Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:16]=2[F:29])=[C:11]([F:30])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].BrCC(O[CH:42]([CH3:44])[CH3:43])=O.O>CN(C=O)C>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:16]=2[F:29])=[C:11]([F:30])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:42]([CH3:44])[CH3:43])=[O:7]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)c(F)c(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A mixture of 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenoxy]acetic acid (I(g)) (300 mg, 0.83 mmol, 1.0 eq) and Cs2CO3 (407 mg, 1.25 mmol, 1.5 eq) in DMF (5 mL) was stirred at room temperature for 1 h, then isopropyl bromoacetate (171 mg, 0.91 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (310 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[C:10]=[S:11]
Reactant: Nc1cccc(F)c1Cl
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1cccc(N=C=S)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Into a solution of 2-chloro-3-fluoroaniline (2.61 g, 17.94 mmol) in 50 mL of toluene at room temperature, thiophosgene (2.1 mL, 26.91 mmol) and triethylamine (3.02 mL, 26.91 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layer was then concentrated to give the desired product (2.99 g, 89%). 1H NMR (CDCl3) δ 7.10 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([NH2:12])=[C:2]([NH:1][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNc1cc(C(=O)OC)ccc1N
Temperature: 25 °C
Reaction time: 22 h

Procedure:
In DMF (40 ml), methyl 3,4-diaminobenzoate (2.01 g) was dissolved and then the solution was added with potassium carbonate (2.00 g) and 1-iodopropane (1.4 ml), followed by stirring at room temperature for 22 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.06 g).
Reaction SMILES: OC[CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.[SH:10][CH2:11][CH2:12][OH:13].N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCOCC1>[OH:13][CH2:12][CH2:11][S:10][CH:3]1[CH:4]2[CH2:9][CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: OCC1CC2C=CC1C2
Reactant: OCCS
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Product: OCCSC1CC2CCC1C2
Reaction time: 8 h

Procedure:
In a nitrogen atmosphere, to a stirred solution of 12.4 grams (0.1 mole) of 2-hydroxymethyl-5-norbornene in 100 ml of dioxane was added in one portion 17.2 grams (0.22 mole) of 2-mercaptoethanol. The temperature rose from 25° to 50°. The mixture was then heated at 70° for 6.3 hours during which time a solution of 1.6 grams of α,α'-azobisisobutyronitrile in 20 ml of dioxane was added in portions. After standing overnight, the dioxane solvent and excess 2-mercaptoethanol were removed under reduced pressure. The residue was distilled to give the 2-methylol- 5 or 6-(2'-hydroxyethylthio)norbornane intermediate as a viscous oil with a boiling point of 140°-142°/0.05 mm in a yield of 15.0 grams (74%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[CH:19][N:20]=4)[CH:17]=3)=[CH:9][N:10]=2)[N:7]=1.[CH2:21]([N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[CH:14][C:15]5[N:16]([CH:18]=[CH:19][N:20]=5)[CH:17]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: Clc1ccc2ncc(Cc3ccc4nccn4c3)n2n1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCn1cc(-c2ccc3ncc(Cc4ccc5nccn5c4)n3n2)cn1

Procedure:
The title compound was prepared in analogy to Example 9 using chloro-3-imidazo[1,2-a]pyridin-6-ylmethyl-imidazo[1,2-b]pyridazine (Example 74) instead of (rac)-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanol (Stage 9.1) and 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole instead of 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (tR 2.88 min (conditions 3), MH+=344.1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:3]1.[OH-].[CH2:16]([N+:23](C)(C)C)[C:17]1C=CC=C[CH:18]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(#N)C=C>[CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[O:14][CH2:18][CH2:17][CH2:16][NH2:23])[CH2:3]1
Reactant: CC1CCN(Cc2cccc(O)c2)C1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C=CC#N
Product: CC1CCN(Cc2cccc(OCCCN)c2)C1

Procedure:
28.7 g (0.15 mol) of 3-[(3-methylpyrrolidin-1-yl) methyl]phenol are heated under reflux together with 100 ml of acrylonitrile and 1.5 ml of 40% methanolic benzyltrimethylammonium hydroxide solution for 18 hours. The excess acrylonitrile is evaporated off under vacuum and the residue is taken up with ether, washed with 5% NaOH and reduced to the amine by reaction with 7.6 g (0.2 mol) of LiAlH4 in a manner analogous to Example 64 b. 14.9 g (40% of theoretical) of a pale yellow oil is obtained in a sufficiently pure form for subsequent reactions.
Reaction SMILES: C[O:2][C:3](=[O:45])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12](S(C1C=CC=CC=1)(=O)=O)[CH:11]=[C:10]2[C:25]1[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:28]=[C:27]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]=1[O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl>[C:35]([C:27]1[C:26]([O:39][CH2:40][C:41]([F:44])([F:42])[F:43])=[C:25]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:45])=[O:2])[CH:8]=3)[NH:12][CH:11]=2)[CH:30]=[C:29]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH:28]=1)([CH3:36])([CH3:37])[CH3:38]
Reactant: COC(=O)C=C(C)c1ccc2c(c1)c(-c1cc(C(C)(C)C)cc(C(C)(C)C)c1OCC(F)(F)F)cn2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(=CC(=O)O)c1ccc2[nH]cc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3OCC(F)(F)F)c2c1
Yield: 53 %

Procedure:
3-{1-Benzenesulfonyl-3-[3,5-di-tert-butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-indol-5-yl}-but-2-enoic acid methyl ester was dissolved in methanol (1.5 mL)/dioxane (3 mL) and treated with 1N NaOH (2.0 mL) at 60° C. for 2.5 h. Diluted with 1N HCl (15 mL) and extracted with ethyl acetate (3×15 mL). The combined organic portions were washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to provide 145 mg of crude material. The material was purified using radial chromatography by (eluet: hexane/ethyl acetate gradient) to provide 72 mg (53%) of a pale yellow solid. Mp. 146-153° C. 1H NMR (250 MHz, CDCl3): δ 8.43 (bs, 1H), 7.95 (s, 1H), 7.53 (d, 1H, J=2.4), 7.46 (m, 3H), 7.38 (d, 1H, J=2.5), 6.26 (d, 1H, J=1.1), 3.86 (q, 2H, J=8.6), 2.69 (d, 3H, J=1.0), 1.49 (s, 9H), 1.37 (s, 9H). MS [EI+] 488 (M+H)+, [EI−] 486 (M−H)+. Analytical (C29H37NO3): Calculated C, 68.98; H, 6.62; N, 2.87. Found: C, 66.45; H, 6.85; N, 2.59.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1Br.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C)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>[Cl:33][C:31]1[CH:30]=[CH:29][C:28]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[C:27]([CH2:26][C:25]([O:24][CH3:23])=[O:35])[CH:32]=1
Reactant: COC(=O)Cc1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: CN(C)C=O
Product: COC(=O)Cc1cc(Cl)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
A vigorously stirred mixture of the tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-4) (1.40 g, 4.53 mmol), methyl(2-bromo-5-chlorophenyl)acetate (1-2) (1.31 g, 4.98 mmol), potassium phosphate tribasic (2.85 g, 13.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.262 g, 0.227 mmol) in N,N-dimethylformamide (22 mL) was degassed via three vacuum/nitrogen ingress cycles and then heated at 100° C. for approximately 18 h. After cooling to room temperature, the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-25% ethyl acetate/hexanes as eluent) afforded 1-5 (0.967 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(N(CC)CC)C.[Br-].Br[CH2:19][C:20]1[CH:25]=[CH:24][NH+:23]=[CH:22][CH:21]=1>C(O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1cc[nH+]cc1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (300 mg, 2.1 mmol) was dissolved in absolute ethanol (10 mL), then triethylamine (650 μL, 4.6 mmol) and 4-(bromomethyl)pyridin-1-ium bromide (587 mg, 2.3 mmol) were added. The mixture was stirred overnight at room temperature, and the solvent was evaporated. The residue was dissolved in DCM and purified on silica gel using 10% DCM/MeOH to afford, after washing with water, 6-methyl-2-[(pyridin-4-ylmethyl)sulfanyl]pyrimidin-4-ol as white solid (128 mg, 26% yield); 1H NMR (400 MHz, MeOd4): δ 2.24 (s, 3H), 4.47 (s, 2H), 6.00 (s, 1H), 7.52 (dd, J=4.5 Hz, J=1.6 Hz, 2H), 8.45 (dd, J=4.5 Hz, J=1.6 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].[OH2:18]>CO.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: Fc1cccc(CCN2CCCCC2)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(CN1CCCCC1)c1cccc(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethan Intermediate (64.1) (1.50 g; 6.78 mmol; 1.00 eq.) in MeOH (15 mL) was added sodium borohydride (0.38 g; 10.17 mmol; 1.50 eq.) and 1 mL of water and 1 drop of 10% NaOH. Then the mixture was stirred at 50° C. for 5 hours. The reaction mixture was partitioned between CHCl3 and water. The organic layer was separated, dried over MgSO4 and concentrated. The residue was purified through flash chromatography on silica gel to yield 1-(3-fluoro-phenyl)-2-piperidin-1-yl-ethanol. LC-MS: 224 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([O:19]C(C)(C)C)=[O:18].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: Cc1cc(-c2cc(F)c(CC(=O)OC(C)(C)C)cc2C)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(F)c(CC(=O)O)cc2C)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of tert-butyl 2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetate 191-5 (80 mg, 0.37 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 2 hours. The solvent and TFA was removed by rotary evaporation to give 2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetic acid 191-6. The product was used for next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][N:7]=1.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[C:3]1[S:4][C:5]([CH2:8][NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:6][N:7]=1
Reactant: Nc1nccs1
Reactant: CN(c1ncc(C=O)s1)C1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(c1ncc(CNc2nccs2)s1)C1CCCCO1
Yield: 14.6 %

Procedure:
A solution of 2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carbaldehyde (250 mg, 1.10 mmol) and 2-aminothiazole (110 mg, 1.10 mmol) in toluene (11 mL) and molecular sieves 3 Å were stirred at reflux overnight. The strongly yellow solution of the corresponding imine was then poured over NaBH4 (212 mg, 5.61 mmol) in hot EtOH (80 mL). The colorless solution was filtered, concentrated and purified by column chromatography yielding N-methyl-N-(tetrahydro-2H-pyran-2-yl)-5-((thiazol-2-ylamino)methyl)thiazol-2-amine (50 mg, 17%) as a solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[CH2:15][S:16][C:17](=[NH:19])[NH2:18].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(OCC)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@:9]12[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:15][S:16][C:17]([NH2:18])=[N:19]2
Reactant: N=C(N)SCC1=C(c2ccccc2F)CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3ccccc3F)CCCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[2-(2-Fluorophenyl)cyclohex-1-enylmethyl]isothiourea hydrochloride obtained in Preparation Example 1-(5) (6.38 g) was dissolved in TFA (32.0 mL) under ice-cooling, and trifluoromethanesulfonic acid (6.40 mL) was added dropwise at the same temperature. The reaction solution was stirred overnight with gradual warming to room temperature. The reaction solution was poured into ice, diluted with diethyl ether and then neutralized with sodium bicarbonate. The generated reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (4.58 g).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[N:5][N:4]=1)[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(-c2ccc(CO)cc2)o1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCc1nnc(-c2ccc(C=O)cc2)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of (4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)methanol (1.8 g, 8.8 mmol) in CH2Cl2 (50 mL) was added molecular sieves (1.5 g, 4 Å) and the mixture was cooled to 0° C. Pyridinium chlorochromate (2.27 g, 10.5 mmol) was added in portions to the reaction mixture then it was warmed to room temperature. After stirring for 2 hrs, the mixture was filtered through Celite and rinsed with additional CH2Cl2. The filtrate was concentrated in vacuo. Purification by chromatography (EtOAc-hexanes) provided 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde as an off-white solid (1.3 g, 70%).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27]C)=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:24][O:23][C:21]([CH:20]([CH2:19][C:18]1[CH:29]=[CH:30][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)=[CH:16][CH:17]=1)[C:25]([OH:27])=[O:26])=[O:22]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3c(c2)CCCC3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of dimethyl 4-[2-(5,6,7,8-tetrahydro-2-naphthoxy)ethoxy]benzylmalonate (0.44 g, 1.07 mmol) in a mixture of methanol (4.3 ml) and tetrahydrofuran (2.1 ml) at 0° C. is added a 2 mol/L aqueous solution of sodium hydroxide (0.59 ml, 1.18 mmol). The mixture is stirred for 2 h at room temperature, and then the solvent is removed under a vacuum. The residue was dissolved in saturated aqueous sodium bicarbonate (10 ml) and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (0.38 g, 90%). HRMS calcd for C23H26O6: 398.4558. Found: 398.4556. MA calcd for C23H26O6: C, 69.33%; H, 6.58%. Found: C, 69.32%; H, 6.59%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:21]([CH:18]3[CH2:20][CH2:19]3)=[O:22])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1)C1CC1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (40 mg) was reacted with 27 μL of cyclopropanecarbonyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6]S(C)(=O)=O.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1O.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([CH3:11])[CH2:5][O:6][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Br:14]
Reactant: COC(=O)C(C)(C)COS(C)(=O)=O
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)COc1ccccc1Br
Temperature: 100 °C
Yield: 69.5 %

Procedure:
A first intermediate compound 3-(2-Bromo-phenoxy)-2,2-dimethyl-propionic acid, was produced as follows: To a mixture of 3-methanesulfonyloxy-2,2-dimethyl-propionic acid methyl ester (20.00 g, 95.23 mmol) and 2-bromophenol (16.48 g, 95.23 mmol) in acetonitrile (200 mL) was added Cs2CO3 (46.50 g, 142.80 mmol) and the mixture was heated at 100° C. in a sealed flask overnight. The resulting suspension was filtered. The solvent was evaporated and the crude material was partitioned between dichloromethane (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL), dried over Na2SO4 and evaporation of the solvent gave 3-(2-bromo-phenoxy)-2,2-dimethyl-propionic acid methyl ester (19.00 g, 70%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H), 7.26–7.22 (m, 1H), 6.87–6.80 (m, 2H), 4.02 (s, 2H), 3.72 (s, 3H), 1.40 (s, 6H).
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([O:8]N1C(=O)CCC1=O)=O)[CH:3]([CH3:5])[CH3:4].[NH2:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26].CCN(CC)CC>CN(C=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:2]([C:6]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)O

Procedure:
Boc-Val-OSu (12.6 g, 40 mmol) and H-Val-OH (4.68 g, 40 mmol) were condensed in DMF (250 ml) for 96 hours in the presence of 2 ml Et3N. More Et3N was added when needed to maintain the reaction slightly basic. The remaining insoluble material was filtered off and the filtrate evaporated to dryness (45°). The residue was partitioned between ether and dilute H2SO4 (~1%) and the organic layer washed with water (3×), dried over Na2SO4 and evaporated to a foamy glass. The product was crystallized from ether and petroleum ether: Yield, 12.2 g (96.4 %); mp 155°-158°; [α]D25 = +1.10° (c 1, DMF.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].Cl>O>[CH2:20]([O:19][C:17]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium carbonate (1.59 g, 0.0150 mol) was added to a solution of piperidine-4-carboxylic acid (0.970 g, 0.00751 mol) in water (15 mL). After the solid was dissolved, benzyl chloroformate (1.54 g, 0.00901 mol) was added dropwise. The mixture was stirred at rt for 3 h. The mixture was carefully acidified (pH=4) with 2N HCl, and then was extracted with DCM (4×10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([F:26])=[CH:7][C:8]([NH2:25])=[C:9]([CH:24]=1)[NH:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C(O)(=O)C.[N:31]([O-])=O.[Na+]>O1CCCC1.O>[C:1]([NH:4][C:5]1[C:6]([F:26])=[CH:7][C:8]2[N:25]=[N:31][N:10]([C:11]3[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[C:9]=2[CH:24]=1)(=[O:3])[CH3:2]
Reactant: O=N[O-]
Reactant: COC(=O)C(C)Oc1ccc(Nc2cc(NC(C)=O)c(F)cc2N)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)Oc1ccc(-n2nnc3cc(F)c(NC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of methyl 2-[p-(5-acetamido-2-amino-4-fluoroanilino)phenoxy]propionate (7 g, 0.019 mol) in tetrahydrofuran is added dropwise to a 50% acetic acid solution at 0° C. To the resultant mixture, a solution of sodium nitrite (2.81 g, 0.041 mol) in water is added dropwise. After the addition is complete, the reaction mixture is warmed to room temperature, stirred for 3 days and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with brine and water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as an orange solid which is identified by NMR spectral analyses.