Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[C:4]=1[CH:5]=[O:6])[CH3:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[CH2:1]([C:3]1[CH:10]=[C:9]([O:11][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH:8]=[C:7]([OH:12])[C:4]=1[CH:5]=[O:6])[CH3:2]
Reactant: CCc1cc(O)cc(O)c1C=O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: CCc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
To a mixture of 2-ethyl-4,6-dihydroxy-benzaldehyde (1 g, 6.02 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (1.1 mL, 12.05 mmol) and pyridium p-toluenesulfonic acid (0.010 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-ethyl-6-hydroxy-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (1.56 g, 100%). 1H NMR (400 MHz, CDCl3δ 12.40 (s, 1H), 10.08 (s, 1H), 6.48 (s, 1H), 6.40 (s, 1H), 5.50 (m, 1H), 3.84 (m, 1H), 3.60 (m, 1H), 2.90 (m, 2H), 2.00-1.50 (m, 6H), 1.30 (m, 3H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:39][CH3:40])=[C:36]([OH:38])[CH:37]=1>C1COCC1>[OH:38][C:36]1[CH:37]=[C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])[CH:33]=[CH:34][C:35]=1[O:39][CH3:40]
Reactant: COc1ccc(N)cc1O
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cc(C)nn5C)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.240 mmol) and THF (1.5 mL). To the resulting solution was added 5-amino-2-methoxyphenol (39 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The solid precipitate that formed was filtered and washed with ˜1 mL of ice cold THF yielding 61% (34 mg, 0.065 mmol) of the title compound.
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[C@H:17]([C:31]([O-:33])=O)[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:35][C@@H:36]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].F[P-](F)(F)(F)(F)F.CN([C+](N(C)C)N1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:49]([O:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][C@H:36]([NH:35][C:31]([C@@H:17](/[CH:16]=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:33])[C:37]([O:39][CH3:40])=[O:38])=[CH:43][CH:44]=1)[C:50]#[C:51][CH3:52]
Reactant: CCCCCCCSCCCCCC/C=C/[C@H](C(=O)[O-])[C@@](O)(CCOC)C(=O)OC(C)(C)C
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Agent: CN(C)[C+](N(C)C)n1n[n+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCSCCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, at room temperature, to 1-tert-butyl (2S,3S)-3-((E)-8-heptylsulfanyl-oct-1-enyl)-2-hydroxy-2-(2-methoxy-ethyl)-succinate (210.0 mg, 0.430 mmol) obtained in Step C-6b in DMF (4.2 mL), were added methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate hydrochloride (148.4 mg, 0.516 mmol), 1-[bis(dimethylamino)methyliumyl]-1H-1,2,3-triazolo[4,5-B]pyridine-3-oxide hexafluorophosphate (179.1 mg, 0.473 mmol), and N,N-diisopropylethylamine (299.0 μL, 1.72 mmol) in order. After stirring for 8 hours, the progress of the reaction was stopped by adding water. The mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was then washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled out of the filtrate under reduced pressure. The resulting residue was purified with SP1 (SiO2 cartridge, 20% ethyl acetate/n-hexane, Rf=0.35) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804240; 249.3 mg, 2 steps, 80% yield).
Reaction SMILES: BrC1N=C(C[P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])C=CC=1.[Br:17][C:18]1[CH:19]=[C:20]([CH2:25]O)[C:21]([F:24])=[N:22][CH:23]=1>>[CH2:11]([O:10][P:9]([CH2:25][C:20]1[C:21]([F:24])=[N:22][CH:23]=[C:18]([Br:17])[CH:19]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: CCOP(=O)(Cc1cccc(Br)n1)OCC
Reactant: OCc1cc(Br)cnc1F
Product: CCOP(=O)(Cc1cc(Br)cnc1F)OCC

Procedure:
Prepared according to the same procedure as diethyl (6-bromopyridin-2-yl)methylphosphonate, starting with (5-Bromo-2-fluoropyridin-3-yl)methanol. 1H-NMR (CDCl3, 500 MHz) δ: 8.18 (d, J=1.2 Hz, 1H), 7.94 (dt, J=8.4, 2.5 Hz, 1H), 4.10-4.16 (m, 4H), 3.10-3.20 (m, 2H), 1.31 (t, J=7.2 Hz, 6H). 13C-NMR (CDCl3, 126 MHz) δ: 147.1, 144.5, 117.0, 116.5, 62.7, 26.9, 25.7, 16.5. Mass spec.: 328.0 (MH)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.CC(C)N=C=NC(C)C.C1C=C2N=NN(O)C2=CC=1.O>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AM using 5-({cyclopropyl[(4-methoxy-2,6 dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (126 mg, 0.33 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (59 mg, 0.30 mmol), DIC (79 μL, 0.5 mmol) and HOBt monohydrate (76 mg, 0.5 mmol) in DCM (2.5 mL). The crude product was purified by FCC eluting with 95:5 DCM:7N NH3 in MeOH.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1.[Li+].[Cl-].[Sn](C)(C)(C)[CH3:20]>CN(C=O)C.C(Cl)Cl.O.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>[CH3:20][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:16])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc2c(cc1Br)SCC(=O)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc2c(cc1C)SCC(=O)N2
Temperature: 100 °C
Yield: 44.2 %

Procedure:
Methyl 7-bromo-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (1.44 g, 4.75 mmol) was dissolved in DMF (20 mL) and treated with PdCl2(PPh3)2 (167 mg, 0.238 mmol), LiCl (604 mg, 14.2 mmol) and Me4Sn (0.66 mL, 4.75 mmol). The reaction was heated at 100° C. for 30 min, at which point the reaction was no longer proceeding. An additional 0.25 mL of Me4Sn was added and the reaction was heated for an additional 4 h. After cooling, the reaction was diluted with DCM and water. The product was extracted into DCM and the combined extract was dried (Na2SO4) and filtered and the concentrated in vacuo. Purification provided product (500 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][C:14]#[N:15])[C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:13][CH2:14][NH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N(CC#N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N(CCN)Cc1ccccc1
Yield: 96 %

Procedure:
The compound (5.00 g, 24.7 mmol) obtained in step A was dissolved in tetrahydrofuran (100 ml), and the mixture was stirred under ice-cooling. Lithium aluminum hydride (1.87 g, 49.4 mmol) was gradually added at the same temperature, and the mixture was stirred at room temperature for 2 hr. After ice-cooling again, water (1.9 ml), 1N aqueous sodium hydroxide solution (3.8 ml) and water (1.9 ml) were gradually added in this order, and the mixture was stirred at room temperature for 1 hr. The insoluble material was filtered off through celite, and the obtained solution was concentrated under reduced pressure to give the title compound (4.89 g, yield 96%) as a pale-yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([C:29]#[N:30])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:31][C:32]1[CH:57]=[CH:56][C:35]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(=O)CN(C)CC(=O)O3)=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:57][CH:56]=3)=[CH:44][CH:43]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([C:29]#[N:30])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])([CH3:20])([CH3:19])[CH3:21]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
Pd(Ph3P)4 (144 mg, 0.125 mmol) was added to an argon-degassed solution (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.624 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (179 mg, 0.687 mmol), potassium phosphate tribasic (994 mg, 4.68 mmol) in dioxane (4 ml) and water (0.8 ml) stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-70% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 291 mg (76%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.3 (m, 2H), 7.19 (br. s, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.08-7.06 (m, 1H), 7.02-7.00 (m, 2H), 5.91 (br. s, 1H), 4.94 (br. s, 1H), 4.28-4.23 (m, 1H), 4.19-4.15 (m, 1H), 3.44-3.40 (m, 4H), 3.05 (t, J=6.2 Hz, 2H), 2.45 (s, 3H), 2.06 (s, 3H), 1.80 (br. s, 1H), 1.69 (br. s, 1H), 1.55 (br. s, 1H), 1.34-1.32 (m, 1H), 1.29 (s, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.15-1.1 (m, 12H). UPLC (M+H)=616.6.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH3:15][CH:16]([OH:20])[C:17]#[C:18][CH3:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:20][CH:16]([CH3:15])[C:17]#[C:18][CH3:19])[N:3]=[CH:4][N:5]=1
Reactant: CC#CC(C)O
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)Oc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 449 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 272 mg of 3-pentyn-2-ol, to which 130 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 510 mg of 4-(2-fluorophenyl)-6-(1-methyl-2-butynyloxy)pyrimidine (the present compound (151)).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=C(C#N)[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:25])([CH3:24])[C:12]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[C:36]([OH:39])(=[O:38])[CH3:37]>>[CH2:1]([N:8]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:37]([C:36]([OH:39])=[O:38])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:25])([CH3:24])[C:12]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC1(C)Oc2cc(F)c(C#N)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O
Agent: Cl
Solvent: O
Product: CC1(C)Oc2cc(F)c(C(=O)O)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O

Procedure:
4-[2-(Dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (588 mg) was dissolved in acetic acid (5 ml), and thereto was added conc. hydrochloric acid (5 ml), and the mixture was refluxed for 75 hours. The reaction solution was cooled, and thereto was added water, and filtered. The solid collected by filtration was washed with water and dried at 70° C. for 18 hours to give the title compound (406 mg).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[CH:19]1([NH:25][C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)NC3CCCCC3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and cyclohexylamine by the method described in Example 2 Method B reversing the order of addition such that intermediate solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. Colorless solid (80 mg, 89%). 1H NMR (CDCl3) 1.18-1.36 (m, 1H), 1.36-1.50 (m, 1H), 1.60-1.82 (m, 4H), 1.98-2.10 (m, 2H), 2.37 (d, J=0.9, 3H), 3.90-4.04 (m, 1 H), 5.88 (br d, J=7.0, 1H), 7.49 (d, J=4.0, 1H), 7.51 (d, J=3.5, 1H). 19F NMR −63.36. LC/MS 7.18 min, [M+1]+ 359.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:16])[N:14]2[CH:10]([S:11][CH2:12][CH:13]2[C:17](=O)[NH2:18])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15](=[O:16])[N:14]2[CH:10]([S:11][CH2:12][CH:13]2[C:17]#[N:18])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CC2SCC(C(N)=O)N2C1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccccc2)CC2SCC(C#N)N2C1=O
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of compound 17 (380 mg, 1.0 mmol) in CH2Cl2 (50 mL) was added TFAA (252 uL, 1.2 mmol) dropwise at room temperature, followed by the addition of Et3N (404 mg, 4 mmol). After stirring for 1 h, the mixture was washed with brine, dried over Na2SO4. After concentration, the residue was purified by column chromatography on silica gel (PE: EA=15:1) to give compound 18 (300 mg, 83.6%). 1 H NMR (400 MHz, CDCl3) δ 1.40 (s, 9 H), 3.26-3.27 (m, 1 H), 3.30-3.31 (m, 1 H), 3.31-3.34 (m, 1 H), 3.43-3.47 (m, 1 H), 5.06 (bs, 1 H), 5.22 (bs, 1H), 5.50 (bs, 1H), 7.37-7.49 (m, 5H). MS (M+1): 360.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1OC
Yield: 72 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,4-dimethoxyphenylboronic acid (142 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 171 mg (72%) of the title compound as an amorphous foam. mp 108°-112°. FDMS: m/e=365. α[D]589 =+73.75 (c=0.56, chloroform).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12]O>>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[OH:11]
Reactant: CO
Reactant: Oc1cccc2ccccc12
Product: Cc1ccc2ccccc2c1O

Procedure:
α-Naphthol is methylated using methanol to form 2-methyl-1-naphthol over a catalyst bed of alumina. The reaction provides high selectivity to 2-methyl-1-naphthol. Alumina catalysts derived from alumina alkoxide hydrolysis are preferred.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NCc4ccccc4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 54 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, benzyl isocyanate (0.32 g, 2.41 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:CH3OH 96:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(benzylamino)carboxamide (0.42 g, 54%) as a white solid: mp 192-194° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.69 (m, 3H), 7.34-7.19 (m, 5H), 6.67 (t, J=5.8 Hz, 1H), 6.60 (t; J=5.9 Hz, 1H) 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H) 4.67 (d, J=5.9 Hz, 2H), 4.23 (d, J=5.8 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.07-2.03 (m, 1H); 13C NMR (DMSO-d6) δ 175.63, 172.75, 167.56, 167.03, 158.05, 141.01, 140.70, 134.61, 133.31, 131.52, 128.19, 126.98, 126.55, 121.66, 48.83, 42.99, 30.93, 21.98; Anal. Calcd. For C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 62.78; H, 4.53; N, 13.18.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:9][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)[nH]cc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 58.4 %

Procedure:
A one liter round bottom flask was charged with 5-chloro-4-hydroxypyridin-2(1H)-one (10 g, 68.7 mmol), t-butyl 4-hydroxypiperidine-1-carboxylate (16.59 g, 82 mmol), triphenylphosphine (27.0 g, 103 mmol) and DMF (200 ml). This mixture was stirred for 40 minutes to form a clear and homogeneous solution. The solution was then cooled to 0° C. and diisopropyl azodicarboxylate (16.23 mL, 82 mmol) was added drop-wise while maintaining the temperature below 20° C. during the addition. After the addition, the reaction mixture was allowed to warm to room temperature overnight. The reaction was then heated to 60° C. for 0.5 hours. After cooling the reaction mixture to room temperature, the DMF was distilled from the reaction under high vacuum at 50° C. to yield a brownish, viscous oil. The oil was dissolved in 300 mL of chloroform and then was washed with dilute sodium bicarbonate (pH 8-10) (3×50 mL) The chloroform layer was directly concentrated to afford a light yellow viscous oil, which was partitioned between 250 mL of diethyl ether and 70 mL of 1 N NaOH. The aqueous phase was extracted thoroughly with diethyl ether until LCMS showed no triphenylphosphine oxide or other impurities in the aqueous layer. The aqueous layer was purged with nitrogen to remove residual ether and then acidified slowly with 1 N HCl (˜70 mL) to pH 5 followed by cooling to 0° C. for 2 hours. The precipitates were collected by filtration, washed with ice water (2×20 mL), and air dried overnight. The light yellow solid was further vacuum dried at 40° C. to a constant weight to yield t-butyl 4-(5-chloro-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (13.2 g, 40.1 mmol, 58.4% yield) as a light yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 12.5 (br, s, 1H), 7.19 (s, 1H), 5.75 (s, 1H), 4.34-4.41 (m, 1H), 3.40-3.48 (m, 2H), 3.26-3.37 (m, 2H), 1.71-1.83 (m, 2H), 1.60-1.71 (m, 2H), 1.32 (s, 9H); MS m/e 329.3 (M+H+), 273.20 (M+H+-t-butyl).