suspended in MeOH (14 ml), heated to 50° C. and stirred overnight. LCMS analysis showed the reaction was incomplete after this time so a further portion of hydroxylamine.HCl (978 mg) was added and the reaction temperature raised to 80° C. The reaction was complete after 4 hours. The reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The residue was treated with 1M aqueous HCl (50 ml) and extracted with EtOAc (2×50 ml). This failed to extract the product from the aqueous solution so it was treated with 2M aqueous NaOH to adjust the pH to approximately 7 then re-extracted with EtOAc (3×50 ml). The combined organics were washed with brine (30 ml), dried over MgSO4, filtered and evaporated to dryness to give the title compound (1.36 g) as a brown oil. δH (MeOD, 400 MHz) 6.50 (1H, s), 7.27 (1H, s), 7.36-7.45 (2H, m), 7.88 (1H, s). MS (ES): C9H8N3O requires 175; found 176 (MH+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][C:22](=[O:30])[C:23]([F:29])([F:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C@@H:8]([CH2:20][CH2:21][CH:22]([OH:30])[C:23]([F:28])([F:29])[CH2:24][CH2:25][CH2:26][CH3:27])[C@H:7]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCCC(F)(F)C(=O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-oxooctyl)-3-(2-tetrahydro pyranyloxy)cyclopentyl]heptanate (15) (71.01 g, 133.3 mmol) in methanol (284 ml) was cooled to approximately −20° C., and sodium borohydride (5.08 g, 134 mmol) was added thereto. After stirring for approximately 40 minutes, acetic acid (7.6 ml, 133 mmol) was added drop wise, and the reaction mixture was concentrated under reduced pressure. The residue was supplemented with water (325 ml) and extracted three times with ethyl acetate (228 mL). The organic layers were combined, washed with 3% aqueous sodium chloride (325 ml) and saturated aqueous sodium chloride (325 ml), and dried with anhydrous magnesium sulfate (51 g). The solution was concentrated under reduced pressure to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-(4,4-difluoro-3-hydroxyoctyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (16) (70.64 g; 132.1 mmol; yield: 99.1%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[C:16]([O:24][CH2:25][CH2:26]Br)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([O:24][CH2:25][CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Product: CC(C)(C)OC(=O)Nc1cccc(OCCOC(=O)c2ccccc2)c1

Procedure:
2-(3-(tert-Butoxycarbonylamino)phenoxy)ethyl benzoate (42B) was prepared following a similar procedure as that described in example 39, except tert-Butyl 3-hydroxyphenylcarbamate (42A) was used instead of 3-(dimethylamino)phenol and 2-bromoethyl benzoate was used instead of 2-bromoethyl acetate in step 1 of example 39.