Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][CH:8]=1.[CH3:15][C:16]([O:19][C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24](NCOC)=[O:25])([CH3:18])[CH3:17]>O1CCCC1>[CH3:18][C:16]([O:19][C:20](=[O:30])[NH:21][CH2:22][CH2:23][C:24]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)=[O:25])([CH3:15])[CH3:17]
Reactant: COc1cccc(Br)n1
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)CCNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
Butyl lithium (2.5M solution in hexanes, 1.4 ml) was added to a solution of 6-bromo-2-methoxypyridine (690 mg, 4.0 mmol) in tetrahydrofuran (4 ml) at −78° C. and stirred for 1 h. A solution of [3-(methoxymethylamino)-3-oxopropyl carbamic acid 1,1-dimethylethyl ester (344 mg, 1.42 mmol) in tetrahydrofuran (3 ml) was added and the mixture was warmed to 0° C. over 3 h. The mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (three times) The combined organic extracts were dried (sodium sulphate), evaporated and purified by chromatography on silica eluting with petrol-acetone to give the sub-title compound as a colourless oil (291 mg, 73%).
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[F:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][C:6]=1[F:14]
Reactant: CC(=O)c1ccc(OCC(F)F)c(F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)c(F)c1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (1.44 g, colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-fluorophenyl)ethanone (1.16 g, 5.31 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH2:19]>C(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2c1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
4-Chloro-6-nitro-quinazoline 4b crude product (6.06 g, 28.90 mmol) was dissolved in 100 mL of isopropanol, followed by addition of 3-chloro-4-(2-pyridylmethoxy)aniline 4c (7.47 g, 31.8 mmol). The reaction mixture was heated to reflux for 5 hours. The mixture was cooled to room temperature, the solid was precipitated, filtered and the filter cake was washed with ethyl acetate, saturated brine (50 mL) and water (150 mL) successively, dried under vacuum to obtain the title compound N-[3-chloro-4-(2-pyridylmethoxy)phenyl]-6-nitro-quinazolin-4-amine 4d (8.38 g, yield 74.8%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]([NH:25][CH2:26][CH:27]=[CH2:28])[CH2:18][CH2:19]OS(C)(=O)=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH:17]2[CH2:18][CH2:19][N:25]2[CH2:26][CH:27]=[CH2:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCNC(CCOS(C)(=O)=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CC#N
Product: C=CCN1CCC1[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of (R)-3-(1-allylamino-3-methanesulfonyloxypropyl)piperidine-1-carboxylic acid benzyl ester (326 mg, 0.794 mmol) in CH3CN (12 mL) was heated at 100° C. for 1 h using microwave irradiation. After cooling to RT, the reaction mixture was concentrated in vacuo. The residue was partitioned between 2M sodium carbonate and EtOAc. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-5% 2M NH3/MeOH in DCM) affording the title compound (0.2127 g, 85%, 2 steps) as a colourless gum. LCMS (Method B): RT 2.03 min [M+H]+ 315.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=1.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(C(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
4-Methoxybenzyl alcohol (11.9 mL, 95.2 mmol) was dissolved in DMF (150 mL), and at 0° C., 55% sodium hydride (4.15 g, 95.2 mmol) was added thereto, followed by stirring at room temperature for 1 hour. A DMF (10 mL) solution of 6-chloronicotinic acid (5.00 g, 31.7 mmol) was added to the reaction mixture, followed by stirring at 80° C. for 2 hours. Water (200 mL) was added to the reaction mixture, and 4 mol/L hydrochloric acid (30 mL) was added dropwise thereto, and the precipitated solid was collected by filtration to afford 6-(4-methoxybenzyloxy)nicotinic acid (8.15 g, 99%).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)=[O:3].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Reactant: Fc1cccc(CBr)c1
Product: CS(=O)c1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(F)c5)o4)cc32)cc1
Yield: 77 %

Procedure:
In the same manner as in Example 7 and using 5-[1-[4-(methylsulfinyl)phenyl]-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 77%) was obtained as colorless crystals.
Reaction SMILES: CC1C=CC=C2C=1C(=O)N(C1C=CC=CC=1)C(C(NC1N=CN=C3C=1N=CN3)CC)=N2.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)COC(C)(C)C.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC.[NH2:84][C:85]1[N:93]=[C:92]2[C:88]([NH:89][CH:90]=[N:91]2)=[C:87](Br)[N:86]=1.BrC1N=CN=C2C=1NC=N2.NC1N=C2C(N=CN2)=C([NH:115][CH:116]([C:123]2[N:132]([C:133]3[CH:138]=[CH:137][CH:136]=[CH:135][CH:134]=3)[C:131](=[O:139])[C:130]3[C:125](=[CH:126][CH:127]=[CH:128][C:129]=3[CH3:140])[N:124]=2)[CH2:117][O:118]C(C)(C)C)N=1>FC(F)(F)C(O)=O>[NH2:84][C:85]1[N:93]=[C:92]2[C:88]([N:89]=[CH:90][NH:91]2)=[C:87]([NH:115][CH:116]([C:123]2[N:132]([C:133]3[CH:134]=[CH:135][CH:136]=[CH:137][CH:138]=3)[C:131](=[O:139])[C:130]3[C:125](=[CH:126][CH:127]=[CH:128][C:129]=3[CH3:140])[N:124]=2)[CH2:117][OH:118])[N:86]=1
Reactant: Cc1cccc2nc(C(COC(C)(C)C)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Agent: Brc1ncnc2nc[nH]c12
Agent: CC(C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2nc(C(CO)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 68 was prepared using the general procedure described above with respect to compound 14, but 2-benzyloxycarbonylamino-3-tert-butoxy-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and 2-amino-6-bromopurine was substituted for 6-bromopurine in step D. The obtained 2-[1-(2-amino-9H-purin-6-ylamino) -2-tert-butoxy-ethyl]-5-methyl-3-phenyl-3H-quinazolin-4-one was then dissolved in trifluoroacetic acid and allowed to stir at ambient temperature for 5 hours. Purification by LC provided the product 68 as a white solid. MS (ES): m/z 429 (M+H), 215, 206, 151. Compound 68 is shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[CH3:14][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[O:13])[C:9]=2[CH:10]=[C:11]([CH3:12])[C:2]=1[NH:1][C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc2c(c(C)c1N)CCCC2=O
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCCC2=O
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of 6-amino-5,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (1 g, 5.3 mmol) and triethylamine (1.07 g, 10.6 mmol) in anhydrous dichloromethane (20 ml) was added dropwise tert-butylacetyl chloride (0.78 g, 5.8 mmol) at room temperature. The reaction mixture was stirred an additional 3 hours at this temperature. The solvent was removed under reduced pressure, and the residue was purified by Biotage (hexane/EtOAc, 0-40%, 40 min) to give a white solid (1.4 g, 92%). 1H-NMR δ (CDCl3, 300 MHz): 7.82 (s, 1H), 6.73 (brs, 1H, exchangeable with D2O), 2.85 (t, J=6.0 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 2.33 (s, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 2.15 (m, J=6.0 Hz, 2H), 1.16 (s, 9H). MS: 288 (M+1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[C:19]1([I+]C2C=CC=CC=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C([O-])(=O)C1C=CC=CC=1.[Cu+2].C([O-])(=O)C1C=CC=CC=1>[F:14][B-:15]([F:18])([F:17])[F:16].[C:19]1([S+:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: [Cu+2]
Agent: F[B-](F)(F)F
Agent: O=C([O-])c1ccccc1
Product: c1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
A mixture was heated with stirring under nitrogen of 4.6 parts of dibenzothiophene, 9.25 parts of diphenyliodonium fluoroborate and 0.2 part of copper benzoate at 210° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature resulting in a crystalline product. The product was washed several times with anhydrous diethylether and then collected by filtration. Recrystallization from methylene chloride-ethyl ether gave a 55% yield of pure S-phenyldibenzothiophenium fluoroborate having a melting point of 237°-242° C. and the formula,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH:16]=1
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(OC)c(-c2cccc(N)c2)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
2,5-dimethoxyphenyl boronic acid (0.126 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.091 g in 91% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[NH:15][C:14](=O)[CH2:13][NH:12][C:11]2=O)=[CH:7][CH:6]=[CH:5][N:4]=1.CSC.B.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][NH:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CC1NC(=O)CNC1=O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: COc1ncccc1CC1CNCCN1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added 3-((2-methoxy-3-pyridinyl)methyl)-2,5-piperazinedione (398 mg, 1.69 mmol) and borane methyl sulfide, complex (0.64 mL, 6.77 mmol, Aldrich, St. Louis, Mo.) in THF (10 mL). The reaction mixture was stirred at 70° C. for 2 h. The mixture was cooled to room temperature, diluted with MeOH (1 mL), followed by 1N NaOH (12 mL), and extracted with DCM (2×50 mL). The organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude 2-((2-methoxy-3-pyridinyl)methyl)piperazine as colorless viscous oil, which was used without purification.
Reaction SMILES: C(OC([NH:11][C@:12]1([C:22]([OH:24])=[O:23])[C@@H:17]2[CH2:18][C@@:14]3([C:19]([OH:21])=[O:20])[C@@H:15]([CH2:16]2)[C@@H:13]13)=O)C1C=CC=CC=1.[H][H]>C(O)C.O.[Pd]>[NH2:11][C@:12]1([C:22]([OH:24])=[O:23])[C@@H:17]2[CH2:18][C@@:14]3([C:19]([OH:21])=[O:20])[C@@H:15]([CH2:16]2)[C@@H:13]13
Reactant: O=C(N[C@]1(C(=O)O)[C@H]2C[C@H]3[C@@H]1[C@@]3(C(=O)O)C2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2C[C@H]3[C@@H]1[C@@]3(C(=O)O)C2
Yield: 27.7 %

Procedure:
To a solution of 1.1 g (3.3 mmole) of (+/−)-(1R*,2R*,3R*,4S*,6S*)-3-benzyloxycarbonylamino-tricyclo[2.2.1.02,6]heptane-1,3-dicarboxylic acid in 100 mL of 1:1 ethanol/water was added 0.25 g of 10% palladium on carbon. The mixture was treated with 60 psi of hydrogen on a Parr apparatus for 24 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuum to give 0.18 g of the title compound as a gray solid sesquihydrate. Extraction of the catalyst and celite with boiling water, filtration of the extracts through a millipore filter and concentration in vacuum led to the isolation of an additional 0.32 g of white solid. This was recrystallized from water to give 0.21 g of the title compound as a white crystalline one-quarter hydrate, m.p.>250° C.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:41]1([CH2:47][CH2:48][OH:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:44]2[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][OH:49])[CH2:42][CH2:43]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reactant: OCCN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCN(CCO)CC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 48 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and 2-(piperazin-1-yl)ethanol (0.97 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-44. Mol. Wt.: 526.5830 (C30H30N4O5); Rf: 0.41 (ethyl acetate:n-hexane=1:2); Yield: 48%; Mp.: 210-211° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 526.2216 (C30H30N4O5+); found, 526.2219; 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 1.92 (t, J=6.0 Hz, 2H, —NCH2—), 2.03 (br, 4H, —CH2—), 2.39 (br, 4H, —CH2—), 2.43 (s, 3H, —CH3), 3.01 (s, 2H, —CH2N—), 3.26-3.30 (m, 2H, —CH2OH), 4.29 (t, J=5.4 Hz, 1H, —CH2OH), 7.43 (d, J=8.1 Hz, 2H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.07-8.19 (m, 4H, Ar—H), 8.27 (d, J=8.7 Hz, 1H, Ar—H), 8.79 (d, J=8.7 Hz, 1H, Ar—H), 10.00 (s, 1H, Ar—NH—), 10.50 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.93, 52.32, 52.93, 58.21, 59.1, 61.69, 125.11, 126.37, 126.72, 126.98, 127.81, 128.04, 128.33, 129.24, 130.53, 130.53, 140.68, 142.70, 166.37 (NCO), 169.28 (NCO), 181.50 (CO), 183.67 (CO).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.N1C=CC=CC=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>N1CCCCC1.O>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][N:6]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ncc(C=O)s1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: Cc1ncc(C=CC(=O)O)s1
Yield: 72 %

Procedure:
A mixture of 29 g of 2-methyl-5-thiazolecarboxaldehyde, 30 ml of pyridine, 29 g of malonic acid and 30 drops of piperidine was heated at 100°-100°C for 5 hours and was then returned to room temperature and poured into 500 ml of water. The pH of the solution was adjusted to 3 by addition of N sulfuric acid and the mixture was vacuum filtered. The recovered precipitate was dried to obtain 27.8 g of 3-(2-methyl-5-thiazolyl)-2-propenoic acid which was crystallized from 800 ml of ethanol containing 10% ethanol to obtain 23.8 of the said product melting at 204°C.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.Cl>[CH2:18]([O:20][CH:21]([O:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([O:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])([CH2:5]3)[CH2:3]1)[CH2:9]2)[CH3:22])[CH3:19]
Reactant: C=COCC
Reactant: C=C(C)C(=O)OC12CC3CC(CC(O)(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC12CC3CC(C1)CC(OC(C)OCC)(C3)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.3 %

Procedure:
Under a nitrogen atmosphere, 23.6 g (0.1 mols) of 1-hydroxy-3-methacryloyloxyadamantane (HAMA) was dissolved in 100 ml of tetrahydrofuran (THF) and 21.6 g (0.3 mols) of vinyl ethyl ether and 0.1 ml (1 mmol) of hydrochloric acid were added, followed by stirring at room temperature for 3 days. The reaction solution was neutralized with an aqueous Na2CO3 solution added and, after phase separation, the upper layer was washed with water so as to adjust the pH to 7. MgSO4 was added and the solution was dehydrated and filtered, and then concentrated to dryness to obtain 30 g of 1-(1′-ethoxyethoxy)-3-methacryloyloxyadamantane (EEAM) (yield: 99%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([N+:19]([O-])=O)=[C:17]([Cl:22])[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)[CH3:2]>C1COCC1.[Ni]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]2[C:18]([NH2:19])=[C:17]([Cl:22])[N:16]=[CH:15][N:14]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Nc2ncnc(Cl)c2N)cc1
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
A mixture of [4-(6-chloro-5-nitro-pyrimidin-4-ylamino)-phenyl]-acetic acid ethyl ester (0.400 g, 1.19 mmol) and Raney Ni (˜0.100 g) in THF (10 mL) is stirred for 20.5 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. Purification of the residue by silica gel column chromatography (Hexane/EtOAc, 70:30) provides the title compound as a yellow solid: ES-MS: 307.1 [M+H]+; single peak at tR=3.81 min (System 1); Rf=0.06 (Hexane/EtOAc, 70:30).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: Brc1ccc(OC2CCCC2)cc1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC3CCCC3)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 1-bromo-4-cyclopentoxybenzene (see Example 48(a)), followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccccn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2ccccn2)cc1
Yield: 70.3 %

Procedure:
2-Chloropyridine (10 g, 88.0 mmol), phenylboronic acid (12.9 g, 105.7 mmol), tetrakis(triphenylphosphine)palladium (0) (5.0 g, 5 mol %) and 2M Na2CO3 (50 mL) were all dissolved in ethylene glycol dimethylether (200 mL) at room temperature, under an atmosphere of nitrogen. The mixture was refluxed for 48 hours. Ethylene glycol dimethylether was evaporated in vacuo to give a red oil, which was partitioned between water (10 mL) and EtOAc (10 mL). The EtOAc layer was separated and the aqueous layer was further extracted with EtOAc (10 mL×2). The combined EtOAc layers were dried (MgSO4) and concentrated in vacuo to a red oil. Purification by flash column chromatography (iso-hexaneethyl acetate 1:5-silica) gave the title product as a colourless oil (9.6 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[F:18]C(C)(C(OCC)=O)C(OCC)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[C:8]([F:18])([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)(F)C(=O)OCC
Product: CC(F)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2-fluoro-2-methyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl 2-fluoro-2-methyl-malonate.