Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10](I)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>CN(C)C=O.C(N(CC)CC)C.[Pd](Cl)Cl.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.[Cu]I>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(I)ccc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(=O)c2cc(C#C[Si](C)(C)C)ccc2[nH]1
Temperature: 45 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a solution of 1.0 g of 2-butyl-6-iodo-4(1H)-quinazolinone 0.043 g of bis(triphenylphosphine) palladium (II) chloride and 5.8 mg of copper (I) iodide in 5.0 ml of N,N-dimethylformamide and 5.0 ml of triethylamine is added 0.36 g of (trimethylsilyl) acetylene. The resulting reaction mixture is heated at 45° C. for 1 hour and then 65° C. for 5 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the residue purified by flash chromatography on silica gel, eluting with 1:3 ethyl acetate-hexane to yield 0.75 g of the desired product as a white solid. CI MASS SPEC 299(MH+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:3]1=2.CCN=C=NCCCN(C)C.Cl.[CH3:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1.Cl>C(Cl)Cl>[CH3:33][C:34]1[S:38][C:37]([NH:39][C:12]([C:10]2[CH:9]=[CH:8][N:7]3[C:2](=[O:1])[C:3]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:4]=4[N:5]=[C:6]3[CH:11]=2)=[O:14])=[N:36][CH:35]=1
Reactant: Cc1cnc(N)s1
Reactant: O=C(O)c1ccn2c(=O)c3c(nc2c1)CCCCCC3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2ccn3c(=O)c4c(nc3c2)CCCCCC4)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the acid prepared from Example 28.1b and EDCI-HCl (80.2 mg, 0.42 mmol) in DCM (10 mL) was added 5-methylthiazol-2-amine (25.5 mg, 0.22 mmol). The mixture was stirred at room temperature for 10 min and then poured into 2 N HCl. The mixture was extracted with DCM (30 mL) and the organic layer was washed with aqueous NaHCO3, brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by preparative HPLC to afford 5.5 mg of desired product. MS (ESI): 369 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.09-9.06 (d, J=7.38 Hz, 1H), 8.22 (s, 1H), 7.60-7.58 (d, J=6.57 Hz, 1H), 7.06 (t, J=5.4 Hz, 1H), 3.01-2.93 (m, 4H), 2.44 (s, 3H), 1.92-1.80 (m, 4H), 1.49 (broad, 4H). mGluR5 PAM EC50: +++++. Fold shift at 10 μM: +.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([O:14][CH2:15][CH3:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH2:15]([O:14][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]([CH3:13])=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)[C:3]=1[CH3:17])[CH3:16]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Product: CCOc1c(C)c(N2CCN(c3ccc(F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 40.8 %

Procedure:
By using 5-bromo-7-ethoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (600 mg, 2.01 mmol) synthesized in Reference example 98 and 1-(4-fluorophenyl)piperazine (723 mg, 4.01 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 327 mg (yield 41%).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[N:23]=[C:22]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH2:21]3)[N:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[N:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:21][C:22]([C:32]([F:38])([F:37])[C:33]([F:35])([F:34])[F:36])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2cccc(C3=CCNCC3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.1 %

Procedure:
5-[2-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-pyridin-6-yl]-1-(2-chloro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (280.0 mg, 0.50 mmol) prepared in Example 155 and trifluoroacetic acid (400.0 uL, 5.0 mmol) were added at 0° C. to dichloromethane (3.0 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 300.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: O=[C:2]([CH2:13][CH2:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:20][CH2:19][CH2:18][O:17]1)[CH2:3][C:4]([NH:6]C1C=CC=CC=1)=[O:5].[NH2:27]N>C1COCC1>[C:21]1([C:16]2([CH2:15][CH2:14][CH2:13][C:2]3[CH2:3][C:4](=[O:5])[NH:6][N:27]=3)[O:20][CH2:19][CH2:18][O:17]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CCCC1(c2ccccc2)OCCO1)CC(=O)Nc1ccccc1
Reactant: NN
Solvent: C1CCOC1
Product: O=C1CC(CCCC2(c3ccccc3)OCCO2)=NN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
Step AAH (5): To a soln of 3-oxo-N-phenyl-6-(2-phenyl-1,3-dioxolan-2-yl)hexanamide (444 mg, 1.256 mmol) in THF (1 mL) was added hydrazine (0.059 mL, 1.88 mmol). The mixture was stirred at rt for 2 h, then at 65° C. for 2 h. The reaction mixture was concentrated in vacuo. Dichloromethane (10 mL) was added to the crude residue. After cooling to 0° C., the product crystallized out. The solid was collected by vacuum filtration and dried under high vacuum to afford 3-(3-(2-phenyl-1,3-dioxolan-2-yl)propyl)-1H-pyrazol-5(4H)-one (250 mg, 73% yield). LC-MS (M+H)+ 275.1.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]([NH:21][S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH3:20]>>[CH2:1]([NH:17][S:22]([NH:21][CH2:18][CH2:19][CH3:20])(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: CCCNS(=O)(=O)Cl
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)NCCC
Yield: 70 %

Procedure:
The title compound was prepared following the method described in Example 6. The starting reactants are 0.15 g (0.6 mmol) of N-hexadecylamine and 0.10 g (0.6 mmol) of N-propylsulfamoyl chloride. 0.15 g of a white solid were obtained. Yield 70%; m.p. 108-110° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[K+]>O.O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:21])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a suspension of 4-benzyl-6-(4-bromo-phenyl)-morpholine (8.70 g; 26.19 mmol) in water (25 mL) and 1,4-dioxane (25 mL) was added KOH (3.23 g; 57.61 mmol), tris(dibenzylideneaceton)dipalladium(0) (479.6 mg; 0.52 mmol) and di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (444.8 mg; 1.05 mmol). The resulting mixture was heated under reflux for two hours. After cooling to RT the reaction mixture was concentrated in vacuo. The residue was partitioned between EtOAc and 5% aqueous NaHCO3 solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-(4-benzyl-morpholin-2-yl)-phenol (3.67 g).
Reaction SMILES: C(C1C2C(=CC=CC=2)C=CC=1C1C=CC2C(C)(C)CC=C(C3C=CC(C)=CC=3)C=2C=1)C.[CH3:32][C:33]1([CH3:65])[CH2:42][CH:41]=[C:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[C:39]2[CH:38]=[C:37]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[C:55]([C:60]([O:62]CC)=[O:61])[CH:56]=4)[CH:51]=3)[CH:36]=[CH:35][C:34]1=2.[OH-].[Na+].Cl>CCO>[CH3:32][C:33]1([CH3:65])[CH2:42][CH:41]=[C:40]([C:43]2[CH:44]=[CH:45][C:46]([CH3:49])=[CH:47][CH:48]=2)[C:39]2[CH:38]=[C:37]([C:50]3[CH:59]=[CH:58][C:57]4[C:52](=[CH:53][CH:54]=[C:55]([C:60]([OH:62])=[O:61])[CH:56]=4)[CH:51]=3)[CH:36]=[CH:35][C:34]1=2
Reactant: CCOC(=O)c1ccc2cc(-c3ccc4c(c3)C(c3ccc(C)cc3)=CCC4(C)C)ccc2c1
Agent: CCc1c(-c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)ccc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(-c4ccc5cc(C(=O)O)ccc5c4)cc32)cc1
Temperature: 0 °C

Procedure:
A solution of ethyl 5′,6′-dihydro-5′,5′-dimethyl-8′-(4-methylphenyl)-2,2′-binaphthalene]-6-carboxylate (Compound 64) 0.19 g, 0.43 mmol), EtOH (8 ml) and 1N aqueous NaOH (2 ml) was heated to 60° C. for 3 hours. The solution was cooled to 0° C. and acidified with 1N aqueous HCl. The product was extracted into ethyl acetate, and the organic layers combined, washed with water, brine, dried (MgSO4), filtered and the solvent removed in-vacuo. The residue was recrystalized from THF/ethyl acetate at 0° C. to give 35 mg of pure material. The mother liquor was concentrated under reduced pressure and the residue purified by silica gel chromatography (100% ethyl acetate) to give an additional 125 mg of the title compound (overall yield=160 mg, 90%) as a colorless solid. 1H NMR (DMSO-d6) δ 8.57 (s, 1H), 8.11 (d, 1H, J=8.7 Hz), 7.96-7.82 (overlapping d's, 3H),7.65 (d, 2H, J=7.6 Hz), 7.50 (d, 1H, J=7.9 Hz), 7.28 (s, 1H), 7.26 (d, 2H, J=8.3 Hz), 7.21 (d, 2H, J=8.3 Hz), 6.01 (t, 1H, J=4.5 Hz), 3.34 (br s, 1H), 2.31 (s, 3H), 2.31 (d, 2H, J=4.5 Hz), 1.31 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27].[C:28]1([NH:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([N:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH2:35])[N:5]=[C:4]([NH:12][C@H:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[C:3]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27]
Reactant: C[C@H](Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: NNc1ccccc1
Product: C[C@H](Nc1nc(N(N)c2ccccc2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Yield: 67.8 %

Procedure:
An ethanolic solution of 0.5 g (1.15 mmol) of sulfone 1 and 0.15 g (1.38 mmol) of phenylhydrazine was refluxed for 14 hours. Cooling, distillative removal of the solvent and chromatography on silica gel (cyclohexane:methyl tert-butyl ether [MTBE] 95:5) gave 0.36 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:17]=1[NH2:18]>>[F:15][C:16]1[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][C:17]=1[NH:18][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)ccc1F
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cc(C(F)(F)F)ccc1F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-fluoro-5-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:6][NH:7][CH:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]([O:11][C:12](C)(C)[CH3:13])=[O:10])#[N:2].[NH2:24][OH:25]>C(O)C.O>[NH2:2][C:1](=[N:24][OH:25])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:6][NH:7][CH:8]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: NO
Reactant: CC(C)CC(NCc1cc(F)cc(C#N)c1)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CC(C)C)NCc1cc(F)cc(C(N)=NO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
To tert-butyl 2-[(3-cyano-5-fluorobenzyl)amino]-4-methylpentanoate (3.0 g, 9.4 mmol) in ethanol (30 mL) was added hydroxylamine (1.2 mL, 0.019 mol) and it was stirred at 0° C. for 16 hrs. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a white solid (2.3 g, 70%). 1H NMR (DMSO-d6, 400 MHz): δ 9.73 (s, 1H), 7.46 (s, 1H), 7.30 (d, J=9.6 Hz, 1H), 7.13 (d, J=9.6 Hz, 1H), 5.84 (s, 2H), 3.75 (d, 1H), 3.55 (d, 1H), 2.98 (s, 1H), 2.38 (brs, 1H), 1.76-1.69 (m, 1H), 1.40 (s, 9H), 1.37 (dd, 2H), 0.96 (d, 3H), 0.87 (d, 3H). LC/MS (Method B) 354.3 (M+H)+. HPLC (Method A) Rt: 2.96 min (Purity 98.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][N:12]([CH3:25])[C:13]([C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]>Cl>[CH3:11][N:12]([CH3:25])[C:13]([C:15]1[CH:16]=[C:17]([S:21]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)=[O:14]
Reactant: CN(C)C(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1sccc1N
Agent: Cl
Product: COC(=O)c1sccc1NS(=O)(=O)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (93 mg, 0.592 mmol) was dissolved in Py (1.5 ml). 3-(dimethylcarbamoyl)benzene-1-sulfonyl chloride (220 mg, 0.887 mmol) was added, and the reaction was stirred at RT for 3 hrs to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with AcOEt. The organic phase was washed with HCl 1N and brine, dried over Na2SO4 and concentrated under vacuum to give methyl 3-(3-(dimethylcarbamoyl)phenylsulfonamido)thiophene-2-carboxylate (Int. 79, 200 mg, 0.543 mmol).
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]([O:9][CH:10]([Cl:12])[CH3:11])=[O:8].CN1CCOCC1>C(Cl)Cl>[C:7](=[O:8])([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][CH:10]([Cl:12])[CH3:11]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)(C)S
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(Cl)OC(=O)SC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of tert-butyl thiol (180 g, 2 mol) and 1-chloroethyl chloroformate (284 g, 2 mol) in CH2Cl2 (1 L) was cooled to 0° C. in an ice-water bath. N-Methylmorpholine (212.1 g, 2.1 mol) was added dropwise over a period of 1 h and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with excess CH2Cl2 (2 L), washed with water (2×1 L), saturated bicarbonate solution (1 L) and brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation (135° C./20 Torr) to provide the title compound (3) as a colorless liquid (350 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 1.50 (s, 9H), 1.79 (d, J=6 Hz, 3H), 6.57 (q, J=5.6 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH3:7][N:8]([CH3:18])[C:9]1[CH:14]=[C:13]([C:15](=O)[CH3:16])[CH:12]=[CH:11][N:10]=1>CO>[CH3:7][N:8]([CH3:18])[C:9]1[CH:14]=[C:13]([C:15](=[N:2][OH:3])[CH3:16])[CH:12]=[CH:11][N:10]=1
Reactant: NO
Reactant: CC(=O)c1ccnc(N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NO)c1ccnc(N(C)C)c1
Reaction time: 0.08 h

Procedure:
To 3.1 g. (45 mmoles) of hydroxylamine hyrochloride in 25 ml. of water and 22.5 ml. of 2 N sodium hydroxide solution was added 4.31 g. (26 mmoles) of 1-(2-dimethylamino-4-pyridyl)-1-ethanone, and the mixture was heated to boiling. After 5 minutes, methanol was added until the mixture became homogeneous. Heating was continued until a precipitate started to appear, and the mixture was then cooled. The solids were filtered, washed with water and dried. Recrystallization from toluene gave 4.03 g. (86%) of product, m.p. 145°-148° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C2C(=NC=CC=2)N(CC2C=CC3N=C(S(C)(=O)=O)SC=3C=2)C=1.[NH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]1[CH2:53][OH:54].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:46][C@@H:47]4[CH2:52][CH2:51][CH2:50][CH2:49][C@H:48]4[CH2:53][OH:54])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: N[C@@H]1CCCC[C@H]1CO
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: CS(=O)(=O)c1nc2ccc(Cn3cnc4cccnc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: OC[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
A 4:1 mixture of 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole and 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfonyl)benzo[d]thiazole (120 mg) from Step 2 of Example 63 was dissolved in anhydrous DMA (2 mL), and then ((1R,2R)-2-aminocyclohexyl)methanol (180 mg, 1.40 mmol) from Step 1 of this Example and DIEA (188 mg, 1.46 mmol) were added. The reaction vessel was sealed and the mixture was heated with stirring at 120° C. for 4.5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford ((1R,2R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexyl)methanol.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=2)=[CH:19][CH:18]=1)=[O:16].COC(=O)C1C=CC(O[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]CCCCCCCC)=CC=1>CCOCC>[CH3:13][O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C@@H:44]([CH3:43])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: COC(=O)c1ccc(-c2ccc(O)c([N+](=O)[O-])c2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CCOCC
Product: CCCCCCCC[C@H](C)Oc1ccc(-c2ccc(C(=O)OC)cc2)cc1[N+](=O)[O-]
Yield: 66 %

Procedure:
DEAD (323 mg, 1.85 mmol), phenol 40 (440 mg, 1.61 mmol), R-2-decanol (268 mg, 1.69 mmol), and TPP (486 mg, 1.85 mmol) in 16 ml anhydrous ether were reacted according to the procedure for compound 35a. The crude product was concentrated and purified via flash chromatography over silica gel with gradual elutions from 95/5 to 65/35 (Hex/EtOAc). Evaporation of the solvent yielded 439 mg (66%) of a yellow solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][CH:12]=1.O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C(=O)Nc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 g of boron tribromide are added dropwise to a solution, cooled to -78° C., of 2 g of methyl N-(3-methoxyphenyl)-oxamate in 20 ml of methylene chloride in the course of 5 minutes. The mixture is stirred at room temperature for 5 hours, 5 ml of water are added, with cooling, and the organic phase is separated off. Drying over sodium sulfate and evaporation gives methyl N-(3-hydroxyphenyl)-oxamate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7]Cl)=[CH:2]1.[C:9](#[N:11])[CH3:10].[Sn](Cl)(Cl)(Cl)Cl>O>[CH3:10][CH:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=[CH:7][NH:11]1
Reactant: CC#N
Reactant: ClCCc1ccsc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Product: CC1NC=Cc2ccsc21
Yield: 51 %

Procedure:
To a solution of 2-(3-thienyl)chloroethane(20 g, 0.136 mol) prepared in the above Step 1 and anhydrous acetonitrile(350 ml) was added tin(IV) chloride(20 ml, 0.17 mol) at room temperature. The reaction mixture was heated to reflux for 16 hours and cooled, to which water was added to remove excess tin(IV) chloride. And then the reaction mixture was washed by dichloromethane. The water layer was separated and basified with aqueous K2CO3 solution under ice-cooling and then extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate and concentrated to give 10.56 g of the titled compound. (Yield: 51%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: ClCCl
Product: O=Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 6 h
Yield: 68.8 %

Procedure:
Dissolve (5-fluoro-2-nitrophenyl)methanol (13.92 g, 81.08 mmol) in dichloromethane (284 mL). Add 4 Å molecular sieves (73 g) and pyridiniun dichromate (36.58 g, 97.3 mmol). Stir the mixture at 20° C. for 6 hours. Filter the crude reaction mixture through a short silica gel column. Remove the solvent under reduced pressure and purify the residue by flash chromatography (silica gel, 10-20% ethyl acetate/hexane) to obtain 9.43 g (69%) of title compound as colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:26]([Mg]Br)[CH3:27].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(C=O)cc3)cc3sccc23)CC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ccc(-c2cc3sccc3c(N3CCN(CC)CC3)n2)cc1

Procedure:
To a solution of 4-(4-ethylpiperazin-1-yl)-6-(4-formylphenyl)thieno[3,2-c]pyridine (0.20 g) in tetrahydrofuran (20 ml) was added 3M ethylmagnesium bromide/diethyl ether solution (0.5 ml), and the mixture was reacted at room temperature for 30 min. To the resulting reaction solution was added an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried. The resulting product was filtered through NH silica gel and washed with ethyl acetate. The filtrate was concentrated, to give 0.17 g of the title compound as white crystals.