Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1>O>[CH2:1]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCOCCOCCS(=O)(=O)c1ccc(C)cc1
Yield: 80.8 %

Procedure:
A mixture of 116 g of 2-[2-(decyloxy)ethoxy]-ethanol, 98.73 g of tosyl chloride and 600 ml of pyridine was stored in a chill room overnight, then poured into water and extracted with ether. The ether extract was washed successively with water, dilute hydrochloric acid and dilute aqueous sodium bicarbonate, dried and the ether removed, giving 146.3 g of the desired compound as an oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][CH:11]=[N:10][C:9]=2[C:13]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ncsc1-c1cccc(I)c1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncsc1-c1cccc(I)c1
Yield: 88.1 %

Procedure:
Reaction of 5.0 g (15.1 mmol) of 5-(3-iodophenyl)-4-thiazolecarboxylic acid with 2.6 g (16.2 mmol) of t-butyl (2-aminoethyl)carbamate in an analogous manner to that described in Example 1(E) yielded 6.3 g (88.1%) of t-butyl [2-[5-(3-iodophenyl)-4-thiazolecarboxamido]ethyl]carbamate as white crystals, melting point 111°-112°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[OH:15])=[C:6](F)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[C:7]2[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(C(O)c2cccn2Cc2c(F)cccc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC(C2Oc3cccc(Cl)c3Cn3cccc32)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of [1-(6-chloro-2-fluorobenzyl)-2-pyrryl](1-methylpiperidin-4-yl)methanol (25.1 g; 0.075 mole) in 230 ml of tetrahydrofuran was added potassium tert-butoxide (9.2 g; 0.082 mole). This was stirred for 0.5 hour at 50° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][C:8]=1[CH2:16][CH3:17])(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:16]([C:8]1[CH:9]=[C:10]([CH2:13][C:14]#[N:15])[CH:11]=[CH:12][C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH3:17]
Reactant: CCc1cc(CC#N)ccc1OS(=O)(=O)C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cc(CC#N)ccc1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
After toluene (150 ml), ethanol (30 ml) and distilled water (30 ml) were added to 4-(cyanomethyl)-2-ethylphenyl trifluoromethanesulfonate (9.7 g, 33 mmol) obtained in Example (26-2), 4-methoxyphenylboronic acid (5.3 g, 35 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (2.7 g, 3.3 mol) and sodium carbonate (10.0 g, 94 mmol), the mixture was stirred at 80° C. for 4 hours. After the reaction mixture was cooled to room temperature, the insolubles were removed by filtration. The obtained filtrate was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=7/1-6/1) to give (2-ethyl-4′-methoxy-1,1′-biphenyl-4-yl)acetonitrile as an oil (5.5 g, yield: 66%).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)#[CH:11]>C(N(CC)CC)C.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>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:10]#[C:11][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: Cc1ccc(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(C#Cc2nc(C)ccc2N)c1
Yield: 46.7 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted with (PPh3)2PdCl2 (37 mg, 0.05 mmol), Cul (10 mg, 0.05 mmol) and 1-ethynyl-3-methoxy-benzene (204 μl, 1.60 mmol) in triethylamine (5 ml) during 1.5 h. The crude residue was purified by flash chromatography (hexane/ethyl acetate 4:1) to yield 118 mg (0.50 mmol, 46%) of (2-(3-methoxy-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2].[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][N:18]=[CH:19]2)=[C:12]=[O:13]>>[CH:19]1[C:20]2[C:15](=[C:14]([NH:11][C:12](=[O:13])[O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: O=C=Nc1cccc2cnccc12
Product: N#Cc1ccc(COC(=O)Nc2cccc3cnccc23)cc1
Reaction time: 2 h
Yield: 44 %

Procedure:
4-Cyanobenzyl alcohol (150 mg, 1.13 mmol) diethyl ether (10 mL) was treated with the product from Example 61A as an ethereal solution. The mixture was stirred for 2 hours, filtered, and the filter cake was washed with diethyl ether to provide the title compound as an off-white solid (150 mg, 44%). 1H HMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.32 (d, J=1.0 Hz, 1H), 8.52 (d, J=6.1 Hz, 1H), 7.88-7.99 (m, 5H), 7.65-7.70 (m, 3H), 5.31 (s, 2H); MS (ESI+) m/z 304 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][C:5]#[CH:6].Cl[CH2:9][C:10]([N:12]1[CH2:20][C:19]2[CH:18]=[N:17][C:16]([NH:21][CH:22]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[N:15][C:14]=2[CH2:13]1)=[O:11].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([O:7][CH2:9][C:10]([N:12]1[CH2:20][C:19]2[CH:18]=[N:17][C:16]([NH:21][CH:22]3[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[N:15][C:14]=2[CH2:13]1)=[O:11])[CH2:4][C:5]#[CH:6]
Reactant: O=C(CCl)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Reactant: C#CCCO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCOCC(=O)N1Cc2cnc(NC3Cc4ccccc4C3)nc2C1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
To sodium hydride (60 wt % in mineral oil, 2.06 g, 51.4 mmol) in tetrahydrofuran (86 mL) at 0° C., add 3-butyn-1-ol (4.64 g, 5.03 mL, 64.3 mmol), then stir at 23° C. for 15 minutes. Add this solution to 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl]ethanone (8.45 g, 25.7 mmol) in tetrahydrofuran (86 mL) at 0° C. and stir for five minutes. Pour reaction mixture into 50% saturated aqueous sodium bicarbonate solution. Separate the organic layer and further extract the aqueous layer with ethyl ether and ethyl acetate (2×50 mL each). Combine the organic extracts and wash with brine, then dry over anhydrous sodium sulfate, filter, and concentrate. Combine the crude product with the crude product from a second reaction (run reaction under identical conditions and stoichiometry employing 2-chloro-1-[2-(indan-2-ylamino)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethanone (3.0 g, 9.1 mmol)) and purify by silica gel column chromatography (gradient elution: 25% ethyl acetate in hexanes to 100% ethyl acetate) to give the title compound (2.90 g, 23%). MS (m/z): 363(M+1).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3([OH:17])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[N:18]1([C:2]2[C:3]3[C:10]([C:11]4([OH:17])[CH2:16][CH2:15][CH2:14][O:13][CH2:12]4)=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: C1COCCN1
Reactant: OC1(c2c[nH]c3ncnc(Cl)c23)CCCOC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OC1(c2c[nH]c3ncnc(N4CCOCC4)c23)CCCOC1
Temperature: 70 °C

Procedure:
To a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)tetrahydro-2H-pyran-3-ol (C32) (200 mg, 0.79 mmol) and morpholine (134 mg, 1.54 mol) in n-butanol (10 mL) was added N,N-diisopropylethylamine (305 mg, 2.36 mol), and the reaction mixture was heated at 70° C. for 2 hours. After concentration in vacuo, preparative reversed phase high-performance liquid chromatography (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: aqueous ammonia, pH 10; Mobile phase B: acetonitrile; Gradient: 9% to 29% B) provided the product as a white solid. Yield: 180 mg, 0.59 mmol, 75%. LCMS m/z 305.1 [M+H+]. 1H NMR (400 MHz, CDCl3+D2O) δ 8.73 (s, 1H), 7.52 (s, 1H), 3.92-4.03 (m, 4H), 3.74-3.88 (m, 4H), 3.32-3.40 (m, 2H), 3.15-3.24 (m, 2H), 2.07-2.16 (m, 1H), 1.88-2.06 (m, 2H), 1.57-1.68 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Br:15])[CH:6]=1)=[O:4].[C:16]([O:24]CC(C1C=C(C(F)(F)F)C=C(Cl)C=1)=O)(=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[C:16]([O:24][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Br:15])[CH:6]=1)=[O:4])(=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CCC(=O)OCC(=O)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: O=C(CBr)c1cc(Br)cc(C(F)(F)F)c1
Product: COC(=O)CCC(=O)OCC(=O)c1cc(Br)cc(C(F)(F)F)c1
Yield: 60 %

Procedure:
The title compound was prepared from 2-bromo-1-(3-bromo-5-(trifluoromethyl)phenyl)ethanone (Reference Example 42) by a procedure similar to the one described for 2-(3-chloro-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (Reference Example 35) to provide 2-(3-bromo-5-(trifluoromethyl)phenyl)-2-oxoethyl methyl succinate (16.05 g, 60%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:7]=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1>C1COCC1>[CH3:23][C:24]1([CH3:45])[O:28][CH:27]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]([C:39]([C:2]3[CH:17]=[CH:16][C:5]4[N:6]([C:9]5[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=5)[N:7]=[N:8][C:4]=4[CH:3]=3)([OH:44])[C:40]([F:43])([F:42])[F:41])=[CH:31]2)[CH2:26][O:25]1
Reactant: Fc1ccc(-n2nnc3cc(Br)ccc32)cc1
Reactant: CC1(C)OCC(Cn2cc(C(=O)C(F)(F)F)c3ccccc32)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OCC(Cn2cc(C(O)(c3ccc4c(c3)nnn4-c3ccc(F)cc3)C(F)(F)F)c3ccccc32)O1
Reaction time: 0.02 h
Yield: 55.5 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-benzotriazole (145 mg, 0.5 mmol) in anhydrous THF (3 mL) was added n-butyllithium (0.22 mL of a 2.5 M solution in hexanes, 0.55 mmol). After 1 minute, a chilled (−78° C.) solution of 1-[1-(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)-1H-indol-3-yl]-2,2,2-trifluoroethanone (185 mg, 0.57 mmol) in 1 mL of THF was added. After 30 minutes, the mixture was quenched with brine solution (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and solvent evaporated in vacuo to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-60% ethyl acetate in hexanes and fractions corresponding to MS m/z 541 (MH+) peak were pooled and concentrated in vacuo to afford 150 mg of the title compound as a brownish solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(N(CC)CC)C.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:15]([S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])[CH:14]=[CH:13][N:12]=1)[CH3:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(C)c2nccn2S(=O)(=O)N(C)C)c1C
Temperature: 60 °C
Reaction time: 36 h

Procedure:
To a solution of the compound of Example 1 (100 mg, 0.5 mmol) and triethylamine (77 μl, 0.55 mmol) in anhydrous tetrahydrofuran (4 ml), was added dimethylsulphamoyl chloride (59 μl, 0.55 mmol). The reaction mixture was stirred at 60° C., under nitrogen, for 36 h and then concentrated in vacuo. The residue was partitioned between water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was extracted with ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]#[CH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>C(OCC)(=O)C.[Cu]I.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>[Si:1]([O:18][CH2:19][C:20]#[C:21][C:2]1[CH:3]=[CH:4][C:25]2[C:26](=[C:10]3[C:23](=[CH:22][N:24]=2)[CH2:12][CH2:13][CH2:8][CH2:9]3)[CH:7]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CCNCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCC#Cc1ccc2ncc3c(c2c1)CCCC3)(c1ccccc1)c1ccccc1
Reaction time: 11 h
Yield: 149.1 %

Procedure:
To a mixture of Compound 277 (1.28 g, 3.86 mmol), 3-[(tert-butyldiphenylsilyl)oxy]propyne (Compound 278, 1.48 g, 5.02 mmol), and diethylamine (800 mL, 7.73 mmol) in dry degassed N,N-dimethylformamide (7.7 mL) was added copper (I) iodide (74 mg, 0.39 mmol) followed by bis(triphenylphosphine)palladium(II) chloride (135 mg, 0.19 mmol). After being stirred in the dark for 11 hours under argon, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (20 mL×2) and brine (20 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo, and the residue was purified by flash column chromatography (silica, 10 percent ethyl ether in dichloromethane) to give 1.78 g (97 percent) of Compound 279: Rf =0.39 (10 percent ethyl acetate in dichloromethane); IR (film) νmax 3048, 2932, 2857, 2227, 1589, 1568, 1502, 1428, 1370, 1112 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1 H, H6), 7.95 (d, J=8.6 Hz, 1 H, H4), 7.92 (d, J=1.5 Hz, 1 H, H1), 7.84-7.78 (m, 4 H, aromatic), 7.53 (dd, J=8.6, 1.5 Hz, 1 H, H3), 7.48-7.39 (m, 6 H, aromatic), 4.62 (s, 2 H, C≡CCH2O), 3.04 (t, J=5.8 Hz, 2 H, H10), 2.87 (t, J=5.8 Hz, 2 H, H7), 2.01-1.93 (m, 2 H, CH2), 1.93-1.85 (m, 2 H, CH2), 1.12 (s, 9 H, t-Bu); 13C NMR (125 MHz, CDCl3) δ 152.8, 145.6, 141.0, 135.6, 133.1, 130.6, 130.2, 129.7, 129.6, 127.6, 127.5, 120.7, 88.4, 85.3, 53.2, 27.0, 26.7, 24.8, 22.2, 22.1, 19.2; MS (FAB+) m/e (rel intensity) 476 (M+H, 100), 418 (9), 388 (12), 220 (11), 197 (9); HRMS for C32H34NOSi (M+H), calcd 476.2410, found 476.2410.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:7])[NH:5][N:6]=1.C[O-].[Na+].C([O:13][C:14](=[O:21])[C:15](=O)[CH2:16][C:17](=O)[CH3:18])C>CO>[OH:7][C:4]1[C:3]2[C:2](=[N:1][C:15]([C:14]([OH:21])=[O:13])=[CH:16][C:17]=2[CH3:18])[NH:6][N:5]=1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: Nc1cc(O)[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)O)nc2[nH]nc(O)c12

Procedure:
5-Amino-2H-pyrazol-3-ol (3.1 g, 31.6 mmol) were suspended in 100 ml of methanol. Then sodium methoxide (5.1 g, 95 mmol) and 2,4-dioxopentanoic acid ethyl ester (5 g, 31.6 mmol) were added, and the mixture was heated up under reflux for 12 h. The solvent was removed in a rotary evaporator, water was added to the residue, the precipitate was filtered off with suction, and the filtrate was adjusted to pH 6 with dilute hydrochloric acid. The precipitated product (both precipitates) was filtered off with suction and dried. Yield: 4.9 g (70%), M+H+: 194.09.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1.[OH-].[Na+]>C(O)(=O)C>[SH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:3][CH:4]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Sc1ccc(-n2cccc2)cc1

Procedure:
A 1-liter 3-neck flask equipped with stirrer, condenser, heating mantle, addition funnel and thermometer is charged with 25 g (0.2 mole) of 4-aminothiophenol, 26.4 g (0.2 mole) of 2,5-dimethoxytetrahydrofuran, and 150 ml of glacial acetic acid. The reaction mass is refluxed for 30 minutes, cooled and made alkaline to a pH of 9 with 130 ml of 50% aqueous sodium hydroxide while maintaining the temperature of the reaction mixture below 25°C with a cooling bath.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([SH:7])([CH3:6])[CH3:5].C([O:10][C:11](=[O:35])[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=2[CH2:26][N:27]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH3:29])[CH:18]=1)C>CN(C=O)C.O.N#N>[C:4]([S:7][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]([CH2:12][C:11]([OH:35])=[O:10])[CH:14]=[N:15][CH:16]=2)=[C:20]([CH2:26][N:27]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH3:29])[CH:21]=1)([CH3:6])([CH3:5])[CH3:3]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)Cc1cncc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(Cc1cc(SC(C)(C)C)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in mineral oil; 0.042 g, 1.04 mmol) was suspended in DMF (5 mL). After stirring for 10 minutes, 2-methyl-2-propanethiol (0.13 mL, 1.15 mmol) was added, and the mixture was stirred for 30 minutes. (5-{2-[(N-Cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-fluoro-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.20 g, 0.52 mmol) was added, and the reaction was stirred at 90° C. overnight. The mixture was diluted with H2O, and N2 was bubbled through the solution into a bleach trap until all odor was removed. The aqueous layer was washed with EtOAc, and then acidified to pH 4 and extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by preparative HPLC to give Compound 22.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([O:28][C:29]1[N:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[N:30]=1)[C:23]([O:25][CH2:26]C)=[O:24].O>C(#N)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH:22]([O:28][C:29]1[N:30]=[C:31]([CH3:36])[CH:32]=[C:33]([CH3:35])[N:34]=1)[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)Oc1nc(C)cc(C)n1
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C(Oc1cccc(Oc2ccccc2)c1)Oc1nc(C)cc(C)n1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
3-Phenoxyphenol (1.0 g, 5.4 mmol) was placed in a flask with potassium carbonate (0.90 g, 6.5 mmol) and 20 mL of acetonitrile and to this was added dropwise with stirring at ambient temperature, a solution of ethyl 2-chloro-2-(4,6-dimethyl-2-pyrimidinyloxy)acetate (1.40 g, 5.7 mmol) in 5 mL of acetonitrile. The mixture was allowed to stir overnight and was then added to water and the resulting mixture was extracted 3 times with ether. The ethereal solution was extracted 2 times with 1N aqueous sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain about 1 g of the title compound as a crude yellow oil. This oil, which solidified on standing, was chromatographed on silica eluting with an 85:15 mixture of hexane and ethyl acetate to obtain 0.60 g (28 percent of theory) of the title compound as a white solid melting at 111°-112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:9][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1cc(Cl)c(Br)cn1
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a solution of 4-chloro-2-pyridylamine (6.0 g, 46.7 mmol) in chloroform (180 mL) was added N-bromosuccinimide (8.3 g, 46.7 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH2Cl2 (800 mL) and 1N NaOH (100 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (25-35% EtOAc/hexanes) yielding 3.63 g (38%) of 5-bromo-4-chloro-2-pyridylamine. LCMS (m/z): 206.9/208.9 (MH+). 1H NMR (CDCl3): δ 8.18 (s, 1H), 6.62 (s, 1H), 4.52 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:12]3[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[I:27]Cl>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([I:27])=[CH:9][N:8]([C@@H:11]3[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:12]3[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ClI
Reactant: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1ccc2c(Cl)ncnc21
Solvent: ClCCl
Product: CO[C@@H]1[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a solution of compound 5.5 (1.25 g, 3.26 mmol) in CH2Cl2 (80 mL), a 1.0 M solution of ICl in CH2Cl2 (8.12 mmol) was added at room temperature and the resulting dark brown solution was stirred for 4 hr at room temperature. The solvents were evaporated in vacuo at 25° C.-35° C. and the residue was dried under high vacuum for 30 min. A light brown sticky material was obtained which was purified by flash column chromatography using gradient of pure CH2Cl2 to 1.5% MeOH in CH2Cl2 to afford the desired compound 5.6 (1.1 g, 66%) as a white solid.
Reaction SMILES: O[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][CH2:16][C:17]([OH:19])=[O:18].[BrH:20]>C(O)(=O)C.S(=O)(=O)(O)O>[Br:20][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][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Br
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A 2 liter three neck round bottom flask, equipped with a mechanical stirrer, reflux condenser and nitrogen inlet, was charged with 177 g (0.63 moles) of 16-hydroxy hexadecanoic acid 1. To this vessel were added 1000 mL (5 moles) of 30% hydrogen bromide in acetic acid and 310 mL of concentrated sulfuric acid. The system was equipped with sequential traps containing a sodium hydroxide pellet trap, a 25% aqueous sodium hydroxide solution trap and a saturated sodium carbonate trap. The reaction stirred overnight at room temperature before it was heated to reflux for six hours. The reaction mixture was cooled, poured over ice water and the precipitated solid was filtered under vacuum. After drying under high vacuum, 196 g of 16-bromohexadecanoic acid was obtained.