Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[N:11]2[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1>CO.[Pd]>[F:30][C:25]1[CH:24]=[C:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][C:12]2[N:11]3[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:35])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(F)c(F)c3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(F)c(F)c3)nc(=O)c(O)c2C1=O
Yield: 84.8 %

Procedure:
9-Benzyloxy-6-[[2-(3,4-difluorophenyl)phenyl]methyl]-2-isopropyl-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione (170) (160 mg) in methanol (20 ml) was hydrogenated over 10% Pd/C (20.6 mg) at room temperature and at atmospheric pressure for 2 h. The catalyst was filtered off, the filtrate was concentrated in vacuo to give the desired product as a light yellow foam (112 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13]([S:14]([C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH:12]=[C:11]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)[CH:10]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.C(O)C>[ClH:41].[CH3:24][O:23][C:20]1[N:19]=[CH:18][C:17]([S:14]([N:13]2[CH:12]=[C:11]([CH2:25][NH:26][CH3:27])[CH:10]=[C:9]2[C:8]2[C:3]([C:1]#[N:2])=[N:4][CH:5]=[CH:6][CH:7]=2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2C#N)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccc(OC)nc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
tert-Butyl ({5-(2-cyanopyridin-3-yl)-1-[(6-methoxypyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (235 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 161 mg, 79%).
Reaction SMILES: CC1(C)CC(O)CC(C)(C)N1[O:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:21]=3)([CH2:16][CH2:17]1)[O:14][CH2:13]2.CC(O)=O.O>C1COCC1.[Zn]>[O:26]([C:22]1[CH:21]=[C:20]([C:15]23[CH2:18][CH2:19][C:12]([OH:11])([CH2:17][CH2:16]2)[CH2:13][O:14]3)[CH:25]=[CH:24][CH:23]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: OC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.4 %

Procedure:
A mixture of 96B [2,2,6,6-tetramethyl-1-((1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)oxy)piperidin-4-ol] (140 mg, 0.310 mmol), activated zinc dust (203 mg, 3.10 mmol), and HOAc (3.55 mL, 62.0 mmol) in THF (1 mL)/water (0.5 mL) was stirred at rt for 3 days, then was filtered. The filtrate was dissolved in EtOAc (5 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was chromatographed [SiO2; continuous gradient of EtOAc/hexane (0% to 50% over 10 min)] to give the title compound (62 mg, 0.209 mmol, 68% yield) as a clear oil. [M+Na]+=319.1; 1H NMR (CDCl3) δ: 7.38-7.27 (m, 3H), 7.20-7.09 (m, 3H), 7.06-6.99 (m, 2H), 6.92-6.86 (m, 1H), 3.88 (t, J=1.6 Hz, 2H), 2.24-2.12 (m, 4H), 2.01-1.84 (m, 4H), 1.70 (s, 1H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:24][S:25]C(=O)C)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])(=O)C.[OH-].[Na+].Cl>CO>[SH:4][CH2:5][CH:6]([CH2:24][SH:25])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: CC(=O)SCC(CCCCc1nc(-c2ccc(C)cc2)oc1C)CSC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(CCCCC(CS)CS)c(C)o2)cc1
Yield: 95.7 %

Procedure:
To 8 ml of a solution of 830 mg of 4-[5,5-bis(acetylthiomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole in methanol, 8 ml of aqueous 1 N sodium hydroxide solution was added, and heated to reflux for 1 hour. The reaction solution was acidified with 1 N hydrochloric acid, extracted with dichloromethane and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 635 mg of the objective compound as pale yellow oil.
Reaction SMILES: CC([N:5]([CH2:9][C:10](=[O:24])[NH:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:18])C(=O)[O-])(C)C.[ClH:25]>C(OCC)C>[ClH:25].[NH2:5][CH2:9][C:10]([NH:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:18])=[O:24]
Reactant: CC(C)(C)N(CC(=O)Nn1cccc1C(=O)c1cccs1)C(=O)[O-]
Agent: Cl
Solvent: CCOCC
Product: NCC(=O)Nn1cccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a solution of 1,1-dimethylethyl-[2-oxo-2-[[2-(2-thienylcarbonyl)-1H-pyrrol-1-yl]amino]ethyl]carbamate (6.20 g) in 200 ml of dry ethyl ether was added 80 ml of a 3.5M ethereal hydrogen chloride solution. The reaction mixture was stirred at room temperature for 7 days. The precipitate was collected by suction filtration, dissolved in 50 ml of hot isopropanol and evaporated in vacuo. The residual oil was crystallized from isopropanol/ethyl ether affording the product as crystals (2.61 g), m.p. 168°-169° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:31]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[C:17]4[CH:18]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CC#N)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Product: Cc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (28 mg, 22%), MS (ISP) m/z=370.2 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(p-tolyl)-acetonitrile.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:18][C:19]#[CH:20].O>O1CCCC1>[CH3:3][C:2]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=1)([O:1][CH2:20][C:19]#[CH:18])[CH3:4]
Reactant: CCOC(=O)c1cc(C(C)(C)O)on1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOC(C)(C)c1cc(C(=O)OCC)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 10.5 %

Procedure:
2.00 g of ethyl 5-(1-hydroxy-1-methylethyl)isoxazole-3-carboxylate was dissolved in 20 ml of tetrahydrofuran, and 0.44 g of sodium hydride and 1.32 g of 3-bromo-1-propyne were then added under ice-cooling. The mixture was stirred at room temperature for 5 hours. After water was added, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-ethyl acetate to obtain 0.25 g of ethyl 5-[1-methyl-1-(2-propynyloxy)ethyl]isoxazole-3-carboxylate.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.Cl[CH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:19][C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(CCl)no1
Reactant: COc1ccc(CO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(COCc2cc(C)on2)cc1
Temperature: 25 °C

Procedure:
To a resealable vial were added NaH (193 mg, 60% dispersion in mineral oil, 4.82 mmol) and THF. The vial was cooled to 0° C. before addition of (4-methoxyphenyl)methanol (639 μl, 5.14 mmol) and the reaction stirred at 0° C. for 30 min before addition of 3-(chloromethyl)-5-methylisoxazole (423 mg, 3.22 mmol) and tetrabutylammonium iodide (119 mg, 0.322 mmol). The reaction was heated to reflux overnight. The vial was cooled to room temperature before being diluted with ammonium chloride solution. The aqueous was extracted with EtOAc and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford 3-(((4-methoxybenzyloxy)methyl)-5-methylisoxazole. LC/MS m/z 256 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[S:22][CH3:21])[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CSc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2ccccc2SC)CC1
Yield: 71 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1.O.[Li]CCCC>[C:27]([O:26][C:24](=[O:25])[CH2:23][CH:22]([S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COc1ccc(S)cc1OC
Reactant: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To a solution of 3,4-dimethoxythiophenol (8.25 mL, 57.6 mmol) in anhydrous THF (100 mL) at 0° C., is added n-BuLi (2.5 M in hexane, 0.77 mL, 1.92 mmol) and the solution is stirred for 15 minutes under a nitrogen atmosphere. t-butyl 7-phenyl-2-heptenoate (10 g, 38.4 mmol) in THF (100 mL) is added dropwise and the mixture is allowed to warm to room temperature and stir overnight. TLC analysis indicated complete reaction. The reaction mixture is diluted with water (300 mL) and extracted with ether (3×250 mL). Combined organic extracts are washed successively with sat. Na2CO3 solution (4×200 mL), water (200 mL) and brine (200 mL) then dried over MgSO4 and concentrated to afford a pale yellow oil which is chromatographed on silica gel (pet-ether/EtOAc, 9:1) to afford 14.9 g of (±)-t-butyl-3-(3,4-dimethoxyphenyl)sulfanyl-7-phenylheptanoate (90%) as a colorless oil. TLC analysis [pet-ether/EtOAc, 9:1, Rf (heptenoate)=0.80, Rf (heptanoate)=0.50]. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.48-1.68 (m, 6H), 2.42 (dABq, 2H), 2.60 (t, 2H), 3.28 (t, 1H), 3.85 (d, 6H), 6.75 (d, 1H), 7.0 (dd, 2H), 7.15 (d, 3H), 7.25 (t, 2H) ppm. Mass spectrum (FAB) m/z 447 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].CO>C1COCC1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([CH:20]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(c1ccc(OC2CCC(c3ccccc3)CC2)cc1)c1cccs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC(c1ccc(OC2CCC(c3ccccc3)CC2)cc1)c1cccs1

Procedure:
Compound 30 (0.048 g, 0.11 mmol) was added to a 1-dram vial and dissolved in a minimal amount of anhydrous THF. An aqueous solution of lithium hydroxide (2 M, 0.3 mL) was added to the vial. MeOH was added dropwise until the layers were miscible. The vial was sealed and placed on a rotating wheel overnight (18 hours). When the reaction was complete, the solvent was concentrated under a flow of nitrogen until only water was left. The mixture was diluted by the addition of ˜1 mL of water. Hydrochloric acid (3 N aqueous solution) was added dropwise until the pH reached 2. The aqueous solution was extracted with DCM, and the organic layer was dried and concentrated. Flash column chromatography with 0 to 100% EtOAc/hexanes as the eluant and HPLC of the residue afforded 31 as a white film. MS ESI (pos.) m/e: 407.2 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.35-7.2 (m, 7H); 7.17 (dd, J=5.1, 1.0 Hz, 1H); 6.93-6.73 (m, 4H); 4.72 (m, 1H); 4.61 (m, 1H); 3.16 (dd, J=15.9, 7.6 Hz, 1H); 3.07 (dd, J=15.9, 7.9); 2.61 (m, 1H); 2.19 (m, 2H); 2.02-1.95 (m, 2H); 1.73-1.61 (m, 4H); 0.91-0.69 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH:17]=[CH:18][CH:19]=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[CH2:17][CH2:18][CH2:19][CH:29]1[S:25][C:26](=[O:31])[NH:27][C:28]1=[O:30]
Reactant: O=C1CSC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1C=CC=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCCC1SC(=O)NC1=O
Yield: 28 %

Procedure:
A mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (2.00 g), 2,4-thiazolidinedione (1.10 g), piperidine (0.267 g) and acetic acid (15 ml) was heated under reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure. Crystals (1.64 g) of 5-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamilidene]-2,4-thiazolidinedione which was precipitated by addition of saturated aqueous sodium bicarbonate solution was collected by filtration and washed with ether. The crystals were dissolved in tetrahydrofuran (150 ml), and 5% palladium-carbon (1.64 g) was added. The mixture was subjected to catalytic hydrogenation at room temperature at a hydrogen pressure of 3.4 kgf/cm2. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give crystals. The crystals were recrystallized from dichloromethane-methanol to give 5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-propyl]-2,4-thiazolidinedione (0.742 g, 34%). White crystals, mp. 173-174° C.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([NH2:28])=[CH:21]2>ClCCl>[N:28]([C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([CH3:17])=[CH:27][CH:26]=2)=[C:1]=[S:2]
Reactant: Cc1ccc2cnc(N)cc2c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1ccc2cnc(N=C=S)cc2c1
Temperature: 40 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (220 mg, 0.948 mmol) in dichloromethane (10 mL) at ambient temperature was added 6-methylisoquinolin-3-amine (125 mg, 0.790 mmol). The reaction mixture was placed into a preheated oil-bath and stirred at 40° C. for 18 h, then removed from the oil-bath and cooled to ambient temperature. The mixture was concentrated and the crude material was purified by silica gel chromatography (5-30% ethyl acetate in hexanes) to afford 3-isothiocyanato-6-methylisoquinoline (75 mg, 0.375 mmol, 47.4% yield), as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (s, 1H), 7.88 (d, J=8.24 Hz, 1H), 7.56 (s, 1H), 7.46 (dd, J=8.24, 1.53 Hz, 1H), 7.39 (s, 1H) 2.57 (s, 3H). MS (LC/MS) R.T.=1.92; [M+H]+=201.13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[CH:20]=[C:21]([CH:26]=[C:27]([CH3:29])[N:28]=4)[C:22](OC)=[O:23])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[AlH4-].[Li+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:30])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]4[CH:20]=[C:21]([CH2:22][OH:23])[CH:26]=[C:27]([CH3:29])[N:28]=4)[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1cc(C)nc(Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of methyl 2-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)-6-methylisonicotinate (prepared as described for Example 13, using methyl 2-bromo-6-methylisonicotinate) (55.0 mg, 0.137 mmol) in tetrahydrofuran (5.0 mL, 62 mmol) at 0° C. was slowly added 1.0 M of lithium tetrahydroaluminate in tetrahydrofuran (0.20 mL). The reaction was stirred at 0° C. for 30 minutes, and then quenched by the sequential addition of 8 μL water, then 8 μL 15% aq NaOH, then 23 μL water. The resulting mixture was diluted with dichloromethane and stirred at room temperature for 10 minutes, then dried with MgSO4 and filtered through celite. The solution was evaporated in vacuo and the crude product was purified via reverse phase HPLC and lyophilized to yield 20.8 mg (41%) of (2-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-ylamino)-6-methylpyridin-4-yl)methanol. LCMS (ESI): RT (min)=4.542, M+H=374.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.10 (s, 1H), 8.54 (s, 1H), 7.95 (s, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.63 (dd, J=8.5, 1.6 Hz, 1H), 7.42-7.29 (m, 1H), 7.22-7.06 (m, 3H), 6.68 (s, 1H), 5.29 (t, J=5.4 Hz, 1H), 4.46 (d, J=4.7 Hz, 2H), 2.47 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:35]4C(OC(C)(C)C)=O)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4C(=O)OC(C)(C)C)ncn3)cccc2s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4)ncn3)cccc2s1

Procedure:
(2S,5R)-tert-Butyl 2-((2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)-5-phenylpyrrolidine-1-carboxylate, Example 58, (575 mg, 0.8 mmol) was reacted with TFA under the condition of Example 3(c) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 619 (M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH2:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=1)=O)(C)(C)C.O>C(O)=O.C=O>[Cl:22][C:19]1[N:18]=[CH:17][C:16]([CH2:15][N:11]2[CH2:10][C@@H:9]3[CH2:14][C@H:12]2[CH2:13][N:8]3[CH3:6])=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Cl)nc1
Agent: C=O
Solvent: O=CO
Solvent: O
Product: CN1C[C@@H]2C[C@H]1CN2Cc1ccc(Cl)nc1
Temperature: 70 °C
Yield: 61.9 %

Procedure:
(1S,4S)-5-(6-Chloro-pyridin-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.1 g, 3.4 mmol) was dissolved in a mixture of 11.3 ml of formic acid and 22.6 ml of formalin. The reaction was heated at 70° C. for 4 hours, and then cooled to room temperature. Water was added and the aqueous layer was extracted with DCM. The aqueous layer was carefully basified with solid potassium carbonate and extracted 3 times with DCM. The crude product was purified by chromatography using a gradient of 5% to 25% methanol in DCM. Ammonium hydroxide (approximately 2%) had been added to the methanol. 500 mg of a colorless liquid was obtained (61.9%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].IC.[C:20](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:2][C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8]([O:10][CH3:20])=[O:9])([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of 5.50 g (23.5 mmoles) of 3,5-di-t-butylbenzoic acid in 25 ml of dry dimethylformamide was added 5.01 g (35.3 mmoles) of iodomethane, and then 6.49 g of anhydrous potassium carbonate. After stirring at room temperature for 2 hours, water was added, the mixture was extracted three times with diethyl ether, the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to give 5.68 g of the title compound as a crystalline solid, m.p. 52.0°-52.5° C. The structural assignment was supported by 1H NMR.
Reaction SMILES: [CH:1]([C:4]1[CH:44]=[CH:43][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:42])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][NH:25][C:26](=[O:42])[C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:43][CH:44]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccc([N+](=O)[O-])cn4)cc3)cc2)C(=O)O)cc1
Yield: 57.1 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-nitropyridine-6-yl)benzoylamino]ethoxy]phenyl]propionate (397 mg), which is the product of Example 108, was reacted with aqueous sodium hydroxide solution (1N, 1.30 ml) and the reaction mixture was treated to give the title compound (216 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccccc1Cl
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1NCc1ccccc1
Yield: 96.5 %

Procedure:
According to the general procedure A, 2-chlorotoluene (66 mg, 0.52 mmol) reacted with benzylamine (68 mg, 0.64 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (60 mg, 0.63 mmol) in toluene at 100° C. for 4 h to give the title compound (99 mg, 96%) as a solid after recrystallization from hexane: 1H-NMR (300 MHz, CDCl3): δ 7.48-7.35 (m, 5H), 7.14 (m, 2H), 6.75 (t, 1H, J=7.2 and 7.5 Hz), 6.68 (d, 1H, J=7.8 Hz), 4.44 (s, 2H), 3.93 (bs, 1H), 2.24 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.01, 139.46, 130.02, 128.62, 127.50, 127.20, 127.12, 121.86, 117.13, 109.93, 48.26, 17.52. GC/MS(EI): m/z 197 (M+), 120, 106. Anal. Calcd for C14H15N: C, 85.24; H, 7.66; N, 7.10. Found: C, 84.98; H, 7.64; N, 7.20.